Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=S)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12.O>C1COCC1>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:34][CH2:33][C:32]([CH3:36])([CH3:35])[N:31]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC(=S)NC(C)(C)CO)cc23)ccc1Oc1ccn2ncnc2c1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(C)CO4)cc23)ccc1Oc1ccn2ncnc2c1
Reaction time: 1 h

Procedure:
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine was synthesized from 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (322 g) in THF (3 L) at 0° C. Water (10 L) was added, and the solution was allowed to stir for 1 hour, at which point the material oiled out. The organics were then extracted into ethyl acetate (3×5000 mL), combined and washed with water (2×5000 mL) and brine (2×5000 mL). The organics were dried by rotoevaporation, and the material was concentrated to an oil. The oil was observed to solidify at room temperature to yield Form E.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH3:32][O:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15]3)[C:6]=2[N:20]=1)[C:26]([OH:28])=[O:27]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC(C)C1)CCC(=O)N2C
Yield: 74.4 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-58), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.095 g of (rac)-3-methoxy-4-[5-methyl-9-(3-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-58a) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24](=[O:26])[CH3:25]>>[CH3:22][O:23][C:24](=[O:26])[CH2:25][C:2]1[CH:21]=[CH:20][CH:5]=[C:4]([C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])=[C:7]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=4[Cl:18])[O:8][C:4]=3[CH:3]=2)[CH:3]=1
Reactant: COC(C)=O
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Product: COC(=O)Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1

Procedure:
{3-[2-(2,4-Dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid methyl ester was prepared via a Suzuki coupling of (6-Bromo-3-methyl-benzofuran-2-yl)(2,4-dichloro-phenyl)-methanone and 3-Bromo-phenyl)-acetic acid methyl ester as described in method 1 step 5. MS ES (MH+) 453.1, RT=4.27 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.CCN=C=NCCCN(C)C.Cl.[Li+].CC([N-]C(C)C)C.[CH3:47][O:48][C:49](=[O:51])[CH3:50]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C1COCC1>[CH3:47][O:48][C:49](=[O:51])[CH2:50][C:12]([C:9]1([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11]1)=[O:14]
Reactant: COC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CC(C)[N-]C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 39.7 %

Procedure:
To 1-tert-Butoxycarbonylamino-cyclopropanecarboxylic acid 1 (2.077 g, 10.3 mmol) in CH2Cl2 (44 mL) was added DMAP (258 mg, 2.11 mmol), pentafluorophenol (2.100 g, 11.4 mmol) and EDAC (2.369 g, 12.3 mmol) and the reaction mixture was stirred at rt for 1 h 50 min. 1M HCl (aq) (40 mL) was added, the layers were separated and, after washing with saturated NaHCO3 (aq) (40 mL) and then with saturated brine (40 mL), the organic layer was dried (MgSO4), concentrated in vacuo, and placed under high vacuum. To THF (12.5 mL) at −78° C. was added LDA (2.0 M, 17 mL, 34 mmol) followed by methylacetate (2.6 mL, 32.7 mmol) in dropwise fashion. The reaction was stirred for 30 min, and the intermediate ester of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid was added in THF (35 mL), and the resulting mixture was stirred for 3 h 20 min. The mixture was quenched with 1M HCl (aq) (50 mL), the layers were separated and washed with saturated NaHCO3 (aq) (50 mL) and brine (50 mL). Following extraction with EtOAc, the combined organics were dried (MgSO4) and concentrated in vacuo. Purification was carried out by flash column chromatography on silica (eluant 3:7-4:6-1:1 EtOAc/Hexane) to give 2 (1.0526 g, 4.09 mmol, 40%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].[OH-].[K+].BrC[C:17](=O)[C:18]([OH:20])=[O:19].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([OH:12])=[C:17]2[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(=O)CBr
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(O)cnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 144 h
Yield: 56 %

Procedure:
A solution of 5-bromoisatin (2.26 g, 10 mmol) and potassium hydroxide (4.48 g, 80 mmol) in water (10 mL) was warmed until the materials were dissolved then cooled to room temperature, treated with bromopyruvic acid (2.3 g, 14 mmol), stirred for 6 days, adjusted to pH <7 with concentrated HCl, and filtered. The solid was washed with water and ethanol and dried to provide the desired product (1.5 g, 58%). MS (DCI/NH3) m/e 269 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36](Br)[CH:37]=[CH2:38]>CC(C)=O>[CH2:38]([O:23][C:10]1[C:9]([CH3:24])=[C:8]([CH3:25])[C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=3[CH:4]=2)=[CH:12][C:11]=1[CH:13]1[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]1)[CH:37]=[CH2:36]
Reactant: Cc1c(Cc2cc3ccccc3s2)cc(C2OC(CO)CC(O)C2O)c(O)c1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCOc1c(C2OC(CO)CC(O)C2O)cc(Cc2cc3ccccc3s2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
A 20 ml vial was charged with 22 (33.3 mg, 0.08 mmol) and Cs2CO3 (39.3 mg, 0.12 mmol) and to which was added 1 ml of dry acetone, followed by allyl bromide (19.4 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 16 h and the solid was filtered of, washed with acetone. The solvent was evaporated and the crude residue was purified by flash column chromatography on silica gel (4 g column, EtOAc/heptane: 0>>>100%) to afford 17.5 mg (43.1%) of 24 as a white solid. 1H NMR (CD3OD) δ 7.71 (d, J=8.08 Hz, 1H), 7.60 (d, J=7.58 Hz, 1H), 7.13-7.28 (m, 3H), 6.87 (s, 1H), 6.14 (m, 1H), 5.47 (dd, J=17.18, 2.02 Hz, 1H), 5.24 (dd, J=10.61, 1.52 Hz, 1H), 4.51 (d, J=9.60 Hz, 1H), 4.47 (dd, J=12.63, 5.05 Hz, 1H), 4.35 (dd, J=12.63, 5.05 Hz, 1H), 4.23 (s, 2H), 3.47-3.73 (5H), 2.23 (s, 3H), 2.20 (s, 3H), 2.01 (m, 1H), 1.48 (q, J=11.12 Hz, 1H). MS (ES) 477.1 (M+Na+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13]
Reactant: OCCCCCCCCCCCBr
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
To 11-bromo-1-undecanol (5 g) dissolved in methylene chloride (70 ml) were added pyridinium chlorochromate (10.7 g) and Celite (11.0 g), and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was filtered, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (20:1) to give 11-bromo-1-undecanal (3.57 g). To the product dissolved in methylene chloride (50 ml) was added (carbomethoxymethylene)triphenylphosphorane (5.76 g), and the mixture was stirred. The reaction mixture was concentrated, and the residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (20:1) to give the methyl ester of 13-bromo-2-tridecenoic acid (4.16 g). The product was dissolved in methanol and stirred under hydrogen atmosphere in the presence of palladium/carbon (1.5 g) for 18 hours. The reaction mixture was filtered and concentrated to give the methyl ester of 13-bromotridecanoic acid (3.22 g). 50% Aqueous ethanol (100 ml), in which potassium hydroxide (2.95 g) had been dissolved, was added to the methyl ester, and the mixture was stirred at 60° C. for 1 hour. Ethanol in the reaction mixture was removed by distillation, and the residue was acidified to a weak acidic range of pH by adding citric acid and extracted with ethyl acetate. The organic layer was dried and concentrated to give 13-bromotridecanoic acid (2.61 g). After the product was dissolved in N,N-dimethylformamide (DMF, 50 ml), para-nitrophenol (1.24 g) and N,N'-dicyclohexylcarbodiimide (1.84 g) were added, and the mixture was stirred for 12 hours. Then, precipitates produced was removed by filtration and the DMF was removed by distillation. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of 13-bromotridecanoic acid (1.73 g). The active ester (540 mg) was dissolved in DMF (30 ml), and 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (2.0 ml) were added to the solution. The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK276 in the yield of 227 mg.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH3:3])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.4 %

Procedure:
Sodium hydride (4.87 g, 122.0 mmol, 60% dispersion in oil) was added to a solution of 2-methylimidazole (10 g, 122.0 mmol) in DMF (100 ml) and stirred at room temperature for 0.25 h. 1-Fluoro-4-nitrobenzene (17.18 g, 122.0 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. Water (150 ml) and ethyl acetate (250 ml) were added, the aqueous separated and extracted with ethyl acetate (3×150 ml). The combined extracts were washed with water (3×150 ml), dried (Na2SO4) and evaporated to give the desired product (11.5 g, 47%); δ (360 MHz, CDCl3) 2.24 (3H, s, Me); 7.06 (1H, d, J=1.5 Hz, Ar--H); 7.10 (1H, d, J=1.5 Hz, Ar--H); 7.50 (2H, d, J=9.5 Hz, Ar--H); 8.38 (2H, d, J=9.5 Hz, Ar--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(=O)CC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: O=S1(=O)CCCO1
Reactant: COc1cccc(CN)c1OC
Solvent: CCC(C)=O
Product: COc1cccc(CNCCCS(=O)(=O)O)c1OC
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethoxybenzylamine (2.2 mL, 15.0 mmol) in 2-butanone (20 mL) was added 1,3-propane sultone (1.97 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The crude product was suspended in 90% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 seconds, the solid was collected by filtration, and dried in vacuo; affording compound AZ, 1.95 g (45%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>O.CO>[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CCCCN(C(=O)OC(C)(C)C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCCC(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
NaOH (240 mg, 6 mmol) was dissolved in water (3 mL) and MeOH (10 mL). This solution was added to methyl 5-[(tert-butoxycarbonyl)(pyridin-2-yl)amino]pentanoate (200 mg, 0.64 mmol) dissolved in MeOH (15 mL). The mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2N HCl to pH 7. The solvent was removed under reduced pressure. A citric acid solution (10 mL) was added and the mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to give 128 mg (68%) of the product. 1H NMR (CDCl3) 8.36-8.34 (m, 1H), 7.65-7.52 (m, 2H), 7.02-6.98 (m, 1H), 3.97-3.91 (m, 2H), 2.38-2.32 (m, 2H), 1.69-1.62 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: C[O-].[Na+].[C:4](O)(=O)[C:5](O)=O.C(NN)C.C(OC(OCC)C(=N)OC)C.[CH2:25]([O:27][CH:28]([O:35][CH2:36][CH3:37])/[C:29](=[N:33]/[NH2:34])/[NH:30][CH2:31][CH3:32])[CH3:26].Cl.C(=N)(O)C>C(O)(=O)C.CO>[CH2:36]([O:35][CH:28]([O:27][CH2:25][CH3:26])[C:29]1[N:30]=[C:31]([CH3:32])[N:34]([CH2:4][CH3:5])[N:33]=1)[CH3:37]
Reactant: CCN/C(=N\N)C(OCC)OCC
Reactant: O=C(O)C(=O)O
Agent: CC(=N)O
Agent: CCNN
Agent: CCOC(OCC)C(=N)OC
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(OCC)c1nc(C)n(CC)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
To a solution of NaOMe (24 mL, 25% wt in MeOH, 0.105 mol, 4.3 mol %) in MeOH (2.4 L) was added diethoxyacetonitrile (310 g, 2.40 mol), and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo (300 mbar, 44° C.) and the brown oily residue was dissolved into Et2O (2.4 L). The organic solution was washed with water (3×500 mL) and brine (1×400 mL), and dried over Na2SO4. The solvent was removed in vacuo at 0° C. to yield methyl 2,2-diethoxyethanimidoate (333.32 g, 86%) as a clear liquid. To a solution of NaOMe (25% wt in MeOH, 424 g, 2 mol) and MeOH (2 L), was added ethylhydrazine oxalate (150.14 g, 1 mol), and the mixture was stirred for 10 min. Methyl 2,2-diethoxyethanimidoate (161.2 g, 1 mol) was added, and the mixture was stirred at room temperature for 3 h under a blanket of Nitrogen. The product, (1Z)-2,2-diethoxy-N-ethylethanehydrazonamide was used in situ. The crude (1Z)-2,2-diethoxy-N-ethylethanehydrazonamide was treated with acetimidate hydrochloride (109.6 g, 1 mol) and glacial acetic acid (90 g, 1.5 mol), and the mixture was stirred at room temperature for 24 h under nitrogen. LCMS indicated that no reaction had occurred after 24 h. The solvent was removed under vacuum from the reaction mixture and the residue was stored in the freezer. After 8 days the residue was removed from the freezer, warmed to room temperature, and treated with MeOH (1.5 L), acetic Acid (85.7 mL), and acetimidate HCl (98 g, 0.89 mol) from a new bottle, and this mixture was stirred at room temperature for 24 h. LCMS indicated that the starting materials had been consumed and that some of the desired product was present. The solvent was removed in vacuo and H2O (1.5 L) was added to the residue. The mixture was extracted with DCM (5×1 L), and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum to afford 163 g of a crude red oil. The product was purified by flash chromatography using 2% MeOH/DMC as eluent (RF=0.3) affording 56.86 g (23%) of 3-(diethoxymethyl)-1-ethyl-5-methyl-1H-1,2,4-triazole as a red oil, which was 96% pure by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([N:36]([CH3:37])[CH3:35])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNc1nc(-c2cccc(C(=O)N(C)C)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 40.4 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) were added dimethylamine (2.0 M soln. in THF, 0.0275 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (10 mg, 41%). LC-MS m/z 496 (M+H)+; 1H-NMR (MeOD) δ 2.15 (s, 6H), 2.36 (m, 2H), 3.15 (s, 3H), 3.06 (s, 3H), 3.23 (m, 2H), 4.46 (s, 2H), 7.14 (m, 2H), 7.12 (m, 1H), 7.56 (m, 4H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]5[S:24][C:23]([NH:25]CC6C=CC(OC)=CC=6)=[N:22][N:21]=5)[CH:18]=4)[N:13]([S:35]([C:38]4[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=4)(=[O:37])=[O:36])[CH:12]=3)[CH:8]=[N:7][CH:6]=2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]5[S:24][C:23]([NH2:25])=[N:22][N:21]=5)[CH:18]=4)[N:13]([S:35]([C:38]4[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=4)(=[O:37])=[O:36])[CH:12]=3)[CH:8]=[N:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(NC5CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC4CC4)n3)c3cc(-c4nnc(N)s4)ccc32)cc1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-(cyclopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (120 mg, 0.192 mmol) in TFA (1.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 15 min. Then the solvent was removed. The residue was diluted with DCM and washed with sat. NaHCO3, dried, filtered and concentrated to give the crude material, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 504 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C[N+]1([O-])CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CS(C)=O>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:29]=[CH:30][C:20]([N:17]2[CH2:16][CH2:15][C:13]3[NH:14][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][C:7]=4[C:12]=3[CH2:18]2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Agent: C[N+]1([O-])CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
A mixture of 1.5 g (5.8 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.979 g (5.8 mmol) of ethyl 4-fluorobenzoate, 0.68 g (5.8 mmol) of 4-methylmorpholine N-oxide, 3.78 g (11.6 mmol) of Cs2CO3 and 10 ml of dimethylsulfoxide is stirred overnight at 80° C. The reaction mixture is allowed to cool and is diluted with water to yield a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.055 g (2%) of the title compound as a yellow solid: m.p. 241°-243° C.; m/e 405.
Reaction SMILES: C([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]1[N:42]=[CH:41][C:40]2[CH:39]=[CH:38][C:37]3[C:43]([C:47]([O:49]CC)=O)=[N:44][N:45]([CH3:46])[C:36]=3[C:35]=2[N:34]=1)=[O:24])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH4+:52].[OH-]>C(O)C>[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]1[N:42]=[CH:41][C:40]2[CH:39]=[CH:38][C:37]3[C:43]([C:47]([NH2:52])=[O:49])=[N:44][N:45]([CH3:46])[C:36]=3[C:35]=2[N:34]=1)=[O:24]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(Nc3ccccc3NC(=O)[C@@H]3CCCN3C(=O)OCC3c4ccccc4-c4ccccc43)nc12
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(N)=O)c2ccc3cnc(Nc4ccccc4NC(=O)[C@@H]4CCCN4)nc3c21
Temperature: 65 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
Ethyl 8-{2-[((S)—N-FMOC-pyrrolidine-2-carbonyl)-amino]-phenylamino}-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (200 mg, 0.29 mmol) was suspended in 20 mL of ethanol and 20 mL of NH4OH 30% mixture. The mixture was maintained at 65° C. under stirring for 12 h in a closed bottle. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 94/6) to afford 60 mg (47% yield) of the title compound.
Reaction SMILES: C([NH:4][CH:5]([CH2:9][CH2:10][CH:11]([Br:15])[CH2:12][CH2:13][CH3:14])[C:6]([OH:8])=[O:7])(=O)C.[OH-].[Na+]>O>[NH2:4][C@@H:5]([CH2:9][CH2:10][CH:11]([Br:15])[CH2:12][CH2:13][CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CCCC(Br)CCC(NC(C)=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(Br)CC[C@H](N)C(=O)O
Temperature: 37 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To 2-(N-acetylamino)-5-bromooctanoic acid (3.0 g), 20 ml of water was added and 1N NaOH was added to adjust the pH to 8. After warming to 37° C., 400 mg of Aspergillus genus aminoacylaze was added, followed by stirring for 24 hours. After cooling in an ice bath, the obtained precipitate was collected by filtration. The product obtained by filtration was washed with water and ethanol until color disappeared. After drying, 658 mg (52%) of (S)-2-amino-5-bromooctanoic acid was obtained as a white crystal.