Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=1)[CH2:12][CH3:13]
Reactant: CCCN
Reactant: O=C(O)c1ccc(Br)cc1
Product: CCCNC(=O)c1ccc(Br)cc1
Yield: 67 %

Procedure:
Using Preparation Method 1, 4-bromobenzoic acid was reacted with n-propylamine. The resulting reaction mixture was purified using SiO2 With 100% CH2Cl2 to give a white solid (67%). NMR1H (ppm, CDCl3): 7.61 (d, J3=8.60 Hz, 2H), 7.54 (d, J3=8.57 Hz, 2H), 6.06 (br. s., 1H), 3.43-3.37 (m, 2H), 1.62 (sext., J3=7.25 Hz, 2H), 0.97 (t, J3=7.39 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=2[S:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[CH3:28][N:11]1[C:10]2[S:9][C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:38])[F:39])[CH:30]=3)=[C:7]([C:2](=[O:1])[CH2:3][CH:4]([CH3:5])[CH3:6])[C:15]=2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:12]1=[O:27]
Reactant: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CC(=O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 50 °C
Yield: 60 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 22, Step 3, 50 mg, 0.088 mmol) in DMSO (5 mL) was added 2-iodoxybenzoic acid (49.1 mg, 0.176 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT, diluted with water (20 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with aq. NH4Cl (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 1-methyl-5-(3-methylbutanoyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 60.2% yield) as an oil. LCMS: MH+ 569 and TR=2.186 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[C:6]([CH3:18])=[CH:5][C:4]=1[O:19][CH3:20].[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[N:10]([CH3:23])[C:11]3=[O:16])[C:7]=2[C:6]([CH3:18])=[CH:5][C:4]=1[O:19][CH3:20]
Reactant: COc1cc(C)c2c(c1OC)CCC1C(=O)NC(=O)C21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c2c(c1OC)CCC1C(=O)N(C)C(=O)C21
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A solution of 3a,4,5,9b-tetrahydro-6,7-dimethoxy-9-methyl-1H-benz[e]isoindole-1,3-(2H)-dione (1.66 g, 6.1 mmole) and dry DMF (28 mL) was stirred under N2 at 0° as a suspension of NaH (60% in oil, washed with hexane, 0.25 g, 6.4 mmole) and DMF (2.8 mL) was added portionwise. The reaction mixture was stirred for 0.5 hour at 0°, and for 0.5 hour at room temperature, then was cooled again at 0° as methyliodide (9.41 mL, 6.6 mmole) was added dropwise. After one hour at 0° and 1.5 hours at room temperature, the reaction mixture was poured onto ice water. The solid was filtered, washed with water, dried (in vacuo) to yield 1.60 g yellow solid (91%), mp 167°-9° C.; M+ 289.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[O:5][N:4]=4)[CH2:22][CH2:21]3)[CH:7]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2cc(CCl)no2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)on4)CC3)no2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)isoxazole (170 mg) and piperazine (26 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].O>CN(C)C=O>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25]
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Sodium hydride (53 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (276 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. 2,2-Dimethylpropionyl chloride (162 mg) was added thereto, and the mixture was stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized, extracted with dichloromethane, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give benzyl 1-(2,2-dimethylpropionyl)-1H-indole-5-carboxylate (320 mg, Y.:87%) as pale orange crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[C:2]([NH:1][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH:14]=1
Reactant: CN1CCC[C@H]1COc1ccc(C(=O)OC(C)(C)C)c(N)c1
Reactant: O=C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC[C@H]1COc1ccc(C(=O)OC(C)(C)C)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Tert-butyl 2-amino-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}benzoate (400 mg, 1.3 mmol) was dissolved in 20 ml of DCM under argon atmosphere. Tetrahydro-4H-pyran-4-one (0.19 ml, 2.05 mmol), TFA (0.29 ml, 3.69 mmol) and Me4BH(OAc)3, (540 mg, 2.05 mmol) were added. The resulting slurry was stirred overnight at room temperature then quenched with 15 ml of NaHCO3 10% and extracted twice with 20 ml of DCM. The organic layers were then dried over Na2SO4, filtered off and concentrated to yield a yellow oil (448 mg, 1.15 mmol, 88%) which was used in the next step without any further purification.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 38.5 %

Procedure:
Using cyclohexyl{3-propyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.65 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.42 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.38 g, 39%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[C:18]4[S:21][C:22]([CH2:24][OH:25])=[CH:23][C:17]=4[N:16]=[CH:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[K].CC(C)([O-])C.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1.C(OCC)(=O)C>CN(C=O)C.O>[CH:33]1([CH2:36][O:25][CH2:24][C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:6][CH2:7][CH:3]([N:2]([CH3:26])[CH3:1])[CH2:4]5)=[CH:13][CH:12]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CN(C)C1CCN(c2ccc(-n3cnc4cc(CO)sc4c3=O)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(-n3cnc4cc(COCC5CC5)sc4c3=O)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one (20.0 mg) and potassium-tert.-butoxide (7.65 mg) in DMF (0.3 mL) was stirred at 0° C. for 5 min. Then cyclopropylmethylbromide (11.28 mg) was added. The solution was warmed to room temperature and stirred for 2 h. Then ethyl acetate and water were added. The aqueous phase was extracted several times with ethyl acetate, the combined organic phases dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by preparative HPLC. The product with the molecular weight of 424.56 (C23H28N4O2S) was obtained in this way; MS (ESI): 425 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH2:20]O)([CH2:18]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.FC(S(OS(C(F)(F)F)(=O)=O)(=O)=O)(F)F.[C:46]1([CH:52]([NH2:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]2([CH2:20][N:59]([CH:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)(CO)c2ccc(Cl)cc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a stirred mixture of 6-chloro-3,3-bis-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.31 g, 1 mmol), DIPEA (0.645 g, 5 mmol) and acetonitrile (5 mL) at −25° C. under nitrogen was added a solution of trifluoromethylsulfonic anhydride in DCM (1 M, 2.1 mL) dropwise over 0.3 h (T<−20° C.) and resulting mixture was stirred at −20° C. for 1 h), then a solution of C,C-diphenylmethylamine (0.179 g, 0.98 mmol) in acetonitrile (2 mL) was added (T<−20° C.) and stirring continued for 0.5 h. Mixture was warmed slowly to 20° C. and left thus for 16 h, heated at 75° C. for 8 h and then evaporated in vacuo. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (0.273 g). 1H NMR (CDCl3): 7.47 (4H, d), 7.35-7.27 (6H, m), 7.22 (2H, t), 7.05 (1H, dd), 4.41 (1H, s), 4.15-4.10 (2H, m), 3.37 (2H, d), 3.30 (2H, d), 1.64-1.55 (9H, m).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[N:18]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[C:19]=[O:20]>O1CCCC1>[F:28][C:27]([F:29])([F:30])[C:25]1[CH:26]=[C:21]([NH:18][C:19]([N:1]2[CH2:4][CH:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:2]2)=[O:20])[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 2 (986 mg) in tetrahydrofuran (12 mL) was dropwise added 1-isocyanato-3,5-bis(trifluoromethyl)benzene (0.85 mL), and the mixture was stirred for 30 minutes. The reaction solution was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (1.413 g) having the following physical data.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([N:23]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]2)[N:18]=1.[CH2:30]([O:32]C=O)[CH3:31]>O1CCCC1>[Cl:16][C:17]1[C:22]([CH:30]=[O:32])=[N:21][CH:20]=[C:19]([N:23]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]2)[N:18]=1.[Cl:16][C:17]1[N:18]=[C:19]([N:23]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]2)[C:31]([CH:30]=[O:32])=[N:21][CH:22]=1
Reactant: CCOC=O
Reactant: Cc1cc(C)n(-c2cncc(Cl)n2)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2cnc(C=O)c(Cl)n2)n1
Product: Cc1cc(C)n(-c2nc(Cl)cnc2C=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3 %
Yield: 13 %

Procedure:
2,2,6,6-Tetramethylpiperidine (20.3 mL, 117 mmol) was added to a solution of n-butyllithium (2.5 M in hexanes, 46 mL, 115 mmol) in dry tetrahydrofuran (1.1 L) at −30° C. The mixture was warmed to room temperature and stirred for 15 minutes. After cooling to −78° C. 2-chloro-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazine (20 g, 96 mmol) in dry tetrahydrofuran (15 mL) was added and the mixture was stirred at −78° C. for 1 h. Ethylformate (12 mL, 143 mmol) was added and the mixture stirred for an additional 2 hours at −78° C. The reaction was quenched with aqueous ammonium chloride, warmed to room temperature and diluted with ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate, filtrated and evaporated to give the crude product as a yellow solid. The crude products were purified by flash chromatography (ethyl acetate/heptane as eluent) to give 3-chloro-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde (2.9 g, 13%) as a yellow solid and 5-chloro-3-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde (700 mg, 3%) as a yellow solid.
Reaction SMILES: [C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][CH:52]([C:78]([CH3:81])([CH3:80])[CH3:79])[C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:73]3[CH2:77][CH2:76][CH2:75][CH2:74]3)[CH2:61][CH:62]([C:63]3[C:71]4[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=4)[NH:65][CH:64]=3)[CH:56]12)=[O:54]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:4]([O:3][C:1](=[O:2])[N:11]([CH:12]([C:14](=[O:16])[NH:51][CH:52]([C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:73]3[CH2:77][CH2:76][CH2:75][CH2:74]3)[CH2:61][CH:62]([C:63]3[C:71]4[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=4)[NH:65][CH:64]=3)[CH:56]12)=[O:54])[C:78]([CH3:81])([CH3:80])[CH3:79])[CH3:13])[CH3:17])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution containing Cbz-N(Me)Ala-OH (116 mg, 0.5 mmol) in anhydrous NMP (5 mL) was cooled to 0° C. HATU (191 mg, 0.5 mmol) and DIPEA (148 mg, 0.7 mmol) were added followed by the addition of crude 39 (218 mg, 0.5 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 3 h, the reaction mixture was diluted with EtOAc and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg of crude 40 as an amber-colored oil which was used without further purification. Mass spectrum, m/z [646.4] (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[C:3]([CH:8]3[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(=O)N1CCC(c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 80 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(3-(3-fluoropyrazin-2-yl)pyrrolidin-1-yl)ethanone (78 mg, 0.37 mmol), 4-(pyridin-2-ylamino)phenol (139 mg, 0.746 mmol), cesium carbonate (243 mg, 0.746 mmol), and DMSO (1.2 mL). The reaction mixture was degassed and flushed with N2 and heated in an oil bath at 80° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH in EtOAc, to provide 1-(3-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-1-yl)ethanone as an off-white solid. MS (ESI, pos. ion) m/z: 376.1 (M+1). IC50 (uM) 0.0164.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][CH:9]2[NH:15][C:14](=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pt].[H][H]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1CCCCC(Cc2ccc([N+](=O)[O-])cc2)N1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(CC2CCCCCN2)cc1

Procedure:
Hydrogenate 3.72 of 7-(4-nitrobenzyl)perhydroazepin-2-one in 50 mls of ethyl alcohol with platinum/hydrogen. After the absorption of hydrogen has ceased, filter off the catalyst and concentrate the filtrate. Dissolve the thus obtained 7-(4-aminobenzyl)-perhydroazepin-2-one in tetrahydrofuran. Add 680 mg of lithium aluminum hydride and boil the mixture under reflux. After cooling, treat it with ice-water and extract it with diethyl Dry the organic phase over sodium sulphate and concentrate it to obtain 2.0 g of the brown oily title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1.O>[CH:16]1([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1nc(Cl)nc(NC2CCCCC2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2,4,6-Trichloro-1,3,5-triazine (92.2 g) was dissolved in 300 mL of dioxane at room temperature. 53 g of Na2CO3 was dissolved in 300 mL of distilled water and was slowly added into the above solution. Cyclohexylamine (49.95 g) in a dropping funnel was slowly added into the above solution while stirring at 0-5° C. for 2 hr. The stirring was continued for another 3 hr at 0° C., 1 hr at room temperature, and the resultant white precipitate was then filtered and washed with water. The white precipitate was dissolved in methylenechloride (MC) and washed with water and MC was evaporated. Finally, 6-cyclohexylamino-2,4-dichloro-1,3,5-triazine having a substituted cyclohexyl was obtained after drying and solvent removal. The yield was more than 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:14]([O:19][CH3:20])[CH:13]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc(Br)ccc1O
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-chloro-phenylboronic acid (1.54 g, 9.85 mmol) and 4-bromo-2-methoxyphenol (1.00 g, 4.92 mmol) in DCM (50.00 mL) was added cupric acetate (1.34 g, 7.39 mmol), powdered 4 A molecular sieves and TEA (3.43 mL, 24.6 mmol) at rt. The resulting mixture was then stirred at rt for 48 h at ambient atmosphere. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in hexane).
Reaction SMILES: C(OC(OCC)[C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[CH2:17][CH2:18][C:19]4[NH:20][C:21](=[O:24])[CH:22]=[CH:23][C:14]([C:15]=43)=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)C.S(=O)(=O)(O)O.C[CH2:34][OH:35]>O>[O:24]=[C:21]1[NH:20][C:19]2[CH2:18][CH2:17][N:16]3[C:11]([C:7]4[CH:6]=[CH:5][C:10]([CH:34]=[O:35])=[CH:9][CH:8]=4)=[N:12][CH:13]=[C:14]([C:15]=23)[CH:23]=[CH:22]1
Reactant: CCOC(OCC)c1cccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
1-(3-Diethoxymethyl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (0.79 g, 2.18 mmol) was dissolved in EtOH (22 mL) and water (22 mL). Concentrated sulfuric acid (0.5 mL) was added, and the reaction brought to reflux for 5 h. The reaction mixture was cooled to rt, and the EtOH removed in vacuo. The residue was diluted with saturated NaHCO3, and the resulting solids were filtered and washed with water, then dried under vacuum overnight to produce 0.47 g (74%) of white solid: 1H NMR (DMSO-d6) δ 3.54-3.55 (m, 2H), 4.50-4.51 (m, 2H), 7.39 (t, 1H, J=7.8 Hz), 7.88-7.96 (m, 2H), 8.09-8.10 (m, 4H), 8.46-8.50 (m, 1H), 10.13 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:25]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.O1CCCC1>[OH-].[OH-].[Pd+2]>[CH3:32][N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:21][CH:20]=3)=[N:27][C:26]=2[CH2:28]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(=O)[nH]3)cc2)nc2c1CCN(C)C2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound wz: (S)-6-(benzyloxy)-N-(4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (0.099 g, 0.19 mmol) was purged under nitrogen then added 20% Palladium hydroxide on carbon (2:8, Palladium hydroxide:carbon black, 0.0927 g) followed by dry Methanol (2.80 mL, 69.1 mmol) Acetic acid (0.26 mL, 4.6 mmol) and dry Tetrahydrofuran (2.80 mL, 34.5 mmol) purged with hydrogen, heated at 40° C. and stirred overnight under an atmosphere of hydrogen. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 9.09 (s, 1H), 8.19 (d, J=8.8, 2H), 7.74 (s, 2H), 7.41 (t, J=7.9, 1H), 6.30 (s, 1H), 5.99 (d, J=7.6, 1H), 4.13 (d, J=6.8, 1H), 3.89 (d, J=11.3, 1H), 3.77-3.68 (m, 1H), 3.60 (dd, J=21.7, 11.0, 4H), 3.44 (d, J=17.4, 2H), 2.74-2.60 (m, 3H), 2.38 (s, 3H), 1.25 (d, J=6.6, 3H). LC/MS-m/z+433.2 (M+H)+.