Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[CH3:13][O:14][C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29]Br)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:14][C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[CH2:10][CH2:11][CH3:12])=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Reactant: CCCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.4 %

Procedure:
To a mixture of 4-hydroxy-3-propylbenzonitrile (Example 33, 1.33 g, 8.28 mmol) and methyl[5-(3-bromopropoxy)-1H-indol-1-yl]acetate (Example 47, 2.70 g, 8.28 mmol) in DMF (50 mL, containing 1% water), was added cesium carbonate (5.39 g, 16.55 mmol). The mixture was stirred at rt for 24 h and then the solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate and filtered. The filtrate was concentrated and purified via silica gel column chromatography (0-10% EtOAc in hexanes) to give 787 mg (23%) of the product as a solid. This was used in later steps with no further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([OH:9])=[C:4]([CH3:10])[N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)[nH]c(=O)c1O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)nc(N)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-5-hydroxy-6-methyl-4-pyrimidone (0.88 g, prepared as described in Hull, J. Chem. Soc., 2033 (1956)), was treated with pyridine (5 ml) and acetic anhydride (0.5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 18 hours. Filtration provided a white solid (0.64 g). Recrystallization (absolute ethanol) afforded a white crystalline solid (m.p.: 273°-276° C.).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([N:19]5[CH2:23][CH2:24][CH2:25][S:26]5(=[O:28])=[O:27])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1c1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylamine (500 mg, 1.82 mmol) in DMF (10 mL) was added NaH (220 mg, 5.46 mmol) at 0° C. The mixture was allowed to warm to rt and then stirred for 30 min. A solution of 3-chloropropane-1-sulfonyl chloride (450 mg, 2.55 mmol) in DMF (2 mL) was added and the reaction mixture was stirred for 2 h. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (elute: 2% dichloromethane in methanol). This afforded 217 mg (31%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzothiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:16]1(=[O:21])[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1ccco1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccco2)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 0 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxamide (0.050, 0.135 mol) and 2-furanylboronic acid (0.020, 0.175 mol) was dissolved in a 6:1 solution of 1,4 dioxane (3 L)/water (0.5 L) in a 20 L microwave reaction vessel. potassium carbonate (0.093, 0.673 mol) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.017, 0.023 mol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% NH4OH. The desired fractions were concentrated, giving 0.018 g (37%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([N:19]3[CH:23]=[CH:22]N=C3)=[O:18])=[C:4]2[CH2:3]1.C(=NO)([NH2:26])C>CN(C)C=O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]3[O:18][N:26]=[C:23]([CH3:22])[N:19]=3)=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccccc2C1=O
Reactant: CC(N)=NO
Solvent: CN(C)C=O
Product: Cc1noc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Reaction time: 5.5 h

Procedure:
9.30 g (30.2 mmol) of 1-[(5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)carbonyl]imidazole are suspended in 60 ml of N,N-dimethylformamide and the suspension is treated with 3.0 g (40.5 mmol) of acetamidoxime. After stirring at 60° for 5.5 hours the mixture is evaporated to dryness, 70 ml of glacial acetic acid are added to the residue and the solution is heated to 120° for 2.5 hours. The solution is then evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained 4,5-dihydro-5-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 257°-260°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)[C:37](N)=[O:38])=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.OCC1C=C(B(O)O)C=CC=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([CH2:37][OH:38])[CH:40]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Agent: OCc1cccc(B(O)O)c1
Product: Nc1ccc(-c2cccc(CO)c2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (3-(hydroxymethyl)phenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.42-7.38 (m, 2H), 7.38-7.16 (m, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.81 (d, J=9.5 Hz, 2H), 6.58 (d, J=8.8 Hz, 1H), 6.43 (s, 1H), 6.17 (m, 2H), 5.35-5.24 (m, 1H), 4.71 (s, 2H), 3.53 (s, 2H), 2.96-2.84 (m, 1H), 2.81 (d, J=7.1 Hz, 1H). MS (m/z) 531.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][S:9]([C:11]2[S:12][C:13]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[O:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:14]=3[N:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.CO>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][S:9]([C:11]2[S:12][C:13]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[O:24][CH2:25][C:26]([OH:28])=[O:27])[C:14]=3[N:15]=2)=[O:10])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S(=O)CC(c3ccccc3)c3ccccc3)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1cccc2c1CCc1sc(S(=O)CC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of ethyl [(2-(2,2-diphenylethylsulfinyl)-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (0.50 g, 0.965 mmol) in a mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-aqueous sodium hydroxide (2 mL) dropwise, and the mixture was stirred at room temperature for 20 minutes. After the solvent was distilled off under reduced pressure, 1N-hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.36 g of the title compound as amorphous solid. Yield 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:23]([N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1)[CH2:24][CH3:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:23][CH2:24][CH3:25])[N:27]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: CCCn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 67 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), 1-propyl-1H-pyrazol-3-ylamine (40 μL, 0.29 mmol) and N,N-diisopropylethylamine (151 μL, 0.87 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-propyl-1H-pyrazol-3-yl)-acetamide (88 mg, 67%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H25ClN4O4S [M+] 452.13, found 453 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.98 (t, J=7.5 Hz, 3H, CH3), 1.64 (m, 4 H, 2×CH2), 1.87 (m, 6 H, 3×CH2), 3.29 (s, 3 H, SO2CH3), 4.01 (st, J=7.0 Hz, 32H, NCH2), 4.88 (m, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.31 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.66 (d, Jm=1.6 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.16 (s, 1 H, NH).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11]2)[CH2:6][CH2:5]1>O>[CH2:15]([CH:12]1[CH2:13][CH2:14][CH:10]([CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)[CH2:11]1)[CH2:16][CH3:17]
Reactant: CCCC1CCC(C2CCC(=COC)CC2)C1
Solvent: O
Product: CCCC1CCC(C2CCC(C=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
Hydrochrolic acid (1 M) (30 ml) was added to 1-methoxymethylene-4-(3-propylcyclopentyl)cyclohexane (17.0 g) obtained in the first step, which was dissolved in (200 ml), and the mixture was stirred at room temperature for 2 hours. Water (100 ml) was added to the mixture, which was extracted with toluene. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (200 ml) and toluene (50 ml) was added to the residue, and a NaOH aqueous solution (20%) (30 ml) was added under ice-cooling, and the mixture was stirred at room temperature for another 3 hours. A saturated aqueous solution of ammonium chloride was added to neutralize and the mixture was extracted with toluene. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate, and the toluene was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/20 by volume) to give 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (15.0 g).
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C@H:13]3[CH2:14][S:15][C:16](=[C:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[C@H:12]3[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]2=[O:31])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C)C.[Pd]>[C:1]1([C@H:7]([N:9]2[C@H:13]3[CH2:14][S:15][CH:16]([CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[C@H:12]3[N:11]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:10]2=[O:31])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(C(=O)O)=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Product: CCCC(C(=O)O)C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2[C@H](C)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 78.6 mg of (3aS,6aR)-hexahydro-1-[(R)-(1-phenylethyl)]-2-oxo-3-benzylthieno-[3,4-d]-imidazol-4-ylidene pentanoic acid in 5 ml of isopropanol was placed in a 100-ml autoclave and 39 mg of palladium (5 percent) on carbon was added. The autoclave was flushed twice with hydrogen and the mixture was stirred under 50 bars of hydrogen pressure at 50° C. for 24 hours. Then the catalyst was filtered off and the solvent evaporated off. The product, (3aS,6aR)-hexahydro-1-[(R)-(1-phenylethyl)]-2-oxo-3-benzylthieno-[3,4-d]-imidazol-4-yl pentanoic acid, was obtained as a colorless oil in a yield of 56.1 mg (72 percent).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7]O)[S:5][CH:6]=1.FC(F)(F)S(Cl)(=O)=O.CCN(CC)CC.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.O>[N:24]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[N:3]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1nc(Br)cs1
Agent: O=S(=O)(Cl)C(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc(Br)cs1
Reaction time: 8 h

Procedure:
(4-Bromo-thiazol-2-yl)-methanol (1.1 g, 5.7 mmol) in DMF (15 ml) is treated at room temperature under nitrogen atmosphere with trifluoromethanesulfonyl chloride (0.61 ml, 1 equivalent), and Et3N (0.8 ml, 1 equivalent). The reaction mixture is stirred for 3 hours at room temperature before the addition of sodium azide (1.11 g, 3 equivalents), followed by overnight stirring at the same temperature. The reaction mixture is diluted with water and extracted with DCM and diethyl ether. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to afford the crude product, which is used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc(N)c1N

Procedure:
The mixture of 206 g (1.14 mol) of 6 and 20.6 g of 10% Pd on charcoal in 824 ml of THF and 824 ml of methanol was hydrogenated with a total of 6 equivalents of hydrogen (130 l) at 2048° C. over 24 h. The mixture was filtrated and the solvents were evaporated.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[C:8]([N+:25]([O-:27])=[O:26])=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: O=S(=O)(O)O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
0.5 g (1.4 mmol) of 3-(4-chloro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 10 ml of concentrated sulfuric acid, and 0.1 g (1.1 mmol) of 60% nitric acid was dropwise added thereto at -20° C. After stirring at -20° C. for 10 minutes, the reaction solution was poured into ice water and extracted with 50 ml of chloroform. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.3 g (yield: 53.3%) of the desired product as a pale yellow crystals. Melting point: 174-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][CH:13]1[CH2:15][CH:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:11].[C:38]([O:43][CH2:44]Cl)(=[O:42])[CH:39]([CH3:41])[CH3:40]>C(Cl)(Cl)Cl>[C:38]([O:43][CH2:44][S:11]/[C:10](=[N:9]\[C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])/[NH:12][CH:13]1[CH2:15][CH:14]1[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)(=[O:42])[CH:39]([CH3:41])[CH3:40]
Reactant: Cc1cccc(C)c1NC(=S)NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)C(=O)OCCl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1/N=C(/NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)SCOC(=O)C(C)C
Temperature: 100 °C
Yield: 19.4 %

Procedure:
To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[CH2:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C@@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:29]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:27][C:4]1[N:3]=[C:2]([N:35]2[CH2:34][CH2:33][C:32]3([CH2:28][N:29]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:44])[C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31]3)[CH2:37][CH2:36]2)[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:12])([F:11])[F:13])[N:5]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-2-amine (57.3 g, 137 mmol, Step 1) in dioxane (500 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (48 g, 124.9 mmol), and NaHCO3 (31.5 g, 375 mmol). After 5 h, an additional amount of NaHCO3 (31.5 g, 375 mmol) was added and the reaction mixture was heated to 90° C. for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:27]([CH3:28])[CH2:26][CH2:25][C:24]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][N:39]([CH3:46])[CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:34][CH:33]=3)=[O:30])=[CH:23][C:22]=2[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:28][N:27]1[C:21]2[CH:20]=[CH:19][C:18]([C:3]3[CH:8]=[CH:7][C:6]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:5][CH:4]=3)=[CH:47][C:22]=2[CH:23]=[C:24]([C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([CH2:38][N:39]([CH3:46])[CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:36][CH:37]=2)=[O:30])[CH2:25][CH2:26]1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: [O-]B([O-])Oc1ccc(N2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc21
Reaction time: 0.67 h
Yield: 19.2 %

Procedure:
In water/ethanol/toluene (1:1:10, 18.0 ml) were dissolved 4-(1-piperidinyl)phenyl borate (179 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (353 mg), and to the mixture was added potassium carbonate (242 mg). Under argon atmosphere, the mixture was stirred for 40 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (34 mg). Under argon atmosphere, the mixture was refluxed for 15 hours, and the mixture was dilute with ethyl acetate (200 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate/ethanol=9:1) and recrystallized from ethanol to give 1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(1-piperidinyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 316) (79 mg, 19%).