Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[O:12][CH2:11][CH2:10][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccnc2)OCCO1

Procedure:
3-Acetylpyridine (10 g), ethylene glycol (50 ml) and p-toluenesulfonic acid (0.5 g) were dissolved in toluene and the solution was refluxed at 150° C. for 1 day with the by-product water being constantly removed. After cooling, saturated aqueous sodium hydrogen carbonate and toluene were added and the mixture was stirred and allowed to stand. The aqueous layer was separated and extracted with 2 portions of toluene. The toluene layers were combined, washed sequentially with saturated aqueous sodium hydrogen carbonate, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 2-methyl-2-(pyridin-3-yl)-1,3-dioxolane (13.6 g).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[N:10]=[C:9]([Cl:20])[N:8]=1)(=O)=O.[I-:21].[Li+]>O1CCOCC1>[Cl:20][C:9]1[N:10]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[CH:12]=[C:7]([CH2:6][I:21])[N:8]=1
Reactant: [I-]
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Agent: [Li+]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(CI)nc(Cl)n1
Temperature: 107 °C
Yield: 85.3 %

Procedure:
(R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated at 107° C. for 1 hour. The reaction mixture was quenched with water (250 ml), extracted with EtOAc (3×250 ml), the organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. Fractions containing product were evaporated and the residue was then triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g, 86%); m/z: (ESI+) MH+, 354.27.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:22][C:23]([F:28])([F:27])[C:24](O)=O>>[CH3:21][N:17]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:10][CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:24]([C:23]([F:28])([F:27])[F:22])=[N:2][C:3]=2[CH:4]=1)[C:18](=[O:20])[CH3:19]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Agent: Cl
Product: CC(=O)N(C)c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Yield: 90 %

Procedure:
A solution of N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylacetamide hydrochloride (2.77 g, 10 mmol) in trifluoroacetic acid (60 mL) was heated to reflux for 18 h. After evaporation of the solvent, the residue was dissolved in EtOAc (200 mL), washed with 2N NaOH (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel to give 3.18 g (90%) of a white solid as the title compound. MS (ESI) (M+H)+=356.02.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH:9]([OH:11])[CH2:10][CH:3]1[CH:4]1[CH:6]2[O:5]1.C[O:13][C:14](=O)[C:15]([OH:26])([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.[H-].[Na+].O>ClCCl>[CH3:1][N:2]1[CH:7]2[CH2:8][CH:9]([O:11][C:14](=[O:13])[C:15]([OH:26])([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH:3]1[CH:4]1[CH:6]2[O:5]1
Reactant: CN1C2CC(O)CC1C1OC12
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1C2CC(OC(=O)C(O)(c3cccs3)c3cccs3)CC1C1OC12
Temperature: 70 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
The product of step (b) (2.00 g, 12.9 mmol) and the product of step (a) (3.61 g, 14.2 mmol) were melted together at 70° C., under a vacuum of 210 Torr for 1 h. Sodium hydride (60% suspension in oil, 620 mg, 15.5 mmol) was added and the reaction mixture was stirred at 70° C. under 210 Torr for 3 h. The reaction mixture was allowed to cool to ambient temperature and then water (30 mL) and dichloromethane (30 mL) were added. The organic layer was separated and washed with water (2×20 mL), dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography (5% MeOH/DCM) to give the title compound as a solid (2.03 g, 5.4 mmol, 42%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.BrCC1CCCCO1>>[O:29]1[C:28]2[CH:33]=[CH:34][C:25]([CH2:24][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:21]5[C:12](=[CH:13][C:14]6[O:19][CH2:18][CH2:17][O:16][C:15]=6[CH:20]=5)[O:11][CH2:10]4)[C:2]3=[O:22])=[CH:26][C:27]=2[O:32][CH2:31][CH2:30]1
Reactant: BrCc1ccc2c(c1)OCCO2
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc3c(c2)OCCO3)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al., Tetrahedron, (2001), 57:8297-304) to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (100%) as a colorless solid: mp 120-123° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.20 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.15 (dd, J=7.4, 0.8 Hz, 1H), 7.01 (ddd, J=7.5, 7.4, 0.7 Hz, 1H), 6.85-6.79 (m, 4H), 6.50 (s, 1H), 6.24 (s, 1H), 4.93 (d, J=8.7 Hz, 1H), 4.92 (d, J=15.5 Hz, 1H), 4.76 (d, J=15.5 Hz, 1H), 4.65 (d, J=8.7 Hz, 1H), 4.23 (s, 4H), 4.22-4.17 (m, 2H), 4.14-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 155.4, 144.7, 143.8, 143.3, 142.3, 138.4, 132.4, 129.0, 128.9, 123.9, 123.4, 121.2, 120.5, 117.8, 116.5, 111.8, 109.5, 99.5, 80.4, 64.6, 64.44, 64.41, 64.0, 58.2, 43.8; MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[N:14]=[C:13]([CH:19]3[S:24][CH2:23][CH2:22][CH2:21][S:20]3)[C:12]=2[CH:25]=1>O.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:17])([CH3:18])[N:14]=[C:13]([CH:19]3[S:20][CH2:21][CH2:22][CH2:23][S:24]3=[O:2])[C:12]=2[CH:25]=1
Reactant: CC1(C)N=C(C2SCCCS2)c2cc(Br)ccc2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)N=C(C2SCCCS2=O)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
A solution of sodium periodate (430 mg) in water (6 ml) was added to a solution of Compound 105 (600 mg) in methanol (18 ml) and the mixture was stirred at room temperature for 18 hours. The methanol was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by chromatography on silica gel to obtain a solid. The solid was recrystallized from ethyl acetate to obtain 2-(6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)-1,3-dithian-1-oxide (331 mg) (Compound 111).
Reaction SMILES: [Cl:1][C:2]([Cl:32])([Cl:31])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[O:14][CH:13]=[C:12]([C:27]([OH:29])=O)[C:11]2=[O:30])=[O:6].S(Cl)([Cl:35])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:31])([Cl:32])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:24])[Cl:25])=[O:20])[O:14][CH:13]=[C:12]([C:27]([Cl:35])=[O:29])[C:11]2=[O:30])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
The compound (57.3 mg) obtained in Example 5 was dissolved in 10 ml of benzene, and with stirring at room temperature, 0.5 ml of thionyl chloride was added. The mixture was refluxed for 3 hours with stirring. The reaction mixture was concentrated, and 5 ml of n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dried to afford 34.8 mg of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH2:11]O)[CH3:2].O=S(Cl)[Cl:15]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:15][CH2:11][C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCc1cccc(CC)c1CO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a mixture of (2,6-diethylphenyl)methanol (1.83 g, 11.1 mmol), toluene (20 mL) and DMF (6 drops) was added SOCl2 (2.1 g, 1.6 eq). The resulting solution was stirred at RT (1 h). After evaporating to dryness, the residue was taken up in heptane (˜50 mL) and washed with water (˜5 mL), dried (Na2SO4), filtered and evaporated to give 1.97 g (yield of 97%) of title product. 1H NMR (300 MHz, CDCl3) δ 1.28 (t, 6H), 2.79 (q, 2H), 4.70 (s, 2H), 7.09 (d, 2H), 7.20 (m, 1H).
Reaction SMILES: [CH2:1]([CH:8]([C:20]1[N:24](CC2C=CC(OC)=CC=2)[N:23]=[N:22][N:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([CH:8]([C:20]1[NH:24][N:23]=[N:22][N:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nnnc2C(CC(=O)c2ccc(Cl)c(Cl)c2)Cc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CC(Cc1ccccc1)c1nnn[nH]1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
5-[1-benzyl-3-(3,4-dichlorophenyl)-3-oxo-propyl]-1(4-methoxybenzyl)-1H-tetrazole (1.6 g, 3.3 mmol), from the previous step) and TFA (20 ml) were mixed and stirred at room temperature under nitrogen atmosphere for 40 hours. The mixture was diluted with water (100 ml) and extracted with methylene chloride (3×200 ml). The organic layers were combined, washed with water (2×100 ml), brine (1×100 ml) and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was flash chromatographed by using cyclohexane/ethyl acetate 0÷20 as eluent. The title compound was obtained as a colourless solid (0.6 g, 50%) (m.p. 172°-174° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:42]([F:45])([F:44])[F:43])[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[N:8]=[C:7]2[CH:12]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:13]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[O:22])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:42]([F:44])([F:43])[F:45])[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[N:8]=[C:7]2[CH:12]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:13]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1nn(C)c2c(Cl)cc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1nn(C)c2c(Cl)cc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the slower-eluting enantiomer of the product from Step B (4.6 mg, 0.0069 mmol) in DCM (1 mL) was added TFA (1 mL, 13 mmol), and the solution was stirred for 30 minutes at RT. The solution was concentrated, then the residue was purified by reverse phase HPLC eluting with acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the enantiopure title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.92 (s, 1H); 7.62 (d, J=8.5 Hz, 2H); 7.53 (d, J=8.3 Hz, 2H); 7.43 (s, 1H); 7.36 (d, J=8.2 Hz, 2H); 7.33 (d, J=8.5 Hz, 2H); 4.78 (d, 3=11.5 Hz, 1H); 4.26 (s, 3H); 3.72 (td, J=11.4, 3.2 Hz, 1H); 3.52 (t, J=6.9 Hz, 2H); 2.55 (t, J=6.9 Hz, 2H); 1.68-1.57 (m, 1H); 1.50-1.43 (m, 1H); 1.05-0.97 (m, 2H); 0.73 (t, J=7.3 Hz, 3H); LC2 1.31 min. (M+H)+ 606.
Reaction SMILES: [C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C([NH:16][C:17]1[N:26]=[C:25]([NH:27]C(C(C)(C)C)=O)[C:24]2[CH2:23][C:22](=O)[CH2:21][CH2:20][C:19]=2[N:18]=1)=O)(C)C>>[NH2:16][C:17]1[N:26]=[C:25]([NH2:27])[C:24]2[CH2:23][C:22](=[N:9][O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][CH2:20][C:19]=2[N:18]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Product: Nc1nc(N)c2c(n1)CCC(=NOCc1ccccc1)C2

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
1.0 g of the product obtained in Example 8 and 2.0 ml of benzoylchloride were dissolved in 5 ml of tetrahydrofuran. Tetrahydrofuran was distilled off to a great extend and the residue was refluxed for 2 h. After cooling ether was added to the mixture and the product was filtered and triturated with ethylmethylketone. Yield 0.50 g (29%), m.p. 206°-210° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[C:16]([F:18])([F:17])[F:15])=[CH:5][N:6]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cnc(Br)s1)C(F)(F)F
Yield: 38.9 %

Procedure:
According to Reference Example 8-2, by use of 2-bromothiazole-5-carbaldehyde (500 mg, 2.60 mmol) dissolved in N,N-dimethylformamide (7.5 mL), potassium carbonate (72 mg, 0.52 mmol) and (trifluoromethyl)trimethylsilane (0.461 mL, 3.12 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=40/1) was performed to give 1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethanol (Compound EG) (265 mg, yield: 39%).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[CH:18]=[N:17]2)=[CH:13][CH:12]=1>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][C:25]=3[Cl:8])[CH:18]=[N:17]2)=[CH:27][CH:28]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2cc(-c3csc(N)n3)cn2)cc1
Solvent: CC#N
Product: COc1ccc(Cn2cc(-c3nc(N)sc3Cl)cn2)cc1
Yield: 28.9 %

Procedure:
According to Scheme 6, Step 2: NCS (8.14 mmol, 1.09 g) was added to a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine (8.14 mmol, 2.33 g) in acetonitrile (20 mL) and the reaction mixture was stirred under reflux for 1.5 hour. After evaporation of the solvent, the crude residue was diluted in EtOAc. The organic phase was washed with water and brine, was dried over Na2SO4, was filtered and was concentrated. The crude mixture was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 90:10) as eluent to yield 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-amine (2.35 mmol, 755 mg, 29%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:31]([O-:33])=[O:32])=[C:13]([CH:30]=1)[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15]>>[CH:26]1([NH:25][C:23]([C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:30]=[C:9]([N:6]4[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]4)[CH:10]=[CH:11][C:12]=3[N+:31]([O-:33])=[O:32])[CH:22]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN[C@H](C)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material (R)-2-methylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3R)-3-methylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 1.04 (d, 3H), 2.30 (s, 3H), 2.52 (m, 2H), 2.71 (m, 2H), 2.84 (m, 2H), 2.98 (d, 1H), 3.92 (t, 2H), 7.04 (m, 2H), 7.27 (d, 1H), 7.56 (d, 1H), 7.97 (s, 1H), 8.03 (d, 2H), 8.35 (d, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 438.
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1COCC1>[C:1]12([NH:11][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=CC(=O)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 0.1 %

Procedure:
1-Adamantylamine (0.76 g; 5.0 mmol) and triethylamine (0.77 ml; 5.5 mmol) were dissolved in dry THF (40 mL) on an ice bath. After dropping acryloyl chloride (0.45 ml; 5.5 mmol) onto the solution, the mixture was stirred for 4 hours. After the reaction, the precipitate was removed by filtration, and the supernatant liquid was concentrated under reduced pressure. The resulting crude product was recrystallized from chloroform to give N-(1-adamantyl)acrylamide (0.85 mg; yield: 83%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>C(#N)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OB(O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixture of (4-(bromomethyl)phenyl)boronic acid (500 mg) and potassium carbonate (643 mg) in acetonitrile (10 mL) was added morpholine (0.304 mL), and the mixture was stirred at room temperature for 60 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether and ethyl acetate to give the title compound (449 mg).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1>O1CCOCC1>[CH2:1]([NH:5][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCN
Solvent: C1COCCO1
Product: CCCCNCc1ccc(-c2ccccc2C#N)cc1

Procedure:
36 ml (367 mmol) of butylamine are added to a solution of 20.0 g (73.5 mmol) of 4-bromomethyl-2'-cyano-biphenyl (cf. EP 253,310, page 159) in 150 ml dioxane and the mixture is heated under reflux for 3 hours. The reaction mixture is then concentrated by evaporation in vacuo and the residue is partitioned between 300 ml of diethyl ether and 100 ml of water. The ethereal phase is washed twice with water, dried and concentrated by evaporation. The resulting oil is flash-chromatographed on 500 g of silica gel [toluene/methanol(19:1)]. The fractions containing the product are concentrated by evaporation to yield N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine in the form of a yellow oil that has an Rf value of 0.34 [toluene/methanol (4:1)].
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:39]>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:39])[C:8]=2[N:22]=1)[CH3:2]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCCCc1cccnc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCCCc1cccnc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
Under a nitrogen atmosphere, 2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridine (4.6 g) from Part A and ammonium acetate (46 g) were heated in a sealed tube to 150° C. After 65 hours, NMR analysis indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature, dissolved in ethyl acetate, and washed 3 times with 1N potassium hydroxide and once with water. The organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 10% hydrochloric acid and washed 3 times with dichloromethane (DCM). Potassium hydroxide was added to the aqueous layer to bring the pH to 14, and this was subsequently washed 4 times with DCM. The combined organic layers were washed twice with water, twice with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The oil was purified by column chromatography over silica using 98/2 DCM/methanol as the eluant. The oil was then triturated with ethyl acetate/hexane and the resulting solid was recrystallized from ethyl acetate/hexane to yield 2-(ethoxymethyl)-6,7-dimethyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine as a white solid, m.p. 78.0–78.5° C.