Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl (1RS) [1-hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate (4.65 g, 12.0 mmol) in CH2Cl2 (40 ml) at 0° C. under an argon atmosphere was added triethylsilane (2.34 ml, 14.6 mmol), followed by boron trifluoride etherate (8.8 ml, 71 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl (50 ml). The mixture was extracted with EtOAc (150 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/ hexanes to provide the title compound (4.2 g, 95%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:18])[C:9](Br)=[C:10]([CH3:16])[C:11]=2[N+:13]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[CH3:23][OH:24]>[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:18])[CH:9]=[C:10]([CH3:16])[C:11]=2[NH:13][C:23](=[O:24])[C:7]([CH3:12])([CH3:8])[CH3:6])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)c(Br)c(C)c([N+](=O)[O-])c21
Reactant: CO
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-5-bromo-4,6-dimethyl-7-nitroindoline (30 g) was dissolved in a mixture (600 ml) of CHCl3/MeOH=1/1 and 5% Pd-C (5.0 g) was added, which was followed by catalytic hydrogenation at 35° C. The precipitate was collected by filtration together with Pd-C, and dissolved in CHCl3 (300 ml). The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate. The solvent was evaporated under reduced pressure from the filtrate and CHCl3 (300 ml) was added. The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and combined with the layer of above-mentioned CHCl3. The combined CHCl3 layer was washed with saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure and the residue was dissolved in CHCl3 (150 ml). Thereto were successively added at 10° C. pivaloyl chloride (11.7 g) and Et3N (10.8 g). The mixture was stirred at room temperature for 1 hr and CHCl3 (200 ml) was added. The mixture was washed successively with 5% aqueous citric acid and water, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure and the obtained crude residue was washed with cool Et2O (100 ml) to give 21 g of N-(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Product: COc1cc(C(=O)NC2(C(=O)NC3CSc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)ccc43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 570.1 (MH+, 1Cl).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:16]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:16])=[O:4]
Reactant: CO
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Yield: 83 %

Procedure:
2-Amino-3-(4-nitrophenyl)propionic acid (4.60 g, 27.9 mmol) was added to a mixed solution of methanol (100 ml) and chloroform (50 ml), and sulfuric acid (3 ml) was added, which was followed by refluxing under heating for 30 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The pH was adjusted to 8-9 with a 1N aqueous sodium hydroxide solution and the mixture was extracted with chloroform. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 4.06 g of methyl 2-amino-3-(4-nitrophenyl)propionate as a yellow oil (83%). This oil (4.00 g, 17.8 mmol) was dissolved in acetonitrile (56 ml), and pyridine (1.76 ml, 21.4 mmol) and n-butylsulfonyl chloride (2.80 g, 17.8 mmol) were sequentially added, which was followed by stirring at 70° C. for 4.5 hours. After cooling, the reaction mixture was poured into water (70 ml) and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 4.06 g of methyl 2-(n-butylsulfonylamino)-3-(4-nitrophenyl)propionate as an orange oil (66%). This oil (3.40 g, 9.88 mmol) was dissolved in acetic acid (130 ml) and 10% palladium-carbon (1.5 g) was added. The mixture was stirred for 3 days under a hydrogen atmosphere. The reaction mixture was filtered through Celite and acetic acid was distilled away from the filtrate under reduced pressure to quantitatively give 3.16 g of methyl 3-(4-aminophenyl)-2-(n-butylsulfonylamino) propionate as a brown solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[CH:36]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[CH2:37].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH:36]=[CH2:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[CH2:31][C:30]2=[O:35])[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:19][CH2:20]1)=[O:13])[CH3:10]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(C)c4)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
Triethylamine (260 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (263 mg) in dichloromethane (20 ml), 4-vinylbenzenesulfonyl chloride (194 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the material was extracted with dichloromethane, dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from diisopropyl ether to obtain the colorless crystalline title compound (157 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:20])[C:12]1([C:17](O)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C:12]2([N:11]([CH3:20])[CH3:10])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:18])=[N:6][CH:7]=1
Reactant: CN(C)C1(C(=O)O)CCCC1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C1(C(=O)NNc2ccc(F)cn2)CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 200 mg, 1.57 mmol) in DMF (10 mL) were added Intermediate 99a (247 mg, 1.57 mmol), EDC (333 mg, 1.73 mmol) and HOBt (21 mg, 0.16 mmol). The reaction mixture was stirred at RT for 18 h and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-8% (2M NH3 in MeOH) in DCM, to give the title compound (282 mg, 67%). 1H NMR (400 MHz, CDCl3): 1.54-1.73 (4H, m), 1.76-2.04 (4H, m), 2.25 (6H, s), 6.46 (1H, s), 6.64 (1H, dd, J=9.0, 3.5 Hz), 7.23-7.33 (1H, m), 8.04 (1H, d, J=3.0 Hz), 8.94 (1H, s).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[C:12]1([OH:24])[CH:23]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:14]([OH:15])[CH:13]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:8]/[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])=[CH:9]\[CH2:10][C:13]1[C:12]([OH:24])=[CH:23][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:16][C:14]=1[OH:15]
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(O)c(C/C=C(\C)CCC=C(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Geraniol (3 g, 0.0194 mol) and olivetol (2 g, 0.0111 mol) were dissolved in 400 mL of chloroform containing 80 mg of p-toluenesulfonic acid as catalyst and the reaction mixture was stirred at room temperature for 12 h in the dark. After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate (400 mL) and then with H2O (400 mL). The chloroform layer was concentrated at 40 C under reduced pressure, and the residue obtained was chromatographed on a 2.0 cm×25 cm silica gel column using benzene (1000 mL) as the eluent to give 1.4 g (0.00442 mol)(39.9%) CBG as product.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Br:7][C:8]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>>[Br:7][C:8]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: C#CCN(C)C
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OS(=O)(=O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1C#CCN(C)C

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [115] above, 3-dimethylamino-1-propyne was reacted with 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-trifluoromethanesulphonyloxyquinazoline to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-(3-dimethylamino-1-propynyl)quinazoline; NMR Spectrum: (DMSOd6) 2.29 (s, 6H), 3.55 (s, 2H), 4.0 (s, 3H), 7.38-7.83 (m, 3H), 7.67 (s, 1H), 8.05 (s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 430 and 432.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CC[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CC#N>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:4]4[CH2:1][CH2:2][CH:30]([CH2:29][NH:26][CH2:27][CH3:28])[CH2:5]4)[C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C(F)(F)F)C1
Yield: 193.1 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid (0.20 g, 0.61 mmol) 3-((N-ethylamino)methyl)pyrrolidine (0.20 g, 1.6 mmol) and NEt3 (0.20 g, 2 mmol) were refluxed with stirring under N2 in CH3CN (2 mL) for 2 hours. When the reaction mixture had cooled to 20° the yellow solid was collected by vacuum filtration, washed with water (5 mL) and ether (5 mL), and then dried at 110°/0.2 mm to give 1-cyclopropyl-7-(3-((N-ethylamino)methyl)pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid (0.26 g, 97%) as a light yellow solid; mp 239°-241° C. C21H23N3O3F4 requires C, 57.14; H, 5.22; N, 9.52; F, 17.23%. Found, C, 56.77; H, 4.98; N, 9.34; F, 16.95%. Nmr (TFA) δ 9.37 (1H, s, H2), 8.09 (1H, d, J=13.8 Hz, H5), 7.2-7.5 (2H, br s, NH+2), 4.45-4.55 (1H, m, H1 pyrrolidinyl), 4.1-4.4 (2H, m, H5 pyrrolidinyl), 3.9-4.1 (2H, m, H1 cyclopropyl+pyrrolidinyl), 3.3-3.65 (4H, m, CH2s ethylaminomethyl), 2.9-3.1 (1H, m, H3 pyrrolidinyl), 2.5-2.65 (1H, m, H4 pyrrolidinyl), 1.9-2.1 (1H, m, H4 pyrrolidinyl), 1.5-1.8 (5H, m and t, J=7.1 Hz, cyclopropyl and CH3), 0.95-1.4 (2H, m, cyclopropyls). Ir (KBr) 1629, 1456, 1360 cm-1. MS 442 (4, M H⊕), 441 (4, M⊕).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:16]=[O:17])[C:11](OCC)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[O:17]=[C:16]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:11][NH:21][C:19](=[S:20])[NH:18]1
Reactant: CCOC(=O)C(C=O)Cc1ccc(C#N)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: N#Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Temperature: 90 °C
Yield: 69.4 %

Procedure:
To a solution of ethyl 3-(4-cyanophenyl)-2-formylpropanoate (1.3 g, 5.62 mmol) in Ethanol (60 mL) was added thiourea (1.712 g, 22.49 mmol) under argon. The mixture was heated at 90° C. for 3 h. After removing the solvent, the residue was dissolved in water (80 mL), washed with ether twice. The aqueous solution was acidified to pH 4-5 with acetic acid, and the resulting precipitate was collected by filtration, washed with water until the wash waters were neutral to afford the title compound (0.95 g, 3.90 mmol, 69.5% yield). LCMS: rt=1.86 min, [M+H+]=224
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(c2ccc(CO)o2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.52 g, 19.11 mmol) in dry CH2Cl2 (35.2 mL) was treated at 0° C. with Et3N (3.20 mL, 22.93 mmol) followed by DMAP (233 mg, 1.91 mmol) and Ms-Cl (1.63 mL, 21.02 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (35 mL), extracted with CH2Cl2 (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 3.65 g of crude 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane as an orange oil. The crude material in acetone (20 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (1.57 g, 13.91 mmol) in acetone (20 mL). K2CO3 (7.69 g, 55.66 mmol) followed by TBA iodide (1.03 g, 2.73 mmol) were added and the reaction mixture was stirred at rt overnight. Water (100 mL) and EA (100 mL) were added. The aq. layer was extracted with EA (100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as an orange oil. TLC: rf (60:40 hept-EA)=0.31. LC-MS-conditions 02: tR=0.91 min. 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 3.99 (dd, J=4.5, 2.5 Hz, 2H), 4.06 (dd, J=4.4, 2.5 Hz, 2H), 5.31 (s, 2H), 6.35 (d, J=3.3 Hz, 1H), 6.42 (d, J=3.3 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:12]=[N:13][NH:14][C:3]1=2.C1(=O)O[CH2:18][CH2:17][O:16]1>>[OH:16][CH2:17][CH2:18][C:12]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:2]([CH3:1])[C:3]=2[NH:14][N:13]=1
Reactant: CN1c2ccccc2Oc2cn[nH]c21
Reactant: O=C1OCCO1
Product: CN1c2ccccc2Oc2c(CCO)n[nH]c21
Reaction time: 0.33 h

Procedure:
A mixture of 9.36 g (50 mmols) of 9-methylpyrazolo[4,3-b][1,4]benzoxazine and 13.2 g (150 mmols) of ethylene carbonate is stirred at 180°-200° C. for 10 minutes and at 200°-220° C. for 20 minutes and the mixture is separated by chromatography on silica gel with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 55 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 55%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 3.16-3.21 (m, 4H), 3.75-3.79 (m, 4H), 4.15 (s, 3H), 6.52-6.59 (m, 3H), 7.31 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]=1[CH3:8].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([CH3:24])[C:21]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C:3]3=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]([CH3:8])=[C:2]3[N:1]=[C:2]2[CH:7]([CH3:8])[CH3:6])=[CH:13][CH:14]=1)=[O:25]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(Nc2ccc(CCO)cc2)c(N)c(C)c1Br
Product: Cc1nc2c(nc(C(C)C)n2-c2ccc(CCOC(=O)C(C)C)cc2)c(C)c1Br

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4) and isobutyryl chloride.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[I-].[K+].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.[Ag]=O>[OH:3][CH2:2][CH2:1][O:4][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCO
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
621 mg (corresponding to 10.0 mmol) of ethylene glycol was dissolved in 100 mL of methylene chloride. To this solution under an ice bath, 3.49 g (corresponding to 15.0 mmol) of silver oxide, 350 mg (corresponding to 2.1 mmol) of potassium iodide and 2.10 g (corresponding to 11.0 mmol) of p-toluenesulfonylchloride were added. The resulting mixture was stirred at 0° C. for 2 hours. Insoluble matters were filtered out of the reaction mixture, and were washed with ethyl acetate. The washings were combined with the filtrate, and the mixture was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 643 mg (corresponding to 2.97 mmol) of 2-hydroxyethyl-p-toluenesulfonate (FIG. 1-3, Step 3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([CH3:18])[CH:20]=2)[N:3]=1
Reactant: Cc1cccc(CN)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: Cc1cccc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-methylbenzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][CH2:25][CH2:26][O:27][CH3:28])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: COCCN
Product: COCCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with aminoethylmethyl ether using an analogous method to that described for the equivalent step in Example 1 to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine; 1H NMR Spectrum: (DMSO-d6) 2.15 (brs, 1H); 2.76 (t, 2H); 3.25 (s, 3H); 3.46 (t, 2H); 3.85 (s, 2H); 3.97 (s, 3H); 7.21 (s, 1H); 7.28 (t, 1H); 7.51 (m, 2H); 8.33 (s, 1H); 8.44 (s, 1H); 9.78 (s, 1H); Mass Spectrum: (M+H)+ 391.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[C:28](Cl)(=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:31][CH:30]([CH3:32])[CH2:29][C:28]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=2[C:7]#[N:8])[CH2:16]1)=[O:33]
Reactant: CC(C)CC(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCCNC2)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
To a suspension of (S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 1d, 35.84 g, 120.41 mmol) in DCM (600 mL) cooled to 0° C. in an ice bath was added triethylamine (42 mL, 300.94 mmol) followed by dropwise addition of isovaleryl chloride (2.77 mL, 132.35 mmol). The reaction mixture was stirred under N2 for 30 minutes at 0° C., then at room temperature overnight. The solution was diluted with DCM and successively washed with 10% citric acid, saturated NaHCO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to afford crude (S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile as a golden brown oil (43.26 g). MS 346 (MH+). This material was used without purification in the next step.