Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]([CH2:26][O:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])=[C:24]3[C:19]([NH:20][C:21]([CH3:39])([CH3:38])[C:22](=[O:37])[N:23]3[CH3:36])=[CH:18][CH:17]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=O)C1C=CC=CC=1.O.Cl>CO.O1CCCC1.[OH-].[Na+]>[F:34][C:32]1[CH:31]=[CH:30][C:29]([CH3:35])=[C:28]([CH:33]=1)[O:27][CH2:26][C:25]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]=2[O:40][CH3:41])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]([CH3:36])[C:22](=[O:37])[C:21]([CH3:39])([CH3:38])[NH:20]2
Reactant: COc1cc(OC(=O)c2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85 %

Procedure:
7-(4-Benzoyloxy-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 6-31, 422 mg, 0.761 mmol) was dissolved in mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 4N aqueous sodium hydroxide solution (0.761 mL, 3.04 mmoL) was added thereto. After the reaction mixture was stirred at room temperature for 40 minutes, water (100 mL) and 1N aqueous HCl solution (4 mL) were added thereto. After the mixture was extracted with ethyl acetate mL), the organic layer was washed with water mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with a mixed solvent of hexane (10 mL) and ethyl acetate (10 mL) to give the titled compound (292 mg) as a colorless solid. (Yield 85%)
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:42][CH2:41][CH2:40][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][CH:30]4[C:36](OC)=[O:37])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:42][CH2:41][CH2:40][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][C@@H:30]4[C:36]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:37])[N:28]=3)[CH:18]=2)[CH2:15][CH2:16]1
Reactant: COC(=O)C1C[C@@H](OC)CN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(F)nc2)N(c2nc3c(c(Nc4cc(C5CC5)[nH]n4)n2)CCC3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-fluoropyridin-3-amine (1.2 g, 11.30 mmol) in dry THF (20 mL) was added 2M solution of isopropylmagnesium chloride in THF (9.4 mL, 18.8 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of (4R)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate (3 g, 7.53 mmol) in THF (10 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT overnight. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×100 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded a diastereomeric mixture of Compound 21. The diastereomers were separated by reverse phase followed by chiral HPLC to afford (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide (Compound No. 21a, 208 mg) and (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide (Compound No. 21b, 193 mg). Compound No. 21a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 2.70-2.81 (m, 1H), 3.90-4.02 (m, 1H), 4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H). Compound No. 21b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 3.80-4.01 (m, 2H), 4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]2=3)[CH2:4][CH2:3]1.C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C.O>[Br:26][C:16]1[CH:17]=[CH:18][C:9]2[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(N2CCCCc3ccccc32)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(N2CCCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of compound 3 (0.73 g, 2.99 mmol) in DMF (5 mL) was treated with a solution of NBS (0.53 g, 2.99 mmol) in DMF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and stored at 0° C. overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated. The product was filtered through a short plug of silica gel (2.0 N NH3 in MeOH:CH2Cl2, 2.5:97.5) to give compound 4 (0.915 g, 95.3%) as a yellow oil. 1H-NMR (DMSO-d6) δ 1.56 (m, 4H), 1.72 (m, 4H), 1.96 (td, 2H, J=10.9, 2.2 Hz), 2.15 (s, 3H), 2.65 (m, 2H), 2.76 (m, 2H), 2.93 (m, 2H), 3.14 (m, 1H), 6.83 (d, 1H, J=8.5 Hz), 7.19 (td, 2H, J=8.6, 2.4 Hz); EI-MS (m/z, %) 324 (M+, 14) 322 (M+, 14), 98 (25), 97 (100), 96 (25), 71 (38).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[CH2:6][N:5]=[C:4]2[S:9][CH:10]=[CH:11][C:3]=12.[Cl:12][C:13]1[CH:22]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:20]=[C:19]([CH3:26])[C:14]=1[O:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:20]=[C:19]([CH3:26])[C:14]=1[O:15][CH2:16][CH2:17][NH:18][C:2]1[N:7]([CH3:8])[CH2:6][N:5]=[C:4]2[S:9][CH:10]=[CH:11][C:3]=12
Reactant: CCCc1cc(C)c(OCCN)c(Cl)c1
Reactant: CN1CN=c2sccc2=C1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCc1cc(C)c(OCCNC2=c3ccsc3=NCN2C)c(Cl)c1
Yield: 59.5 %

Procedure:
3.7 g (0.02 mole) of 4-chloro-3-methylthieno[2,3-d]pyrimidine, 4.6 g (0.02 mole) of 2-(2-chloro-6-methyl-4-propylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of benzene, and the solution was heated under reflux for 6 hours. At the end of this time, the solvent was distilled off and the residue was washed with water and dried in air. It was then recrystallised from a mixture of benzene and hexane, to give 4.5 g (yield 60%) of the desired Compound No. 19 in the form of colourless needles melting at 66°-68° C.
Reaction SMILES: [CH3:1][OH:2].[CH2:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH3:1][OH:2].[C:3]1([CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:1][CH2:3][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C1CCCCC1
Solvent: CO
Product: CCCCCCC
Product: Cc1ccccc1

Procedure:
The so formed crystalline MeOH solvate Ig may be used in place of compound B in the preparation of crystalline compound Ia as described in Example 6.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl.CCOC(C)=O>[OH:12][C:11]1[C:2]([O:1][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1cc(-c2ccccc2)c2ccc(O)c(O)c2o1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(O)c2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To 7,8-dihydroxy-4-phenyl-2H-chromen-2-one (500 mg, 2 mmol) and 3,4-dihydro-2H-pyran in 4 mL THF and 4 mL DCM was added pyridinium paratoluene sulfonate (PPTS, 8 mg). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with NaHCO3 (sat. 30 mL) and water (50 mL) and dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed (hexane/EtOAc) to afford 8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one as a yellow solid (180 mg, 26%). MS (ESI) m/z 339 (M+H+).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([NH2:12])=[S:1])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: S
Reactant: Cc1ccc(CC#N)cc1C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CC(N)=S)cc1C

Procedure:
The 3,4-dimethylphenyl(thioacetamide) was prepared by passing a slow stream of hydrogen sulphide through a solution of 3,4-dimethylphenylacetonitrile (56.6 g.) in pyridine (60 ml.) and triethylamine (39.4 g.) during 12 hours. The reaction mixture was evaporated under reduced pressure and the residue was recrystallised from a mixture of benzene and light petroleum (b.p. 60°-80°) to give 3,4-dimethylphenyl (thioacetamide), m.p. 91°-94°.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=1.[Cl-:30].[NH4+]>BrC(Br)C.CCOCC.O.O1CCCC1>[ClH:30].[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][C:24]([OH:27])([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:9])[CH2:25][CH2:26]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: [Cl-]
Reactant: Cc1ccccc1Br
Agent: CC(Br)Br
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C1(O)CCN(CCCc2noc3cc(F)ccc23)CC1
Product: Cl
Reaction time: 1 h

Procedure:
To a suspension of 0.9 g of magnesium shavings and a few drops of dibromoethane in 30 ml of ether was added a solution of 6.2 g of 2-bromotoluene in 30 ml of water. After the addition was complete, the mixture was stirred under reflux for one hr, cooled, and a solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was added. After one hr, the mixture was diluted with ether, poured into 400 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to 6.4 g (82%) of product by treatment with ethereal hydrogen chloride. Recrystallization from ethyl acetate/methanol gave the analytical sample, mp 191°-192° C. (dec).
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.[C:22](Cl)(Cl)=[O:23].C1(C)C=CC=CC=1.[CH:33]([N:36]([CH:39]([CH3:41])C)CC)([CH3:35])C.N1CCCC1>C(Cl)Cl.[NH4+].[OH-]>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:22]([N:36]2[CH2:33][CH2:35][CH2:41][CH2:39]2)=[O:23])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCC2)s1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 22C (290 mg, 0.90 mmol) in CH2Cl2 (4.0 mL, 0.2 M) was added dropwise over 17 minutes to a −78° C. solution of 20% phosgene/toluene (630 μL, 1.2 mmol) in CH2Cl2 (5.0 mL, 0.2M). The mixture was stirred cold for 10 minutes after which diisopropylethylamine (140 μL, 0.80 mmol) was added dropwise over 3 minutes. The mixture was stirred cold for 45 minutes and allowed to warm to −20° C. over 1 hour; then allowed to warm to ambient temperature. After 1 hour at ambient temperature, pyrrolidine (135 μL, 1.6 mmol) was added and the mixture was stirred for 16 hours. To the solution was added more pyrrolidine (90 μL, 1.1 mmol), the mixture was stirred for 20 minutes, diluted with concentrated aqueous NH4OH (2 mL) and stirred for 5 minutes. The aqueous phase was separated and extracted with CH2Cl2 (3×). The combined organic phases were dried with Na2SO4, concentrated under reduced pressure, and chromatographed on Alltech silica eluting with 0-10% Et2O in 1:1 CH2Cl2/hexanes to provide the titled compound. 1H NMR (CD2Cl2) δ ppm 1.83 (m, 4H), 2.24 (d, 3H), 3.36 (m, 2H), 3.40 (m, 2H), 6.66 (d, 1 H), 7.25 (d, 1 H), 7.42 (dd, 1H), 7.54 (d, 1H); MS (ESI) 418 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1.[CH2:13]([SH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:13]([S:19][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Brc1conc1-c1cccnc1
Reactant: CCCCCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCSc1conc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a degassed solution of dioxane (30 ml) containing 64 (0.6 g, 2.66 mmol) (see Scheme 12), were added 1.2 eq (0.62 ml) of hexane-1-thiol and 2 eq of triethylamine (0.92 ml). The resulting mixture was stirred for another 2 hours under N2. Successively were added 2.5 mol % of Pd2(dba)3 (61 mg) and 5 mol % Xantphos (77 mg). After the addition, the resulting solution was stirred for 18 hours at 95° C. under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to afford 3-(4-Hexylsulfanyl-isoxazol-3-yl)-pyridine (65B) as an oil (0.25 g, 37%). 1H-NMR (400 MHz, CDCl3): δ 9.24 (d, J=2 Hz, 1H), 8.73 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J=7 Hz, 2H), 1.52-1.43 (m, 2H), 1.35-1.13 (m, 6H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:21])([C@H:15](S(C)(=O)=O)[CH3:16])[CH2:10]S(C)(=O)=O.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]1([CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C@H:15]([CH3:16])[O:21]1
Reactant: c1nc[nH]n1
Reactant: C[C@H]([C@](O)(CS(C)(=O)=O)c1cc(F)ccc1F)S(C)(=O)=O
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Yield: 56 %

Procedure:
In the same manner as that described in Example 7(iv) above, 7.00 g (18.7 mmol) of (2R,3R)-2-(2,5-difluorophenyl)-1,3-bis(methanesulfonyl)-2-butanol [prepared as described in Step 8(iii) above] were reacted with 1H-1,2,4-triazole and the reaction product was purified by chromatography on a silica gel (100 g) column using a 1:1 to 3:2 mixture of ethyl acetate and hexane as the eluant to afford 2.65 g (yield 56%) of the title compound as an oil.
Reaction SMILES: C(O)C.FC(F)(F)S(O[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccccc2F)CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethanol (100 mL) was added to a solution of ethyl 2-trifluoromethanesulfonyloxycyclohex-1-enecarboxylate obtained in Preparation Example 1-(1) (17.0 g) in toluene (200 mL). 2-Fluorophenylboronic acid (7.74 g) and tetrakis(triphenylphosphine)palladium (1.60 g) were added. A 1 N sodium carbonate solution (55.3 mL) was added, followed by replacement of the reaction atmosphere with nitrogen. The reaction solution was heated to 80° C. and stirred for eight hours. After returning to room temperature, the excess of ethanol was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].C1(C)C(C)=CC=CC=1.C[Sn]([N:23]=[N+:24]=[N-:25])(C)C>CO>[Cl:10][C:3]1[CH:4]=[C:5]([C:6]2[NH:25][N:24]=[N:23][N:7]=2)[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(N)c(Cl)c1
Solvent: Cc1ccccc1C
Solvent: CO
Product: Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 135 °C
Reaction time: 8 h

Procedure:
The mixture consisting of 1.07 g of 4-amino-3-chlorobenzonitrile, 30 ml of xylene and 1.7 g of trimethyltin azide was stirred at 135° C. for 8 hours. After cooling, 25 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and the volatile constituents were removed on a rotary evaporator. On stirring, a solid precipitated out of the mixture obtained in this way, and was filtered off with suction and briefly dried under reduced pressure. This solid was dissolved in 1N sodium hydroxide solution and filtered, and the product was precipitated by acidifying with 2N hydrochloric acid, filtered off with suction and dried under reduced pressure.
Reaction SMILES: [C:1]([C:8]1[C:17](=O)[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[Cl:28][C:17]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)c1cnc2c(OC)cccc2c1Cl

Procedure:
3-hexanoyl-8-methoxy-4(1H)-quinolone (4.6 g, 0.017 mol) was heated under reflux in a mixture of phosphorus oxychloride (8 ml) and chloroform (50 ml) for 1.5 hours. When cool, the mixture was poured into a vigorously stirred mixture of sodium hydrogen carbonate solution, ice and chloroform. The layers were separated and the organic solution was washed with sodium hydrogen carbonate solution and brine. Evaporation of the chloroform solution afforded 4-chloro-3-hexanoyl-8- methoxyquinoline as a yellow-brown oil (5 g).
Reaction SMILES: II.C([O:5][CH:6](OCC)[CH:7]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[O:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:32])C>CC(C)=O>[OH:5][CH:6]=[C:7]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[O:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:32]
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OCc1ccccc1)CC2
Agent: II
Solvent: CC(C)=O
Product: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Temperature: 35 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Iodine (2.88 g, 11.4 mmol) was slowly added to a solution of benzyl 3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (20.6 g, 45.4 mmol) in acetone (515 mL) and the mixture was stirred at 35° C. overnight. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-40% ethyl acetate in hexane) to afford benzyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (15.2 g, 88%). ESI-MS m/z calc. 379.1, found 380.3 (M+1)+; Retention time: 2.00 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].Br.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36](=[O:51])[N:37]([CH:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[C:38](=[O:44])[N:39]2[CH2:42][CH3:43])=[CH:34][C:33]=1[N+:52]([O-:54])=[O:53].Cl[C:56]1[C:65]2[C:60](=[CH:61][C:62]([O:68][CH3:69])=[C:63]([O:66][CH3:67])[CH:64]=2)[N:59]=[CH:58][N:57]=1.C(N(CC)CC)C>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36](=[O:51])[N:37]([CH:45]3[CH2:50][CH2:49][N:48]([C:56]4[C:65]5[C:60](=[CH:61][C:62]([O:68][CH3:69])=[C:63]([O:66][CH3:67])[CH:64]=5)[N:59]=[CH:58][N:57]=4)[CH2:47][CH2:46]3)[C:38](=[O:44])[N:39]2[CH2:42][CH3:43])=[CH:34][C:33]=1[N+:52]([O-:54])=[O:53]
Reactant: CCn1c(=O)n(C2CCNCC2)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Br
Agent: CCOC(=O)N1CCC(n2c(=O)c3cc([N+](=O)[O-])c(Cl)cc3n(CC)c2=O)CC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 200.0 mg (0.47 mmol) of 7-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound t) was used in place of Compound a, whereby 150.6 mg of crude 7-chloro-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide was obtained. The product (145.0 mg, 0.31 mmol) was suspended in 10 ml of methanol, and 70 mg (0.31 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 0.11 ml (0.78 mmol) of triethylamine were added thereto, followed by heating under reflux for 1 hour. After the reaction mixture was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration, washed successively with water, methanol, and ether, and dried. Recrystallization of the resulting crude crystals from methanol/water gave 144.6 mg (yield from Compound t: 60%) of Compound 36 as pale yellow crystals.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: COC(=O)c1ccccc1S
Reactant: CCSc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 14 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-ethylthiopyridine (1.02 g, 6.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give precipitated crystals, which were recrystallized from ethanol to give the titled compound (0.26 g, 14%).