Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].O1CCCC1.B>C1COCC1.Cl>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:12])[C:8]([F:10])([F:11])[F:9]
Reactant: O=C(c1ccccc1-c1ccccc1)C(F)(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 1-biphenyl-2-yl-2,2,2-trifluoro-ethanone (300 mg, 1.2 mmol), borane tetrahydrofuran complexes (1.2 ml, 1M in THF, 1.2 mmol) and S-2-methyl-CBS-oxazaborolidine (0.24 ml, 1M in toluene, 0.24 mmol) in THF (8 ml) was stirred at room temperature over night. Several drops of concentrated HCl were added and the mixture was stirred for 30 minutes. The product was purified by SiO2 chromatography (hexane/ethyl acetate=100/0 to 3/1) to give 290 mg of 1-biphenyl-2-yl-2,2,2-trifluoro-ethanol (96% yield).
Reaction SMILES: Cl.BrCCC[NH2:6].C(N(CC)CC)C.Cl[S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])(=[O:17])=[O:16]>ClCCl>[OH:16][S:15]1([OH:17])[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](=[O:21])[NH:6]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: NCCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NS(O)(O)c2ccccc21
Temperature: 25 °C
Reaction time: 66 h
Yield: 33.3 %

Procedure:
3-Bromopropylamine hydrochloride (2.189 g, 10 mmol) was suspended in 15 ml of dry dichloromethane, and to the suspension were added triethylamine (7 ml, 50 mmol) and methyl 2(chlorosulfonyl)benzoate (2.738 g, 10.5 mmol). The mixture was stirred at room temperature for 66 hours, poured into ice water, extracted with dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel to give 617 mg of 1,1-Dihydroxy-3-oxo-3H-benzo[d]isothiazole (20%). The isothiazole was etherified with Deg. B-Bh-Ester by the NaH/DMF method described above, and the compound was subjected to deprotection to remove the Bh group by the TFA/Anisole method described above, providing 309 mg of the desired compound 120 (97%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]12[CH2:41][CH2:40][CH2:39][C:37]3[C:38]1=[C:33]([CH:34]=[CH:35][CH:36]=3)[NH:32][C:31]2=[O:42].C(=O)([O-])[O-].[K+].[K+].O>CO.Cl.CN(C)C=O>[CH:24]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]45[CH2:41][CH2:40][CH2:39][C:37]6[C:38]4=[C:33]([CH:34]=[CH:35][CH:36]=6)[NH:32][C:31]5=[O:42])[CH2:13][CH2:12]3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCCCc3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2cccc3c2C1(CCCCN1CCN(C2CCCCc4ccccc42)CC1)CCC3
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
1-t-Butoxycarbonyl-4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)piperazine (340 mg, 1.0 mmol) was dissolved in 10% hydrochloric acid methanol (4 ml) and stirred at 40° C. for 3.5 hours. The solvent was removed by evaporation under a reduced pressure, and the thus obtained residue was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (310 mg, 1.0 mmol) and potassium carbonate (490 mg, 3.5 mmol) and stirred overnight at room temperature in N,N-dimethylformamide (3 ml). This was mixed with water, the precipitate was collected by filtration and then the reaction product was extracted from the mother liquid with ethyl acetate. The extract was washed with water and saturated brine and dried with anhydrous sodium hydrogensulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography. The thus purified compound was combined with the aforementioned precipitate and thoroughly washed with ethyl acetate to obtain 370 mg (0.81 mmol, 80%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([N+:11]([O-])=O)[CH:10]=1)(=[O:4])=[O:3].NC1C=CC=CC=1.[N-]=[C:23]=[O:24]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([N:11]=[C:23]=[O:24])[CH:10]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: [N-]=C=O
Solvent: Nc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)cc1N=C=O

Procedure:
5-Methylsulfonyl-2-methylphenyl isocyanate was prepared from the corresponding 5-methylsulfonyl-2-methyl-1-nitrobenzene via reduction to the corresponding aniline followed by conversion to the isocyanate as described previously.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Methyltriphenylphosphonium bromide (11.7 g, 32.7 mmol) was suspended in tetrahydrofuran (50 mL), and the suspension was cooled to 0° C. Potassium tert-butoxide (3.61 g, 37.6 mmol) was added, and the mixture was stirred for 1 hr. To the mixture was added dropwise a solution (25 mL) of tert-butyl 4-oxopiperidine-1-carboxylate (5.02 g, 25.2 mmol) in tetrahydrofuran, and the mixture was stirred for 2.5 hr with warming to room temperature. To the reaction mixture was added aqueous ammonium chloride solution (100 mL), and the mixture was extracted with a mixture of diethyl ether/ethyl acetate=1/1 (200 mL×2). The organic layers were combined, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to give the title compound (4.71 g, 95%) as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[O:64]1[C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=[N:65]1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][N:51]([C:69]([C:68]5[O:64][N:65]=[CH:66][CH:67]=5)=[O:70])[CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.3 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and isoxazole-5-carboxylic acid (0.110 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine as a white solid (0.045 g). 1H NMR Spectrum: (DMSO d6 373K) 1.86 (m, 2H), 2.10 (m, 2H), 3.59 (m, 2H), 3.88 (m, 2H), 3.98 (s, 3H), 4.92 (m, 1H), 6.87 (s, 1H), 7.26 (m, 1H), 7.38 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 8.62 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 498.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:29])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.0 g) in N,N-dimethylformamide (10 ml) were added potassium tert-butoxide (0.38 g) and methyl iodide (0.33 ml) and the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture were added additional potassium tert-butoxide (0.38 g) and methyl iodide (0.17 ml) and the mixtures was stirred at ambient temperature for more 2 hours. The mixture was poured into water (100 ml) and the resulting precipitates were collected by filtration. The precipitate was recrystallized from a mixture of methanol and water (5:1) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.83 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4](CC2C=CC(OC)=CC=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:53][C:54]1([CH3:61])[O:58][C@H:57]([CH2:59][OH:60])[CH2:56][O:55]1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:53][C:54]1([CH3:61])[O:58][C@H:57]([CH2:59][O:60][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:9]=3[N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[NH:4][N:3]=2)[CH2:56][O:55]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H]4COC(C)(C)O4)c23)CC1
Yield: 114.5 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.15 g, 0.24 mmol, see Example 9), Cu(I)I (0.046 g, 0.24 mmol), 1,10-phenanthroline (0.043 g, 0.24 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.95 g, 7.2 mmol) and KF on Al2O3 (40%; 0.24 g, 1.68 mmol) in toluene (4 mL) was stirred at 110° C. for 60 hours. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The reaction was then concentrated to dryness, and the residue was purified by column chromatography (hexane:ethyl acetate=1:1) to give (R)-tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.14 g, 93%) as a solid. MS APCI (+) m/z 630.2 detected.
Reaction SMILES: [CH2:1]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:13][O:14]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 10 (40.5 g, 0.2 mol), 4-bromobenzaldehyde (37 g, 0.2 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30](=[O:48])[NH:31][C:32]3[CH:33]=[N:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)=[N:36][CH:37]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30](=[O:48])[NH:31][C:32]3[CH:37]=[N:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:45])[F:46])[CH:39]=4)=[N:34][CH:33]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To methyl 3-(3-((4-(piperidin-1-yl)-2-((2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)carbamoyl)phenyl)carbamoyl)-benzylthio)propanoate (280 mg, 0.41 mmol, 1.00 equiv) in tetrahydrofuran (8 mL) was added LiOH H2O (500 mg, 11.90 mmol, 25.00 equiv) in water (2 mL) and the resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solution was adjusted to pH 5-6 with hydrochloric acid and then extracted with 2×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum until about 5 mL remained. The product was then precipitated with petroleum ether and the resulting solids were collected by filtration and washed with ether. This resulted in 0.22 g (80%) of product as a yellow to green solid. 1H-NMR (400 MHz, DMSO, ppm): δ 12.24 (s, 1H), 10.92 (s, 1H), 10.91 (s, 1H), 9.27 (s, 2H), 8.64 (m, 2H), 68.06 (d, 1H), 7.89 (d, 2H), 7.75-7.80 (m, 2H), 7.47-7.53 (m, 2H), 7.39 (s, 1H), 7.25 (d, 1H), 3.83 (s, 2H) 3.24 (m, 4H), 2.58 (t, 2H), 1.67 (m, 4H). 1.58 (m, 2H). MS (ES, m/z): 664 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=2)[CH:10]=1.[NH2:19][C@@H:20]([CH3:37])[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:34]=[C:33]([F:35])[C:30]([C:31]#[N:32])=[C:29]([Cl:36])[CH:28]=2)=[N:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:36][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][N:22]([CH2:21][C@@H:20]([NH:19][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([NH:4][C:3]([N:2]([CH3:1])[CH3:18])=[O:17])=[CH:10][N:9]4[CH:11]=3)=[O:16])[CH3:37])[N:23]=2)[CH:34]=[C:33]([F:35])[C:30]=1[C:31]#[N:32]
Reactant: CN(C)C(=O)Nc1ccc2nc(C(=O)O)cn2c1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc(NC(=O)N(C)C)ccc2n1
Yield: 34.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylic acid (0.270 mmol, 0.067 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.108 mmol, 0.04 g) using DMF (4 ml) as the solvent. HBTU (0.027 mmol, 10.24 mg) was used instead of HOBt. The product precipitated into the water phase and was separated by filtration. The organic phase also contained the product. The organic phase was dried, filtered and evaporated. The combined precipitates were purified by preparative HPLC. 0.0192 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, 3H), 2.95 (s, 6H), 4.30-4.54 (m, 3H), 7.01 (d, 1H), 7.40-7.45 (m, 1H), 7.47-7.52 (m, 1H), 7.87 (d, 1H), 7.93 (dd, 1H), 7.97 (s, 1H), 8.30 (s, 1H), 8.39 (bs, 1H), 8.49 (d, 1H), 8.87-8.91 (m, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:19])[C:17]=3[CH2:18][C@H:9]2[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[C:41]([O:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][C@H:9]1[CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:37])[CH3:38])[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:10]1[CH2:11]2)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(OC(=O)c4ccccc4)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
2 g (3.58 mmole, from Example 18) of (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethyl-silyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-ol, which contains 6% para-cyclized isomer, in dry tetrahydrofuran (20 ml) was treated with sodium hydride (0.29 g, 7.16 mol) at 0° C. and stirred for 10 minutes at room temperature, followed by dropwise addition of benzoyl chloride (0.63 ml, 5.37 mmol). After 30 minutes, the reaction was cooled to 10° C., diluted with ice cold brine (10 ml) and extracted with ethyl acetate (10 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. 2.1 g of (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyl dimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl benzoate was obtained. The product was then dissolved in tetrahydrofuran (4.2 ml), and treated with acetic acid (12.6 ml) and distilled water (4.2 ml) overnight at room temperature. The reaction then was diluted with saturated sodium bicarbonate aqueous (50 ml) and extracted with ethyl acetate (60 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The product was obtained in a crystalline form. MP:140˜141° C. Yield: 68%.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][CH:38]=[C:39]([C:45](OCC)=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CCCCCC>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[C:29]2[C:28]=1[NH:37][CH:38]=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:45]2=[O:46]
Reactant: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Yield: 65.3 %

Procedure:
6 mL of Dowtherm was added to a long-neck 25 mL flask, fitted with a reflux condenser. The Dowtherm was heated to 200° C. and degassed for 20 minutes. Diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate (1 g, 2.73 mmol) was then added and the solution was then heated to reflux for 2.5 h under N2. The reaction mixture was cooled after 2.5 h, then diluted with hexane (12 mL) to produce a fine, light brown precipitate. The reaction mixture was filtered, and the precipitate washed with hexane until the color was removed. The product was air dried to obtain ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate as a light brown solid (0.57 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1ccc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2c1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2c1
Yield: 80.9 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (42 mg, 0.084 mmol) was reacted to give the title compound (27 mg, 82%). LCMS (Method E): RT=3.70 min, [M+H]+=399. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, J=8.7 Hz, 1H), 7.44-7.25 (m, 9H), 7.09-7.04 (m, 2H), 7.83 (s, 3H), 2.35-2.26 (m, 2H), 2.17 (bs, 2H), 2.06-1.87 (m, 3H), 1.64-1.53 (m, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12](F)=[C:13]([C:15](=[O:30])/[CH:16]=[C:17](/[NH:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([Br:27])=[CH:22][C:21]=2[O:28][CH3:29])\[CH3:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:19]([C:20]1[CH:25]=[C:24]([F:26])[C:23]([Br:27])=[CH:22][C:21]=1[O:28][CH3:29])[C:17]([CH3:18])=[CH:16][C:15]2=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)c(F)cc1N/C(C)=C/C(=O)c1cc(SCc2ccccc2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Br)c(F)cc1-n1c(C)cc(=O)c2cc(SCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of (E)-1-(5-(benzylthio)-2-fluorophenyl)-3-((4-bromo-5-fluoro-2-methoxyphenyl)amino)but-2-en-1-one (3.7 g, 7.34 mmol) in dimethyl sulfoxide (20 mL) was added potassium carbonate (2.028 g, 14.67 mmol), and the reaction was stirred at 80° C. After 2 hours, the reaction mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic layer was concentrated and purified by column chromatography, eluting with 20-60% (3:1 ethanol/ethyl acetate) in heptane, to provide 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-methylquinolin-4(1H)-one (2.2 g, 4.54 mmol, 61.9% yield) as an off-white solid. LC/MS (ESI+): m/z (ESI) 484.0, 486.0 (M+H; two bromine isotopes).