Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[CH:14]=[CH:15]\[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2.[Zn](CC)[CH2:20]C.II>C(Cl)Cl.ClCl.[Zn]>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@H:14]3[CH2:20][C@H:15]3[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC[Zn]CC
Reactant: CC1(C)CCC(C)(C)c2cc(/C=C\CO)ccc21
Agent: ClCl
Agent: II
Agent: [Zn]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc([C@H]3C[C@H]3CO)ccc21
Temperature: -22 °C
Reaction time: 0.75 h

Procedure:
1.67 g of of (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-prop-2-en-1-ol were dissolved in 36 ml of CH2Cl2. At 0° C. 7.62 ml of Et2Zn-solution (1M[hexane]) was added, followed 15 min. later by 1.33 ml of L-(+)-diethyl tartrate, dissolved in 18 ml of CH2 Cl2. Stirring was continued for 45 min. The reaction flask was then cooled to -22° C. and another portion of 13.8 ml of Et2 Zn-solution (1M[hexane]) was added, followed by 2.23 ml of CH2 I2. The reaction flask was allowed to reach +18° C. during 16 h. After quenching with crushed ice/NH4CI-solution, the mixture was extracted with EtOEt, washed with dil. HCI and H2O, dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica gel, hexane/AcOEt=87/13) yielded 1.057 g of (1R,2S)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropylmethanol, 99% pure according to GC. The absolute configuration was assigned in analogy to Chemistry Letters 1992, 61, but not rigorously proven; the optical purity was determined at the next stage.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15]>C(O)(=O)C>[Br:1][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:3])=[C:5]([C:14]([OH:16])=[O:15])[CH:6]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc2ccccc2c1O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Bromine (6.1 mL, 120 mmol) was added to a solution of naphthoic acid 17 (18.9 g, 100 mmol) in glacial acetic acid (250 mL). The mixture was stirred at room temperature overnight. The resulting solid was filtered and dried in vacuo to provide the titled compound 18 (24.7 g, 92%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:27])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1NCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of N-benzyl(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (393 mg, 1.14 mmol) in 20 mL of 1,2-dichloroethane was placed in a pressure vessel and heated to 70° C. The rapidly stirred solution was then treated with 5 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (239 mg, 1.25 mmol), the reaction vessel was capped, and heating was continued for 2 h. The reaction mixture was then cooled to ambient temperature and treated with 50 mL of CH2Cl2. The reaction mixture was washed with H2O, 1% Na2CO3 solution (3×), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated. Chromatography (SiO2, 5% MeOH/CHCl3) followed by crystallization from propyl acetate/hexanes gave N-benzyl-2-butyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (237 mg) as light-yellow crystals. mp 159.3–160.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.54 (m, 1H), 7.42–7.31 (m, 6H), 5.44 (s, 2H), 5.26 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 2.71 (t, J=8.4 Hz, 2H), 1.74 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 346 (M+H)+; Anal. Calcd for C21H23N5: C, 73.02; H, 6.71; N, 20.27. Found: C, 72.75; H, 6.55; N, 20.46.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:17][OH:18]>O>[O:1]([CH:8]([CH3:12])[C:9](=[N:17][OH:18])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C(C)Oc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=NO)C(C)Oc1ccccc1

Procedure:
3-Phenoxybutan-2-one (69.6 g.) and ethanol (300 ml.) were added to a solution of hydroxylamine hydrochloride (70 g.) and fused sodium acetate (70 g.) in water (130 ml.). The resulting solution was refluxed for 31/2 hours and evaporated to near dryness under reduced pressure. The residue was partitioned between water and ether. The ether extract was washed with water, dried over anhydrous potassium carbonate and evaporated. The residue was distilled to give a fraction, b.p. 154°-155°/14 mm. which crystallised. Recrystallisation from petroleum ether (b.p. 60°-80°) gave pure 3-phenoxybutan-2-one oxime, m.p. 65°-67°.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27](OC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:45][CH:42]1[CH2:43][CH2:44][N:39]([C:27]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:40][CH2:41]1
Reactant: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1)c1ccccc1

Procedure:
550 mg (1.04 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate were initially charged in 14 ml of DMF, and 315 mg (3.12 mmol) of piperidin-4-ol and 144 mg (1.04 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 430 mg (84% of theory)
Reaction SMILES: C(N(C(C)C)CC)(C)C.CC1C=CN=C(N)C=1C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[CH2:30]([N:37]1[CH2:41][CH:40]([C:42]2[S:43][CH:44]=[C:45]([Br:47])[CH:46]=2)[CH:39]([CH2:48][OH:49])[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:37]1[CH2:41][CH:40]([C:42]2[S:43][CH:44]=[C:45]([Br:47])[CH:46]=2)[CH:39]([CH2:48][O:49][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Agent: Cc1ccnc(N)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CC2c2cc(Br)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Diisopropylethylamine (20.2 g, 0.156 mol), dimethyl aminopyridine (320 mg, 2.6 mmol) and TsCl were (9.88 g, 0.052 mol) were added, respectively, to the product of step b) (9.1 g, 0.026 mol) in 150 mL of dichloromethane at 0° C. The reaction mixture was stirred overnight at room temperature and then was quenched with 75 mL of 1 M HCl and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried with MgSO4 and evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 0-50% methanol-dichloromethane gradient to give the subtitle compound (6.7 g, yield: 51%). MS calculated for C23H24BrNO3S2 +H: 506, observed: 506 and 508.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([OH:42])[CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)=[O:17])=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@@H:4]([OH:42])[C:3]([OH:43])=[O:2])=[O:41])=[CH:13][CH:12]=2)[C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:31][CH:30]=2)[CH:24]=[CH:23][CH:22]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cccc(C(C)(C)C)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cccc(NC(=O)N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
(R)-3-{4-[3-(3-tert-Butylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester (0.11 g, 0.188 mmol) was dissolved in ethanol (4 mL) and sodium hydroxide (4 N, 0.28 mL, 1.128 mmol) was added. The reaction was stirred for 1.5 hour and concentrated in vacuo to remove the ethanol. The residue was diluted with water (10 mL), acidified with hydrochloric acid (4 N, 0.3 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with water (3×10 mL) and dried with magnesium sulphate and concentrated in vacuo to afford the title compound (0.10 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:20][N:21]([CH3:23])[CH3:22])[N:3]=1.[CH3:24][S:25]([O:27][Na])=[O:26]>CN(C=O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[N:3][C:4]([CH2:20][N:21]([CH3:23])[CH3:22])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)O[Na]
Reactant: COc1ccc2c(Cl)nc(CN(C)C)c(-c3ccccc3)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(S(C)(=O)=O)nc(CN(C)C)c(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
A mixture of 1-(1-chloro-6-methoxy-4-phenylisoquinolin-3-yl)-N,N-dimethylmethanamine (75 mg), 1 mL DMF, and MeSO2Na (41 mg) was stirred at 80 C for 48 h, then at 100 C for 96 h. The solution was cooled and purified directly by reverse-phase HPLC to give the titled compound.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][CH2:46][CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: COCCN
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCNC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and 2-methoxyethanamine (212 mg) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the solid was recrystallized from diisopropyl ether/heptane to give the title compound (31 mg).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[N:21]3[CH:22]=[N:23][CH:24]=[C:20]3[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[N:21]3[CH:22]=[N:23][CH:24]=[C:20]3[CH2:19][CH2:18]2)[CH:14]=[CH:15][C:16]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc(C2CCc3cncn32)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CCc3cncn32)cc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a stirred and cooled (-10° C.) amount of 180 parts of sulfuric acid there were added portionwise 24.0 parts of 5-(3-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole mononitrate (described in U.S. Pat. No. 4,617,307). Stirring at 0° to -10° C. was continued for 2 hours. After cooling to -78° C., the mixture was diluted with 100 parts of water and then neutralized with a solution of 141 parts of NaOH in 200 parts of water, keeping the temperature below 28° C. The whole was basified to pH 9 with an excess of Na2CO3 10% and was filtered when reached room temperature. The precipitate was washed with dichloromethane and the filtrate layers were separated. The aqueous layer was diluted with 100 parts of water and the whole was re-extracted with dichloromethane (4×399 parts). The combined dichloromethane layers were washed with NaCl (sat.), dried, filtered and evaporated, yielding 17.1 parts (75.9%) of 5-(3-chloro-4-nitrophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole (interm. 35).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][N:11]([C:14]4[C:15](=[O:28])[NH:16][C:17]5[C:22]([N:23]=4)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=5)[C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.N1C=CC=CC=1.[O:35](S(C(F)(F)F)(=O)=O)[S:36]([C:39]([F:42])([F:41])[F:40])(=O)=[O:37]>ClCCl>[O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][N:11]([C:14]4[C:15]([O:28][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:37])=[O:35])=[N:16][C:17]5[C:22]([N:23]=4)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=5)[C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (140 mg, 0.37 mmol) in dichloromethane (80 ml) was added pyridine (175 mg, 2.21 mmol) and Tf2O (510 mg, 1.81 mmol). The reaction was stirred overnight under atmosphere of nitrogen at room temperature. Then the reaction mixture was quenched with water (200 ml), extracted with dichloromethane (3×20 ml), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-5(6H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a red oil (150 mg, crude), which was used directly in the next step.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)C)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C@:37]12[CH2:46][O:45][C@@H:44]([CH:47]=O)[CH2:43][C@H:42]1[CH2:41][S:40][C:39]([NH:49][C:50](=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[N:38]2>O1CCCC1.C(OCC)(=O)C>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C@:37]12[CH2:46][O:45][C@@H:44]([CH:47]=[C:2]([CH3:3])[CH3:1])[CH2:43][C@H:42]1[CH2:41][S:40][C:39]([NH:49][C:50](=[O:57])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[N:38]2
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.90 mL, 2.25 mmol) was added drop-wise to a suspension of triphenyl(propan-2-yl)phosphonium iodide (1.08 g, 2.50 mmol) in tetrahydrofuran (10 mL) at 0° C. The resulting solution was stirred and allowed to warm to room temperature for 30 minutes, whereupon it was cooled to 0° C. A solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C23) (104 mg, 0.250 mmol) in tetrahydrofuran (1 mL) was added, and stirring was continued at 0° C. for 1 hour, then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (3×20 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) provided the product as a white solid. Yield: 42 mg, 95 μmol, 38%. LCMS m/z 443.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 11.8 (v br s, 1H), 8.24 (d, J=7.4 Hz, 2H), 7.38-7.55 (m, 4H), 6.85-6.97 (m, 2H), 5.27 (d, J=8 Hz, 1H), 4.31-4.40 (m, 1H), 4.19 (d, J=12.1 Hz, 1H), 3.80 (d, J=12.1 Hz, 1H), 3.13-3.22 (m, 1H), 2.98-3.06 (m, 1H), 2.59-2.68 (m, 1H), 2.00-2.13 (m, 1H), 1.75 (s, 6H), 1.59-1.67 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[S:10]1[C:14]([CH:15]=O)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2>>[S:10]1[C:14]([CH2:15][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=2)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: Cc1cc(Br)cc(Br)c1
Product: Cc1cc(Br)cc(Cc2cc3ccccc3s2)c1

Procedure:
3,5-Dibromotoluene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13]COC)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[CH:23]=CC=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1.C(C1[S:31]C=C(C(O)=O)N=1)(C)C.NC1C(Cl)=C(OC)C=CC=1C(=O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[N:19]=[C:20]([CH:24]([CH3:26])[CH3:25])[S:31][CH:23]=2)[CH:3]=1
Reactant: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: COc1ccc(C(C)=O)c(N)c1Cl
Product: COc1ccc2c(Cl)cc(-c3csc(C(C)C)n3)nc2c1Cl

Procedure:
4,8-Dichloro-2-(2-isopropyl-thiazol-4-yl)-7-methoxy-quinoline was prepared in a similar fashion as 4,8-dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline except that 2-isopropyl-thiazole-4-carboxylic acid was used instead of 6-isopropyl-pyridine-2-carboxylic acid and 1-(2-Amino-3-chloro-4-methoxy-phenyl)-ethanone was used instead of 1-[2-amino-3-chloro-4-(2-methoxy-ethoxy)-phenyl]-ethanone
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)CCO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][O:7][C:5](=[O:6])[CH2:4][C:3]([CH2:2][Cl:1])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Product: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1

Procedure:
3.2 ml (23.7 mmol) of ethyl 4-chloroacetoacetate and 5.00 g (23.6 mmol) of 3,3-diphenyl-1-propanol were heated at 130° C. in 100 ml of toluene overnight. Toluene was distilled out under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:30]([F:33])([F:32])[F:31])=[N:20][N:21]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:30]([F:32])([F:31])[F:33])=[N:20][N:21]([C:24]([CH3:29])([CH3:28])[C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propanoic acid (0.037 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.053 mmol, 39%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=0.6 Hz, 1H), 7.33-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.61 (s, 1H), 2.92 (m, 1H), 2.37 (s, 3H), 1.97 (s, 6H), 1.03 (d, J=7.1 Hz, 6H); MS: (ES) m/z calculated for C21H22ClF4N5O [M+H]+ 472.1, found 471.9.
Reaction SMILES: BrC1C=CC=CC=1C(F)(F)F.CCCCCC.C([Li])CCC.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C:34]([NH:36][CH3:37])=[O:35])[CH:28]=[CH:27]2.[CH:38]1[N:42]=[CH:41][N:40]2[CH2:43][CH2:44][C:45](=[O:46])[C:39]=12.[Cl-].[NH4+]>C1COCC1>[OH:46][C:45]1([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[C:29]([C:34]([NH:36][CH3:37])=[O:35])[CH:28]=[CH:27]3)[C:39]2[N:40]([CH:41]=[N:42][CH:38]=2)[CH2:43][CH2:44]1
Reactant: O=C1CCn2cncc21
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Agent: FC(F)(F)c1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: -65 °C
Yield: 44.6 %

Procedure:
Under an argon atmosphere, 2-bromobenzotrifluoride (33.05 g) was dissolved in dry THF (600 ml), and the mixture was cooled to −65° C. in a dry ice-acetone bath. An n-butyl lithium hexane solution (1.6M: 93.7 ml) was added with stirring and the mixture was stirred at the same temperature for 30 min. After stirring the mixture, a dry THF (2.88L) solution of 6-bromo-N-methyl-2-naphthamide (38.03 g) cooled to 10° C. was added at not more than −55° C. The mixture was stirred for 20 min. An n-butyl lithium hexane solution (1.6M: 94.5 ml) was added at not more than −65° C. The mixture was stirred for 30 min and 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (14.66 g) in a dry THF solution (240 ml) was added dropwise. The mixture was stirred at the same temperature for 1.5 h and saturated aqueous ammonium chloride solution (520 ml) was added to stop the reaction. The solvent was evaporated under reduced pressure and an ethanol-soluble material was extracted from the resulting residue and the solvent was evaporated again. The resulting residue was purified by flash silica gel column chromatography (eluent; chloroform/methanol containing ammonia (7%); 19/1→9/1). The eluate was recrystallized from methanol to give the title compound (16.44 g) as colorless crystals. The physical and chemical data were identical with those of the compound obtained in Example 5.