Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH3:26]>>[CH2:35]([O:34][C:33]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:30]=[CH:29][C:28]=1[O:27][CH2:25][CH3:26])[CH3:36]
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC)nc2C)c(=O)n4C)cc1OCC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 49 mg, 0.126 mmol) and 2-(3,4-diethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (stage 27.1.1, 47 mg, 0.161 mmol) to give the title compound as an off-white solid. (HPLC: tR 3.02 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.18 (s, 1H), 8.08-8.02 (m, 1H), 7.95-7.84 (m, 1H), 7.52-7.48 (m, 1H), 7.06-6.97 (m, 3H), 4.22-3.98 (m, 6H), 3.58 (s, 3H), 1.97 (s, 3H) 1.45-1.25 (m, 9H))
Reaction SMILES: C([O:8][C:9](=[O:20])[C:10]([CH3:19])([CH3:18])[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:18][C:10]([CH3:19])([CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:9]([OH:20])=[O:8]
Reactant: CC(C)(CN1CCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CN1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl-2,2-dimethyl-3-piperidin-1-ylpropanoate (117.0 mg, 0.42 mmol) in ethanol (5 mL) was slowly added 10% wt Palladium in carbon (50 mg, 0.05 mmol). The reaction mixture was left to stir at rt for 1 h under hydrogen. The mixture was filtered through Celite and concentrated in vacuo, which afforded the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.22 (s, 6H), 1.28-1.39 (bs, 2H), 1.74-1.79 (m, 4H), 2.76 (s, 2H), 2.79-3.08 (bs, 4H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C:12]1[C:20]2[O:19][C:18]([S:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]([NH:33][C:34]4[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=4[CH:43]([CH3:45])[CH3:44])=[O:32])[CH2:26][CH2:25]3)=[N:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10]>CN(C=O)C>[CH3:3][N:4]([CH3:6])[CH:5]=[CH:10][C:9]([C:12]1[C:20]2[O:19][C:18]([S:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([NH:33][C:34]4[C:35]([CH:43]([CH3:45])[CH3:44])=[CH:36][CH:37]=[CH:38][C:39]=4[CH:40]([CH3:41])[CH3:42])=[O:32])[CH2:28][CH2:29]3)=[N:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc2nc(SCCN3CCN(CC(=O)Nc4c(C(C)C)cccc4C(C)C)CC3)oc12
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3cccc(C(=O)C=CN(C)C)c3o2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 106 %

Procedure:
Dimethylformamide dimethylacetal (146 mg, 1.2 mmol) was dropped into a solution of 2-[4-[2-(7-acetylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropylphenyl)acetamide (214 mg, 0.4 mmol) in DMF (15 ml), followed by stirring at 80° C. for 4 hours. The reaction solution was allowed to cool and extracted with ethyl acetate. The organic layer was washed with water and diluted hydrochloric acid solution successively and dried over sodium sulfate to provide 245 mg of crude 2-[4-[2-[7-(3-dimethylaminoacryloyl)benzoxazol-2-ylthio]ethyl]piperazin-1-yl]-N-(2,6-diisopropylphenyl)acetamide.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.CC(C)([O-])C.[K+].CC(O)C>CC(O)C>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([OH:10])[CH2:3]2
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a 100-mL autoclave were added 3-quinuclidinone hydrochloride (500 mg, 3.1 mmol), [RuCl(p-cymene) [(R)-DM-SEGPHOS]]Cl (3.2 mg, 0.003 mmol), and (R)-DAIPEN (3.9 mg, 0.012 mmol). Under a nitrogen atmosphere, added were IPA (1 mL) and potassium t-butoxide/IPA solution (1.0 mol/L, 3.1 mL) were added thereto. Then, the mixture was stirred under a hydrogen pressure of 3 MPa at 30° C. for 8 hours. After analysis of the reaction solution, (R)-3-quinuclidinol was obtained at an optical purity of 86.3% ee and a conversion ratio of 92.3%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (2.0 g) in trifluoroacetic acid (8 ml) was added concentrated sulfuric acid (2.5 ml) followed by N-bromosuccinimide (3.4 g). After stirring for 24 hours the reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to give 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (2.48 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:28]([OH:33])([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:6][CH:5]=1.[CH3:34]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:28]([CH2:31][CH3:32])([O:33][CH3:34])[CH2:29][CH3:30])=[CH:6][CH:5]=1
Reactant: CCC(O)(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
Sodium hydride (60% in oil, 25.4 mg, 0.635 mmol) was added to a stirred solution of 3-{9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}pentan-3-ol (250 mg, 0.529 mmol) in N,N-dimethylformamide (5.0 mL) at room temperature. After stirring 5 min, methyl iodide (113 mg, 0.794 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (175 mg, 0.360 mmol, 68%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:20].C(OCC)(=O)C>O1CCCC1>[CH2:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)[CH3:20]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(CC)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(CC)cc3)ccc12
Temperature: 67 °C

Procedure:
3.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to a solution of 240 mg of N-[6-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The medium is then maintained at 67° C. for 17 hours, and the resulting mixture is then allowed to return to room temperature and 50 cm3 of ethyl acetate are added. The organic phase is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and with 2×50 cm3 of water, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 2 cm3 of ethyl acetate and then with 10 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 80 mg of N-[6-(4-ethylphenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:23]([OH:25])=[O:24])[C:28]([OH:30])=[O:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O

Procedure:
To a solution of sodium (0.95 g) in ethanol (80 ml) are added diethyl malonate (7.2 g) and 5-(1-benzyloxycarbonyl-4-piperidyl)pentylp-toluenesulfonate (13.7 g). The mixture is refluxed for 2 hours with stirring. After the further addition of a mixture of sodium (0.25 g), ethanol (25 ml) and diethyl malonate (1.8 g), the reflux is continued for further 2 hours. After evaporation of ethanol, the residue is diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract is dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oil. To a mixture of this ester and ethanol (30 ml) is added dropwise a solution of sodium hydroxide (6 g) in water (50 ml). After the addition is complete, the mixture is diluted with water (150 ml) and extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml). The organic extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oil. This acid is heated for 1 hour at 160°-165° C. with stirring. The resulting oil is purified by silica gel column chromatography using hexane-ethyl acetate (3:1-1:1) as an eluent to yield 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid (6.4 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].IC.[F:5][C:6]1[CH:7]=[C:8]([C@@H:14]2[CH2:23][C@H:22]([OH:24])[CH2:21][C@@H:20]3[N:15]2[C:16](=[O:40])/[C:17](=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:28]([O:38][CH3:39])[CH:27]=2)/[CH2:18][CH2:19]3)[CH:9]=[C:10]([F:13])[C:11]=1[F:12].Br[CH2:42]CCC(N1C=CC(=O)CC1C1C=C(F)C(F)=C(F)C=1)=O>C1COCC1.C(OCC)(=O)C.O>[CH3:42][O:24][C@@H:22]1[CH2:21][C@@H:20]2[N:15]([C:16](=[O:40])/[C:17](=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:28]([O:38][CH3:39])[CH:27]=3)/[CH2:18][CH2:19]2)[C@H:14]([C:8]2[CH:7]=[C:6]([F:5])[C:11]([F:12])=[C:10]([F:13])[CH:9]=2)[CH2:23]1
Reactant: O=C1C=CN(C(=O)CCCBr)C(c2cc(F)c(F)c(F)c2)C1
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@@H](O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@@H]3C[C@@H](OC)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (4.0 mg) and iodomethane (6.3 μL) were added to a solution of (E)-(6S,8R,9aR)-6-(3,4,5-trifluorophenyl)-8-hydroxy-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one that is an optically active compound obtained in Example 71 with a retention time of 4.8 minutes (10 mg) in THF (2.0 mL) under ice-cooling, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 3.05 mg of the title optically active compound. The property values of the optically active compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+:19]=[N-:20])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](COS(C1C=CC(C)=CC=1)(=O)=O)C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+:19]=[N-:20])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Product: CCCCC[C@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Yield: 96 %

Procedure:
A procedure similar to that used to prepare compound 160 was used except (3S,5S)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acid tert-butyl ester 168 (4.155 g, 9.74 mmol) was used as a reactant to give 169 as an oil (2.77 g, 96%). MS (APCI) m/z 270 (M+−27, 30%, −N2), 214 (M+−87, 100%, −tBu, −N2).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)=[CH:11][CH:12]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccc(-c2ccccc2)cc1
Product: O=C1CCc2cc(OCCCCSc3ccc(-c4ccccc4)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 4-phenyl-thiophenol and 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[CH3:20][N:18]1[CH:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C@@H:7]3[CH2:8][C@H:6]3[NH:5][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=4)[CH2:26][CH2:27]3)=[CH:10][CH:11]=2)[CH:16]=[N:17]1
Reactant: COC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccc(-c4cnn(C)c4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2ccc([C@@H]3C[C@H]3NCC3CCN(Cc4ccc(C(=O)O)cc4)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of methyl 4-((4-((2,2,2-trifluoro-N-(trans-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate (67 mg, 0.121 mmol) in methanol (2 mL) was added sodium hydroxide (1M, 0.5 mL, 0.500 mmol), and the mixture was stirred at r room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product as combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 25 mg of product (HCl salt) as white solid. MS: (M+H)+=445.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.37 (m, 1H), 1.51-1.72 (m, 3H), 1.88-2.13 (m, 3H), 2.55-2.65 (m, 1H), 2.85-3.05 (m, 4H), 3.12-3.25 (m, 1H), 3.34 (d, J=11.87 Hz, 2H), 4.34 (d, J=5.05 Hz, 2H), 7.11-7.23 (m, 2H), 7.45-7.55 (m, 2H), 7.71-7.81 (m, 2H), 7.83-7.89 (m, 1H), 7.97-8.06 (m, 2H), 8.10-8.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18](Cl)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[O-:33][CH2:34][CH3:35].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:33][CH2:34][CH3:35])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:27])([F:26])[F:28])=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (142 mg, 0.286 mmol) and sodium ethoxide (20% solution in ethanol, 292 mg, 0.858 mmol) in ethanol (1.0 mL) was stirred at 50° C. for 5 hr. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (65.3 mg, 0.286 mmol, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:34]([F:36])[F:35]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH:34]([F:36])[F:35])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OCc1ccccc1
Reactant: FC(F)Cl
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)cc1OCc1ccccc1

Procedure:
Using the compound obtained in Example 266 and chlorodifluoromethane, white powdery 3-[2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-yl]-1-(2-difluoromethoxyphenyl)propan-1-one was obtained following the procedure of Example 19.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:13][CH:12]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Nc1ccc(C2CCCCC2)cc1
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(C2CCCCC2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4-cyclohexylaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-[(4-cyclohexylphenyl)amino]-2-oxoethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 68%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][OH:35])=[CH:6][N:7]2[CH2:32][CH3:33]>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=[O:35])=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(CO)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1cc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a yellow solution of 5-chloro-1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy) quinolin-4(1H)-one (19 g, 30.9 mmol) in Dichloromethane (DCM) (250 mL) was added manganese dioxide (41.1 g, 402 mmol), and the mixture was stirred at r.t. for overnight. The mixture was then filtered through Celite and washed with DCM. The filtrate was concentrated to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (17 g, 27.4 mmol, 89% yield) as a yellow solid, which was used in the next step without further purification. LCMS: (M+H)+: 508.1.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:15])[C:4]([C:7]2[CH:12]=[CH:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=2)=[N:5][N:6]=1.[OH-].[Na+].[CH2:18](O)C.IC>O>[CH3:13][N:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]([CH3:15])[C:2]([S:1][CH3:18])=[N:6][N:5]=2)=[CH:8][C:9]1=[O:14]
Reactant: CCO
Reactant: Cn1c(S)nnc1-c1ccn(C)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nnc(-c2ccn(C)c(=O)c2)n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
The title compound from example 32.1 (600 mg, 2.7 mmol) was dissolved in a solution of sodium hydroxide (216 mg, 5.4 mmol) and water (5 mL). When a clear, uniform solution was observed ethanol (6 mL) was added, followed by iodomethane (268 μL, 4.3 mmol). The reaction was stirred at room temperature for 6 h. The reaction mixture was then diluted with water and extracted four times with chloroform. The organic phase was dried over magnesium sulfate, filtered and concentrated to yield the title compound (yellowish solid, 500 mg, 78%).
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[S:11]1[C:7]2=[CH:6][CH:5]=[CH:4][C:3]([OH:2])=[C:8]2[CH:9]=[N:10]1
Reactant: COc1cccc2sncc12
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc2sncc12
Temperature: 150 °C
Yield: 32.1 %

Procedure:
To a sealed tube was added 4methoxy-benzo[d]isothiazole (760 mg, 4.60 mmol) and pyridine hydrochloride (5.5 g, 48 mmol). The reaction was heated to 150° C. for 18 h and was then cooled to rt. The mixture was partitioned between dichloromethane and water. The organic phase was separated and the aqueous layer was extracted with 2×30 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 3:7] to yield the title compound as a solid (223 mg, 32%); Mass spectrum (ion spray): m/z=151.9 (m+1).