Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[CH3:27][NH:28][NH2:29]>CC(O)=O.CCOCC.C(Cl)Cl>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:4]3[C:1]([CH3:2])=[N:29][N:28]([CH3:27])[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: CNN
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methylpyridin-2(1H)-one (Step 57.1) (300 mg, 0.763 mmol) in AcOH (5 mL) was added methyl hydrazine (0.201 mL, 3.81 mmol) and the reaction mixture was stirred for 18 hr at 100° C. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc. Trituration in Et2O/CH2Cl2 (9:1) afforded the title product (60 mg, 0.149 mmol, 20% yield) as white solid. tR: 4.05 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 403/405 [M+H]+ (LC-MS 2); Rf=0.24 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (s, 3H) 3.41 (s, 3H) 3.89 (s, 3H) 6.07 (s, 1H) 7.26 (d, J=8.2 Hz, 2H) 7.35 (d, J=8.2 Hz, 2H) 7.86 (d, J=2.0 Hz, 1H) 7.90 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:29]([Mg]Br)[CH3:30].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:29][CH3:30]
Reactant: COc1cc2nccc(Oc3ccc(OC(F)(F)F)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(OC(F)(F)F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenz-aldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl}-1-propanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:16]2[C:15]([NH2:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution of 1.0 g 1-benzyl4-piperidone and 1.14 g of 1,2-phenylenediamine in 15 mL of THF was added two spatula tips of molecular sieves 4Å. After stirring at room temperature for 10 minutes, 1.34 g of sodium triacetoxyborohydride was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with 50 mL of CH3OH and diluted with EtOAc. After filtering molecular sieves, the filtrate was concentrated under reduced pressure. The residue was partitioned between 50 mL of EtOAc and 30 ml saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×50 mL EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 100% EtOAc, then 90% EtOAc in CH3OH to give 666 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ1.56 (m, 2H), 2.07 (m, 2H), 2.18(m, 2H), 2.87 (d, J=11.6 Hz, 2H), 3.29(m, 1H), 3.56(s, 2H), 6.69 (m, 3H), 6.72(m, 1H), 7.25-7.61(m, 5H). ESI-MS 282 (M+H); HPLC A: 1.92 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O.[BrH:17]>>[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][Br:17]
Reactant: Br
Reactant: CC(C)CCCC(C)CCO
Agent: O=S(=O)(O)O
Product: CC(C)CCCC(C)CCBr
Temperature: 25 °C
Yield: 82.1 %

Procedure:
48% HBr (200 ml) and concentrated sulfuric acid (0.46 ml) were added to 3,7-dimethyl-1-octanol (21.0 g, 157.9 mmol), and the mixture was heated overnight. After allowing to cool to room temperature, and the mixture was extracted with hexane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated to give the title compound (28.7 g, 82.1%).
Reaction SMILES: C[C:2]1([C:14]([O-])=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:14]([CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylate (3.5 g, 15.3 mmol) in toluene at −78° C. was added DIBAL-H (17.6 mL, 30 mmol, 1.7 M) dropwise while maintaining the reaction temperature below −65° C. The reaction was stirred at −78° C. for 2 h and then quenched with methanol (10 mL). The mixture was then diluted with ethyl acetate (50 mL), saturated NH4Cl was added, and the mixture was stirred vigorously for 20 min at room temperature. The two phases were then separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were then washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to give 3 g of the desired product. MS (ESI): 200 (MH+).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1O)[C:11]([O:13][CH3:14])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:6][CH:3]([CH2:4][F:5])[CH2:2][F:1])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: OC(CF)CF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(CF)CF)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
To a solution of 1,3-difluoropropan-2-ol (2.57 g, 26.8 mmol) in THF (35 mL) was added methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.72 mmol), followed by triphenylphosphine (7.03 g, 26.8 mmol) and DIAD (5.21 mL, 26.8 mmol). The reaction was stirred overnight at room temperature, diluted with EtOAc and washed with brine. The organics were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound (3.743 g) as a clear oil. LCMS m/z=265.1 [M+H]+.
Reaction SMILES: O[Li].O.[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C:8]2([C:16]([O:18]C)=[O:17])[OH:15]>O.C1COCC1>[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C:8]2([C:16]([OH:18])=[O:17])[OH:15]
Reactant: COC(=O)C1(O)CCOc2ccc(F)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(O)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of LiOH.H2O (0.95 g; 22.6 mmol) in water (30 mL) was added to a solution of 6-fluoro-4-hydroxychroman-4-yl-carboxylic acid, methyl ester (2.47 g; 10.9 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at room temperature for 2 days, THF was evaporated and the water phase was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 1.41 g (61%).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: Clc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol,), 1-bromomethyl-4-chloro-benzene (0.246 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.125 g, 97%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.76 (s, 2H), 7.22-7.54 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O.[Cu]I>[F:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:11][C:5]=2[CH:6]=1
Reactant: Oc1cc(F)ccc1C=C(Br)Br
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2ccoc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(2,2-dibromoethenyl)-5-fluorophenol (580 mg, 1.96 mmol) in tetrahydrofuran (20 mL) was added CuI (30 mg, 0.16 mmol), K3PO4 (800 mg, 3.77 mmol) under nitrogen atmosphere. After stirring overnight at 80° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with petroleum ether to afford 6-fluoro-1-benzofuran as a white solid (0.16 g, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1.[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].[K+].Cl.O>CN(C=O)C.CN1CCCC1=O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:18]([F:20])([F:19])[F:17])[C:5]2[O:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: COC(=O)C1CCc2cc(F)cc(I)c2O1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCc2cc(F)cc(C(F)(F)F)c2O1
Temperature: 60 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A suspension of (±)-methyl 6-fluoro-3,4-dihydro-8-iodo-2H-1-benzopyran-2-carboxylate (0.026 mol), (trifluoromethyl)trimethylsilane (0.081 mol), cuprous iodide (0.1 mol) and kalium fluoride (0.081 mol) in a mixture of DMF (50 ml) and 1-methyl-2-pyrrolidinone (50 ml) was stirred for 3 h at 60° C. The cooled reaction mixture was poured out into a solution of iron (III) chloride (200 g) and hydrochloric acid (50 ml) in water (300 mol). This mixture was extracted three times with diethyl ether (150 ml). The combined organic layers were washed with a 5% aqueous Na2S2 O3 solution (decolorization), dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and the solvent was evaporated, yielding 5.7 g (78.8%). This fraction was recrystallized from DIPE. The precipitate was filtered off and dried, yielding 1.2 g (16.6%) (±)-methyl 6-fluoro-3,4-dihydro-8-(trifluoromethyl)-2H-1-benzopyran-2-carboxylate; mp. 71.8° C. (interm 4-b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 13 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3-fluorophenyl isocyanate. The compound of example 13 was used directly without isolation for the preparation of compound of example 14.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[O:21])[CH2:11]2)[CH2:6][CH2:5]1>C(O)C.O>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:12]([OH:21])[CH2:11]2)[CH2:8][CH2:9]1
Reactant: CN1CCN(C2CCc3ccccc3C(=O)C2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1CCN(C2CCc3ccccc3C(O)C2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
8.8 g of sodium borohydride were added over 20 minutes at 22°-26° C to a solution of 8.8 g of the product of Step A in 8.8 ml of ethanol and 8.8 ml of water and the mixture was stirred for 1 hour at 20° C. The ethanol was evaporated and the mixture was poured into water and was extracted with methylene chloride. The organic extracts were washed with water, dried and evaporated to dryness to obtain 9 g of a mixture of the isomers of raw 7-(4-methylpiperazin-1-yl)-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][OH:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCBr
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-bromoethanol (0.052 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (2% methanol/chloroform) to give the subject compound (72 mg, yield 46%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:37](=O)[CH3:38])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:2]([N:1]1[CH:10]=[C:9]([CH3:8])[N:11]=[C:37]1[CH2:38][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[CH:3]=[CH2:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1cc(C)nc1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of the above aldehyde (268 mg, 1.773 mmol) and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (743 mg, 2.13 mmol) in CH2Cl2 (17 mL) was added sodium triacetoxyborohydride (752 mg, 3.55 mmol). The reaction mixture was stirred at room temperature overnight. Then it was extracted with saturated NaHCO3 (3×20 mL). The organic layer was dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a yellow foam. Purification by flash column chromatography on silica gel using 10% CH3OH/ethyl acetate afforded the product as a pale yellow foam (263 mg, 31%). 1H NMR (CDCl3) (as a mixture of regio-isomers) δ 1.52-1.60 (m, total 4H), 1.89-2.11 (m, total 8H), 2.56-2.66 (m, total 4H), 2.55 (t, 2H, J=7.5 Hz), 3.76 (d, 2H, J=6.0 Hz), 3.99 (t, 1H, J=6.0 Hz), 4.84-4.90 (m, total 1H) 4.93 and 4.96 (s, total 1H), 5.03-5.06 (m, total 2H), 5.83-5.87 (m, 1H), 6.43 (s, 1H), 6.99 (dd, 1H, J=3.0 Hz), 7.27 (d, 1H, J=6.0 Hz), 7.68-7.70 (m, 2H), 7.80-7.82 (m, 2H), 8.39 (d, 1H, J=3.0 Hz).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=1.O>CN(C=O)C>[CH3:39][O:38][C:36](=[O:37])[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC(=O)OC)cc1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (278 mg, 0.83 mmol) in anhydrous DMF (5 mL) add cesium carbonate (297 mg, 1.66 mmol) and methyl 4-hydroxyphenylacetate (200 mg, 1.20 mmol). Stir the resulting mixture overnight then pour into water and extract twice with ethyl acetate. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum to give the title compound (290 mg) as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][O:14]C2CCCCO2)(=[O:11])=[O:10])=[CH:5][C:4]=1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[CH:29]=2)[C:24](=[O:37])[N:23]([CH3:38])[CH:22]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:14][CH2:13][CH2:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[CH:29]=3)[C:24](=[O:37])[N:23]([CH3:38])[CH:22]=2)[CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)CCOC2CCCCO2)cc1-c1cn(C)c(=O)c2ccc(-c3cnn(C)c3)cc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CCO)cc1-c1cn(C)c(=O)c2ccc(-c3cnn(C)c3)cc12
Yield: 24.2 %

Procedure:
The title compound of step 6 (80 mg, 0.15 mmol) and pyridinium p-toluensulfonate (59 mg, 0.31 mmol) in DCM (2 mL) were stirred at room temperature for 5 h. After purification by prep-TLC (DCM: MeOH=10:1), the title compound (16.47 mg, 24.4%) was obtained as an off-white solid. 1H NMR: (CDCl3, 400 MHz) δ8.49 (d, J=8.4 Hz, 1H), 8.05 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.59-7.62 (m, 2H), 7.20 (d, J=8.8 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 7.07 (s, 1H), 4.03-4.11 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H), 4.16 (t, J=5.2 Hz, 2H), 2.72 (t, J=6.4 Hz, 1H). LCMS: 454.1 (M+H)+
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=O)C.S([O-])([O-])=O.[Na+].[Na+].[C:27](=O)([O-])O.[Na+].BrCC(O)=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:27][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:7]2[S:6][C:5]([NH2:4])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=C([O-])O
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
4-(2-Acetylamino-methyl-thiazol-5-yl)-benzenesulfonyl chloride (AE2) (0.5 g, 1.5 mmol) in dioxane (2 ml) is added dropwise to a stirred solution of sodium sulfite (0.378 g, 3.0 mmol) and sodium hydrogen carbonate (0.252 g, 3.0 mmol) in water at 75° C. After 1 hour at 75° C., bromoacetic acid (0.417 g, 3.0 mmol) is added and heating continued for 1 hour at 100° C. Sodium hydroxide (0.24 g, 6.0 mmol) in water (0.25 ml) is then added and the mixture is heated with stirring at 90° C. for 16 hours. The reaction mixture is allowed to cool, diluted with water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic extracts are washed with brine (75 ml), dried (MgSO4), filtered, and the solvent removed to give the title compound.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:37])[CH2:35][CH3:36]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and propionic acid (9.0 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].OO.C(=O)([O-])[O-:30].[K+].[K+].O>CS(C)=O>[CH3:26][C:22]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:9]3[CH:8]=[C:7]([C:3]4([C:1]([NH2:2])=[O:30])[CH2:6][CH2:5][CH2:4]4)[CH:12]=[CH:11][CH:10]=3)=[CH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCC3)c2)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 203.6 %

Procedure:
To a solution of 1-cyano-1-[3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-cyclobutane (2.90 g, 8.4 mmol) in DMSO (5 ml) cooled to 0° C. was added 30% H2O2 (2.0 ml) and potassium carbonate (0.4 g). The mixture was allowed to warm to room temperature and stirred overnight, and then stirred for 6 hrs at 60° C. Water (100 ml) was added and the mixture extracted with ethyl acetate (100 ml×3). The combined organic layers were extracted with 2N HCl (100 ml×2) and the aqueous layer washed with ethyl acetate (100 ml×3). The aqueous acidic layer was basified to pH=9 with 5N NaOH (150 ml) and extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford crude product as white solid. Recrystallization from ethyl acetate gave 2.13 g (70%) of the titled compound as a white solid.