Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)Cl)c1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene (5 mL) and thionyl chloride (5.00 g, 3.1 mL) was heated at 80° C. for 2 hours. The mixture was cooled and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[O:35])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C@@:25]2([CH2:11][CH2:10][CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[O:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Product: CC(C)(C)OC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,4-dibromobutyl)benzene (153 mg, 0.4 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-2,4-dioxoimidazolidine-1-carboxylic acid tert-butyl ester (113 mg, 0.33 mmol) (Preparation 11), the above-titled compound was obtained (33 mg) as a white solid. 1H NMR (CDCl3): 7.48 (2H, d, J=8.3 Hz), 7.30 (1H, m), 7.07 (2H, d, J=8.3 Hz ), 6.52 (2H, m), 4.06 (1H, dd, J1=13.1 Hz, J2=5.5 Hz), 2.35-2.6 (3H, m), 2-2.35 (3H, m), 1.66 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:32])=[O:30])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3)sc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (48 mg, 0.115 mmol) was dissolved in DMF (3.00 mL). The vial was charged with HATU (65.6 mg, 0.173 mmol), DIEA (0.060 mL, 0.345 mmol), and NH4Cl (6.16 mg, 0.115 mmol). The reaction mixture was stirred for 10 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol, 85% yield) as a pale orange solid. 1H NMR (400 MHz, CD3OD) δ ppm==3.77 (s, 3 H) 6.40 (d, J=15.66 Hz, 1 H) 6.78-6.90 (m, 3 H) 6.95-7.06 (m, 2 H) 7.16 (d, J=8.59 Hz, 1 H) 7.29-7.49 (m, 4 H) 7.55-7.69 (m, 2 H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.C1(N[S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:25])[CH:11]=[CH:10][C:9]=3[CH3:12])[C:14]2=[O:24])=[CH:19][CH:18]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1=O
Temperature: 120 °C

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (250 mg), N-phenyltrifluoromethanesulfonamide (267 mg) and potassium carbonate (311 mg) were stirred in THF (6 ml) and heated under microwave irradiation (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 120° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography with a gradient of iso-hexane to 70% ethyl acetate/iso-hexane yielded 2-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-1,2-dihydroisoquinolin-7-yl trifluoromethanesulfonate as a cream coloured solid (264 mg); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.67 (m, 2H), 2.10 (s, 3H), 2.83 (m, 1H), 6.87 (d, 1H), 7.49 (m, 2H), 7.76 (s, 1H), 7.86 (d, 1H), 7.93 (d, 1H), 8.00 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+Na+ 489.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Li])CCC.[O:20]1[CH2:22][CH2:21]1>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([CH2:1][CH2:22][CH2:21][OH:20])[CH:7]=1
Reactant: Cc1cc(Cl)cc(N2CCOCC2)n1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCCc1cc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C

Procedure:
2-Methyl-4-chloro-6-morpholino-pyridine (50 mmol) is dissolved in tetrahydrofuran (200 mL). The reaction is chilled to −78° C. under an inert atmosphere. A solution of n-butyllithium in hexanes (24 mL, 2.5M, 60 mmol) is added, and the reaction mixture is stirred for thirty minutes. A solution of oxirane dissolved in tetrahydrofuran (40 mL, 41.5M, 60 mmol) is added, and the reaction is allowed to warm to room temperature while stirring overnight. The solvent is removed under reduced pressure, and the crude material is dissolved in methylene chloride (200 mL) and washed with saturated ammonium chloride (2×50 mL), dried with sodium sulfate, and evaporated to dryness. The compound is purified by column chromatography to give 3-(4-chloro-6-morpholin-4-yl-pyrid-2-yl)-propan-1-ol.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(F)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
To a solution of 2,3-difluorophenol (30.0 g, 231 mmol) and pyridine (18.6 mL, 231 mmol) in dichloromethane (230 mL) at 0° C. was carefully added acetyl chloride (16.4 mL, 231 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was then diluted with dichloromethane (100 mL), washed with 1N aqueous hydrochloric acid (2×50 mL) and brine (75 mL), and concentrated to produce 41.0 g (100%) of the title compound. MS (DCI/NH3) m/z 190 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:38](O)(=[O:41])[CH2:39][CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[CH3:27][CH:25]([CH3:26])[CH2:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[NH:14][C:13](=[O:28])[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:38](=[O:41])[CH2:39][CH3:40])[CH:16]=1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)n3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (60 mg, 0.15 mmol) in dimethylacetamide (4 mL) and diisopropylethylamine (130 pt, 0.76 mmol, 5 eq) was added propionic acid (56 μL, 0.76 mmol, 5 eq) followed by HATU (290 mg, 0.76 mmol, 5 eq). The reaction mixture was stirred at room temperature for 16 h. Formation of product was confirmed by LC/MS and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 17 mg (26%) of the title compound: 1H-NMR (400 MHz, d6-DMSO): δ 11.85 (s, 1H), 8.79 (s, 1H), 8.28-8.35 (m, 1H), 7.64 (s, 1H), 7.49-7.58 (m, 1H), 7.20 (d, 1H), 7.08-7.13 (m, 1H), 6.63 (s, 2H), 4.07-4.14 (m, 1H), 3.83-3.91 (m, 2H), 3.15-3.19 (m, 1H), 2.93-3.03 (m, 2H), 1.95-2.08 (m, 1H), 1.14-1.21 (m, 3H), 0.90-0.96 (m, 6H). MS (EI) for C24H25N5O3: 431 (MH+).
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1

Procedure:
A solution of 2.7 g of (E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 40 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 3.75 g of (E)-2-[2-[3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]phenyl=amino]-2-oxoethyl]benzoic acid; m.p. 209°-210° C. from tetrahydrofuran.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)=[O:20].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[CH:3]=2)[NH:8][C@@H:7]([CH3:18])[CH2:6]1)=[O:20]
Reactant: C[C@H]1CN(C(=O)c2ccco2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.626 g, 1.5 mmol), 1,4-dioxane (15 mL), 4-(methylsulfonyl)phenylboronic acid (0.360 g, 1.8 mmol), and sodium bicarbonate as a 1M solution in water (4.5 mL, 4.5 mmol). The reaction mixture was purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (0.01 M solution in DMF, 7.5 mL, 0.075 mmol) was added, and the reaction mixture was purged with nitrogen and heated to 80° C. overnight. The reaction was diluted with ethyl acetate (30 mL) and washed with brine (15 mL). The aqueous layer was separated and washed with ethyl acetate (30 mL) and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 1:1 hexanes-ethyl acetate) to afford (S)-furan-2-yl(3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (0.33 g, 55% yield) as a viscous yellow oil. MS (ESI, pos. ion) m/z 397 [M+1]+.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1/[O:11][C:12]([CH3:14])([CH3:13])[C:8]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[CH:9]/1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(F)nc1
Temperature: 78 °C
Yield: 38.1 %

Procedure:
To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (150 mg, 0.44 mmol), 6-fluoropyridin-3-ylboronic acid (74 mg, 0.53 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 2M Na2CO3 aqueous solution (0.6 mL, 1.2 mmol). The mixture was heated at 78° C. under N2 for 3 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-3% MeOH/CHCl3 gave (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid (yield: 60 mg, 38%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[O:11][C:8]2=[N:9][CH:10]=1)=[O:4]>CO.C1COCC1>[OH:4][CH2:3][C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[O:11][C:8]2=[N:9][CH:10]=1
Reactant: CN(C)C(=O)c1cc2cc(C=O)cnc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(CO)cnc2o1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (6.0 g, 0.16 mol) was added to a solution of 5-formyl-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide (6.9 g, 0.032 mol) in methanol (80 mL) and THF (20 mL) at 0° C., and the resulting mixture was gradually warmed to 23° C. and stirred for 1 h. The excess of sodium borohydride was carefully quenched with water. The reaction mixture was concentrated, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 70% ethyl acetate in petroleum ether to give the title compound. MS: m/z=221.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C)C=O.FC(F)(F)C(O)=O.[Mn]>[CH3:11][S:8]([NH:7][CH2:6][C:5]1[CH:12]=[CH:13][C:2]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)NCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)Cl
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a stirred solution of N-(4-bromobenzyl)methanesulfonamide (675 mg, 2.555 mmol) in dimethylformamide were added ethyl 2-chloropropionate (0.42 mL), manganese (280 mg) and (2,2′-bipyridine)nickel(II)-dibromide (67 mg, 0.17885 mmol). Trifluoroacetic acid (2 drops) was added. The reaction mixture was stirred for 36 h at 60° C. After cooling down to room temperature, the mixture was hydrolysed by 1N HCl and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@@H:9]([CH3:10])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:10][C@@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1 h

Procedure:
Methanol (1.25 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and bicyclic alcohol (108) (49 mg, 0.177 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1 hour then filtered through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with diethyl ether (3×3 mL) to obtain the crude (3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:12]C(=O)OCC)=S)=[N:7][CH:8]=1.[Cl-].O[NH3+].C([N:24](CC)C(C)C)(C)C.C(O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:24]=[C:10]([NH2:12])[N:9]=2)[CH:8]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: CCO
Product: COc1ccc2nc(N)nn2c1
Yield: 91.7 %

Procedure:
In the same manner as in the below-mentioned Example 23-1 and using ethyl {[(5-methoxypyridin-2-yl)amino]carbonothioyl}carbamate (1.34 g, 5.25 mmol), hydroxylammonium chloride (2.55 g, 36.7 mmol), N,N-diisopropylethylamine (4.57 mL, 26.2 mmol), ethanol (15 mL) and methanol (15 mL) as starting materials, the title compound (790 mg, 92%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([F:26])[C:24]=1F.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C.CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CCOC(=O)C(C)n1ncc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Yield: 52.6 %

Procedure:
Ethyl 2-(6-hydroxyindazol-1-yl)propionate (30 mgs) was dissolved in 0.72 cm3 of a mixture of dry methyl isobutyl ketone (6cm3) and 1 drop of dry DMF. 3-chloro-4,5-difluorobenzotrifluoride (42 mg) and dry potassium carbonate (27mg) were added. The mixture was stirred and heated under reflux for 7 hours, additional dry potassium carbonate being added after 3 hours. After cooling, the solvents were removed under vacuum and diethyl ether added to the residue, the mixture filtered and the inorganic portion washed thoroughly with diethyl ether. The combined ethereal filtrate was concentrated under vacuum and the residue purified by chromatography (SiO2 ; hexane:t-butylmethylether,4:1) to give compound 1, ethyl 2-[6-(2-chloro- 4-trifluoromethyl-6-fluorophenoxy) indazol-1-yl]propionate (29 mg). M+ =430.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCSc1ccccc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Benzenethiol (3.0 g), 1-bromo-5-chloropentane (5.7 g) and potassium carbonate (4.15 g) were suspended in N,N-dimethylformamide (50 ml), and the mixture was stirred at 50° C. for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. Thus, 5-phenylthiopentyl chloride was obtained. This compound was dissolved in formic acid (50 ml) and 2 equivalents of 30% aqueous hydrogen peroxide solution was added thereto, and the mixture was stirred at room temperature for 6 hr.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Yield: 89.7 %

Procedure:
A 3.7 g of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate in 40 ml of acetic acid was stirred at 60° C. for 24 hours while blowing air into the mixture in the presence of 0.4 g of cobalt acetate tetrahydrate. After completion of the reaction, 3N sulfuric acid was added to the solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give 3.3 g (yield 90%) of 5-methoxycarbonylmethyl-3,4-bis(4-methoxyphenyl)isoxazole.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Product: CCCC(=O)OCCCCc1ccccc1
Reaction time: 36 h
Yield: 98.9 %

Procedure:
To 4-phenyl-1-butanol (7.0 g, 0.047 mol) was added anhydrous dichloromethane (20 mL). A solution of butyryl chloride (4.79 g, 0.045 mol) in anhydrous dichloromethane (20 mL) was added dropwise. The solution was stirred for 36 hours. At this point the reaction was concentrated under reduced pressure to give a crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate (3:1)] provided the desired product (9.8 g, 94%) as a clear viscous liquid. 1H (CDCl3) δ(ppm): 0.94 (t, 3H); 1.61-1.71 (m, 6H); 2.27 (t, 2H); 2.64 (t, 2H); 4.08 (t, 2H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.ICCC>COCCOC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH3:22])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCI
Solvent: COCCOC
Product: CCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Temperature: 70 °C

Procedure:
4-Piperidin-4-yl-benzoic acid methyl ester (28 mmol), ethyldiisopropylamine (31 mol) and 1-iodopropane (42 mmol) are dissolved in 1,2-dimethoxyethane (100 ml) and the mixture is heated at 70° C. overnight. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale brown powder with Rf=0.35 (CH2Cl2/MeOH=9:1) is obtained.