Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1)[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1)[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1-n1ncnc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C=CCOc1cc(N)ccc1-n1ncnc1C
Temperature: 65 °C
Reaction time: 0.83 h
Yield: 42.4 %

Procedure:
Iron powder-325 mesh (4.52 g, 76.86 mmol) was added to a round bottom flask charged with a mixture of 1-(2-(allyloxy)-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (4 g, 15.37 mmol), absolute methanol (40 mL), water (8 mL) and ammonium chloride (4.11 g, 76.86 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 50 min. The reaction mixture was filtered and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 3-(allyloxy)-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (1.5 g, 42% yield) as a dark brown solid. LC-MS (M+H)+=231.2 1H NMR (400 MHz, DMSO-d6) δ ppm 7.880 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.35 (s, 1H), 6.24 (d, 1H, J=8.4 Hz), 5.95-5.89 (m, 1H), 5.88 (s, 2H), 5.19-5.16 (dd, 2H, J=1.6, 13 Hz), 4.47 (d, 2H, J=4.8 Hz), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.Br[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Reactant: CC(C)CCBr
Product: CC(C)CCN1CCCC2=C1CC(C)(C)CC2=O

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5(6H)-one was reacted with 1-bromo-3-methylbutane according to the procedures of Part b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methylbutyl)-quinolin-5(6H)-one (18) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmole) in MeOH (100 mL) was added a solution of 2.0 M CH3NH2 in MeOH (126 mL, 252.0 mmole). The reaction was stirred at RT for 2 hrs, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (300 mL), and NaBH4 (2.38 g, 62.8 mmole) was added. After 2 hrs the reaction was concentrated to a slurry and dissolved in 1.0 N NaOH (75 mL). The aqueous solution was extracted with Et2O (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying in high vacuum left the title compound (10.1 g, 92%) as a faintly yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:72]1[CH:77]=[CH:76][C:75]([CH2:78][CH2:79][C:80]2([OH:86])[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]2)=[C:74]([CH3:87])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:54][CH3:55])([C:72]3[CH:77]=[CH:76][C:75]([CH2:78][CH2:79][C:80]4([OH:86])[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]4)=[C:74]([CH3:87])[CH:73]=3)[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:44][C:43]=1[F:49]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
A solution of palladium acetate (3.4 mg, 0.0153 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12.6 mg, 0.0307 mmol) and potassium phosphate (65.3 mg, 0.30 mmol) in water (0.050 mL) and toluene (0.250 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 33.2 mg, 0.16 mmol) and 1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclohexanol (Example 37-(2); 55.4 mg, 0.109 mmol) in toluene (0.150 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for three hours. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (20% ethyl acetate/hexane) to give the title compound (45.6 mg, 76%).
Reaction SMILES: [NH2:1][C:2]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29]([C:31]([NH:33][C:34]4[S:35][CH:36]=[C:37]([CH:39]5[CH2:42][CH2:41][CH2:40]5)[N:38]=4)=[O:32])[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])[CH2:6]1)=[O:3].Cl>O1CCOCC1>[NH2:1][C:2]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29]([C:31]([NH:33][C:34]4[S:35][CH:36]=[C:37]([CH:39]5[CH2:42][CH2:41][CH2:40]5)[N:38]=4)=[O:32])[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:6]1)=[O:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC(N)=O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)OC1CCCN(c2nc3cc(C(=O)Nc4nc(C5CCC5)cs4)ccn3c(=O)c2/C=C/C(=O)O)C1
Reaction time: 2 h

Procedure:
tert-Butyl (E)-3-(2-{3-[(aminocarbonyl)oxy]piperidino}-8-{[(4-cyclobutyl-1,3-thiazol-2-yl)amino]carbonyl}-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-2-propenoate (20 mg, 0.034 mmol) was added with a mixed solution of 4 N hydrochloric acid and dioxane (1.5 ml) at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=10:1) to obtain 9 mg (58% for the two steps) of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH2:17][O:18]C4CCCCO4)[N:14]=[C:13]([NH:25][CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:10]([C:11]3[N:12]=[C:13]([NH:25][CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(COC3CCCCO3)nc(NC3CCCC3)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyrimidinamine (1.18 g, 2.26 mmol) in tetrahydrofuran (20 mL) at 0° C. was added hydrochloric acid (8 mL, 4 N aqueous, 32 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. The solution was diluted and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided [6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinyl]methanol (815 mg, 82%) as a solid. Rf 0.21 (2:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.31 (d, 1H), 7.60 (m, 2H), 7.22 (m, 1H), 7.10 (m, 2H), 7.01 (d, 1H), 6.23 (s, 1H), 5.37 (d, 1H), 4.33 (m, 3H), 3.95 (br, 1H), 2.03 (m, 2H), 1.62 (m, 6H); 19F NMR (CDCl3) δ −112.70; MS m/z 438 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4]2([CH2:10][CH2:9][C@@H:8]([C:11]([O:13]CC3C=CC=CC=3)=[O:12])[CH2:7]2)[O:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:6][CH2:5][C:4]2([CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]2)[O:3]1
Reactant: O=C1NCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)O1
Agent: [Pd]
Solvent: CO
Product: O=C1NCC2(CC[C@@H](C(=O)O)C2)O1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of (7R)-benzyl 2-oxo-1-oxa-3-azaspiro[4.4]nonane-7-carboxylate (20 mg, 0.073 mmol) in methanol (3 mL) was added palladium on carbon (10% wt., 15.46 mg, 0.015 mmol). The resulting mixture was stirred under a hydrogen balloon for 30 min. The reaction mixture was filtered and the filtrate was concentrated to yield (7R)-2-oxo-1-oxa-3-azaspiro[4.4]nonane-7-carboxylic acid (13 mg for each isomer, 0.070 mmol, 97% yield) as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])C.[NH4+:30]>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:30]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1ccco1
Reactant: [NH4+]
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
The process was repeated with ammonium (6R,7R)-3-acetoxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) (40 mg) as substrate and with the addition of pig liver acetylesterase (1 unit). Analysis of the product by TLC (silicachloroform/methanol/90% formic acid - 90:16:4) showed the presence of a new u.v. absorbing spot with an identical Rf to the standard sample of title compound.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[N:9]#[C:10][NH2:11].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[F:5][C:4]([F:7])([F:6])[C:3]1[O:8][C:10]([NH2:11])=[N:9][CH:2]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: N#CN
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncc(C(F)(F)F)o1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
5-Trifluoromethyl-oxazol-2-ylamine: The 5-trifluoromethyl-oxazol-2-ylamine, off-white solid and MS: m/e=152.0 (M+), is obtained using the following procedure: To a solution of 21.6 ml (39.4 g, 0.2 mol) of 97% 3-bromo-1,1,1-trifluoroacetone in 40 ml of tert-butanol are added 12.6 g (0.3 mol, 1.5 equiv.) of cyanamide. A slight exotherm is observed. After stirring for 10 min, 19.7 g (0.24 mol, 1.2 equiv.) of finely powdered sodium acetate were added with vigorous stirring and the suspension is heated for 30 min at 65° C., refluxed for 2 h and then allowed to cool. The mixture is poured into a well stirred mixture of 200 ml of ethyl acetate and 100 ml of water. The pH of the aqueous phase is set to ca. 8-9 with 5% sodium bicarbonate solution. The org. phase is separated. The aqueous phase is extracted with 50 ml ethyl acetate. The combined organic phases were washed twice with 20 ml of water and concentrated in vacuo. The residue, 40.2 g, viscous light orange oil, is then purified by flash chromatography on silica gel using a 2:1 mixture of methylene chloride and ethyl acetate as eluent. The fractions containing the desired compound (6.08 g, light yellow oil) and containing more polar impurities were concentrated and repurified by flash chromatography on silica gel using a 98:2 mixture of methylene chloride and methanol as eluant. One obtains 1.83 g (0.012 mol, 6%) of 5-trifluoromethyl-oxazol-2-ylamine.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](S)=[N:12][C:11]=2[CH:16]=1>>[Cl:4][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:16][C:11]=2[N:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Fc1ccc2sc(S)nc2c1
Product: Fc1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sulfuryl chloride (50 μL, 0.65 mmol) was added neat to 5-fluoro-1,3-benzothiazole-2-thiol (100 mg, 0.54 mmol). The mixture was stirred at ambient temperature for 1 h, then heated at 60° C. for 30 minutes. The resulting solution was cooled to rt, and poured onto ice. The title compound was collected by filtration, washed with water, and dried under vacuum. The solid obtained was used without further purification; LC-MS m/z 188.1 (MH+), ret. time 3.27 min.
Reaction SMILES: C([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12])(=O)C>CO.Cl>[NH2:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1scc(Cl)c1NC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1scc(Cl)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
was obtained by stirring a solution of 7 g of methyl 3-acetylamino-4-chlorothiophene-2-carboxylate in a mixture of 50 ml of methanol and 50 ml of concentrated hydrochloric acid at 60° C. for 4 hours and at room temperature for 2 days. The mixture was filtered, the solvent was distilled to about ⅓ of the starting volume, approx. 100 ml of water were added and the crystals were filtered off after stirring at room temperature. Crystalline product. M.p. 62–64° C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:19])[N:11]([CH3:18])[C:12](=[O:17])[N:13]([CH3:16])[C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:10](=[O:19])[N:11]([CH3:18])[C:12](=[O:17])[N:13]([CH3:16])[C:14]=1[CH2:15][Br:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 57.6 %

Procedure:
(See, e.g., Tsupak et al., Khimiya Geterotsiklicheskikh Soedinenii. 7:1096-1102 (2003); Tsupak et al., Russ. Chem. Bull. 55:2265-2270 (2006)). To a solution of 3 (2.61 g, 10.1 mmol) in chloroform (13 mL) was added bromine (1.62 g, 0.52 mL, 20.3 mmol in 3 mL chloroform) dropwise over 30 min at room temperature. The reaction mixture was further stirred for 1 min at room temperature before concentrated in vacuo. The crude reaction mixture was purified by flash chromatography to yield 4 (1.96 g, 57%); mp 164-167° C.; MS (ES+) (m/z): [M+1]+ calculated for C14H14BrN2O3, 338.18. found 337.15, 338.93. This compound matched analytical data as reported (see, e.g., Tsupak et al., Khimiya Geterotsiklicheskikh Soedinenii., supra; Tsupak et al., Russ. Chem. Bull., supra).
Reaction SMILES: [CH3:1][Mg+].[Br-].[OH:4][C:5]1[C:6]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:19][CH:18]=3)=[CH:15][S:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[C:11]#[N:12]>C1COCC1>[C:11]([C:10]1[C:9](=[O:13])[NH:8][C:7]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:21][CH:22]=3)[C:6]=2[C:5]=1[OH:4])(=[NH:12])[CH3:1]
Reactant: C[Mg+]
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=N)c1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Temperature: 25 °C

Procedure:
MeMgBr (1.4 M in ether, 15 mL, 21 mmol) was slowly added to a solution of 4-hydroxy-3-(2′-hydroxy-1,1′-biphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (1.5 g, 4.18 mmol) in anhydrous THF (90 mL) at 0° C. The reaction mixture was slowly warmed to room temperature over 4 hours and quenched with 1N HCl. It was then filtered, concentrated, and purified on a RP-HPLC system to give the title compound. MS (ESI) m/e 375.0 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 12.37 (br s, 1H), 11.33 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 7.49 (d, J=8.59, 2H), 7.42 (d, J=8.59, 2H), 7.29 (dd, J=7.68, 1.85, 1H), 7.18–7.14 (m, 1H), 6.96 (dd, J=8.29, 1.23, 1H), 6.91–6.84 (m, 1H), 6.75 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:10][CH3:11])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:10][CH3:11])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CCC(C)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CCC(C)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
2-Bromo-4-sec-butyl-phenol (1.50 g) is dissolved in N,N-dimethylformamide (10 ml) and thereto are added potassium carbonate (1.18 g) and iodomethane (1.12 g) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→20:1) to give 2-bromo-4-sec-butyl-1-methoxy-benzene (1.58 g). NMR (CDCl3): 0.80 (3H, t), 1.20 (3H, d), 1.55 (2H, m), 2.51 (1H, m), 3.87 (3H, s), 6.82 (1H, d), 7.07 (1H, d), 7.35 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: COc1cccc(CN2CCC3(CC2)OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(CN2CCC(=O)CC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
To a solution of 8-(3-methoxybenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (16.0 g, 60.76 mmol) from Step A above was added an ice-cold solution of concentrated hydrochloric acid (320 mL). The suspension was stirred at 0° C. for 5 min and then allowed to warm to ambient temperature. After 1 h, the homogeneous solution was poured into a sodium hydroxide solution (21.5 g in 200 mL of water) at 0° C. and then extracted with methylene chloride (2×150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (methylene chloride to 1:1 ethyl acetate/methylene chloride) gave 1-(3-methoxybenzyl)piperidin-4-one (11.0 g, 83%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.28-7.22 (m, 1H), 6.97-6.90 (m, 2H), 6.82 (dd, J=2.1, 7.9 Hz, 1H), 3.82 (s, 3H), 3.60 (s, 2H), 2.75 (t, J=6.1 Hz, 4H), 2.46 (t, J=6.1 Hz, 4H); ESI MS (m/z) 220 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[N:10]2[CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COc1ccc2c(n1)NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 7-(methyloxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (4.974 g, 27.9 mmol) in DMF (100 ml) at 0° C. under argon was treated with sodium hydride (60%, 1.340 g, 33.5 mmol) and allowed to stir at 0° C. for 20 min. The reaction mixture was then treated with (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (7.60 g, 29.3 mmol), stirred at 0° C. and then allowed warm to rt and stirred at rt for 1 h. Water (5 ml) was then added. Reaction was evaporated, saturated aqueous bicarbonate (500 ml) was then added and the mixture was extracted with DCM (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1nccs1
Product: Clc1ccc(-c2nccs2)cc1

Procedure:
Using 2-bromothiazole (0.5 g, 3.05 mmol) and (4-chlorophenyl)boronic acid (0.57 g, 3.65 mmol) and following the procedure described in Example 7, Step 1, the title compound was obtained after purification by column chromatography (15% ethyl acetate in hexane) as colorless viscous liquid (0.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, 2H), 7.92 (d, 1H), 7.80 (d, 1H), 7.55 (d, 2H); LC-MS m/z calculated for [M+H]+195.99. found 195.9.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])C1C=CC=CC=1.Cl.N1C=CC=CC=1>Cl>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(O)cc12
Temperature: 180 °C
Yield: 92.4 %

Procedure:
A mixture of 46.14 g (0.125 mol) of 2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-isoindole-1,3(2H)-dione and 143.35 g (1.24 mol) of piridine hydrochloride was heated at 180° C. for 1.5 hours. The resulting brown solution was cooled to 120° C. and slowly poured in a well stirred mixture of 800 ml of 0.5 N HCl. The precipitate was filtered off and dried: 32.26 g of product as yellow solid were obtained. Yield=92.4%.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:28][N+:29]([O-])=O)[CH2:22][C:23]([O:25]CC)=O)([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]2[CH2:28][NH:29][C:23](=[O:25])[CH2:22]2)([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CC(OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
A 35.12 g (80.46 mmol) portion of ethyl 3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-4-nitrobutanoate was dissolved in 700 ml of ethanol to which, under an atmosphere of nitrogen, was subsequently added 50 ml of Raney nickel. After replacing the atmosphere with hydrogen, this was stirred at 50° C. for 5 hours. After cooling in an ice bath, the reaction solution was filtered through celite and then the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography to give 20.53 g (70.8%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(5-(4-Bromophenyl)thien-2-yl)-3-(2,3-dichloro-4-hydroxyphenyl)prop-2-en-1-one is dissolved in dichloromethane (0.7 g, 1.5 mol/L). Triethylsilane (2.1 eq.) and trifluoroacetic acid (8 eq.) are successively added dropwise. After stirring for 16 hours at room temperature, the reaction mixture is washed with water and then the dichloromethane is removed by evaporation under reduced pressure. The evaporation residue is purified by silica-gel chromatography