Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.C1COCC1.[OH:12][CH2:13][C:14](=[O:16])[CH3:15].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:17]([O:12][CH2:13][C:14](=[O:16])[CH3:15])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 43 h
Yield: 87.8 %

Procedure:
To a pyridine (25 ml) and THF (10 ml) solution of hydroxyacetone (5 g, 67.5 mmol), benzoyl chloride (12 ml, 103 mmol) was added dropwise at 0° C. in a nitrogen atmosphere and the mixture was stirred for 43 hours at room temperature. Ice was added to the reaction mixture, which was then diluted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-1/1 gradient). Desired fractions were concentrated to obtain the title compound (10.56 g, 87.8% yield) as a light yellow oil.
Reaction SMILES: [NH2:1][OH:2].Cl.C[O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CO>[OH:2][NH:1][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: NO
Reactant: COC(=O)CCCCN(Cc1ncccc1C)Cc1ncccc1C
Agent: Cl
Solvent: CO
Product: Cc1cccnc1CN(CCCCC(=O)NO)Cc1ncccc1C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
To a mixture of Na metal (1—mg, 4.91 mmol) in MeOH (5 mL) was added NH2OH—HCl (204 mg, 2.94 mmol) followed by a solution of 5-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-pentanoic acid methyl ester (126 mg, 0.37 mmol) in MeOH (7 mL) and the reaction stirred 1.5 h. An additional amount of Na (134 mg, 5.83 mmol) and NH2OH—HCl (208 mg, 2.99 mmol) was then added and the mixture stirred another 40 min then quenched with water (2-3 mL). The mixture was concentrated and diluted with H2O (10 mL), saturated aqueous NaHCO3 (to pH 10) and CHCl3 (25 mL) and stirred vigorously overnight. The layers were separated and the aqueous was extracted with CHCl3 (2×15 mL). The combined organic extracts were dried (Na2SO4), concentrated and purified by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 50:1:1 then 25:1:1 then 10:1:1) to give COMPOUND 172 (47 mg, 37%) as a white solid: 1H NMR (CDCl3) δ 1.54-1.58 (m, 4H), 2.11 (s, 6H), 2.12-2.15 (m, 2H), 2.52-2.55 (m, 2H), 3.71 (s, 4H), 7.12 (dd, 2H, J=9, 6 Hz), 7.42 (d, 2H, J=9 Hz), 8.36 (d, 2H, J=6 Hz). 13C NMR (CDCl3) δ 17.91, 21.92, 23.16, 31.68, 52.73, 57.23, 122.58, 133.61, 138.43, 145.52, 156.61, 170.55. ES-MS m/z 343 (M+H). Anal. Calcd. for C19H26N4O2.1.3CH3OH: C, 63.48; H, 8.19; N, 14.59. Found: C, 63.66; H, 8.03; N, 14.33.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 96.3 %

Procedure:
A solution of 4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.95 g, 5.5 mmol) and potassium phthalimide (1.54 g, 8.3 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (2.46 g, 96.5%) as crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC1(C)C(C)(C)OB([C:54]2[CH:55]=[N:56][C:57]([NH2:60])=[N:58][CH:59]=2)O1>ClCCCl>[NH2:60][C:57]1[N:58]=[CH:59][C:54]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]3[S:10][C:9]([CH2:11][N:25]4[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]4)=[CH:8][C:6]=3[N:7]=2)=[CH:55][N:56]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: OCCN1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(CCO)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (1.3 g, 4.6 mmol) in 1,2-dichloroethane (45 mL) was added 1-(2-hydroxyethyl)piperazine (0.8 mL, 6.4 mmol) and AcOH (260 μL, 4.6 mmol). After stirring 10 min at room temperature, Na(OAc)3BH (1.2 g, 5.5 mmol) was added and the resulting mixture stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. A portion (0.4 mmol) of the crude intermediate was coupled following General Procedure A with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine to provide 158 after reverse phase HPLC purification (15 mg). MS (Q1) 457 (M)+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C@H:1]12[CH2:7][C@H:4]([N:5]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C

Procedure:
To a stirred, ambient temperature, solution (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [113451-59-5] (1.0 g, 5.0 mmol) and Hunig's base [7087-68-5] (1.4 mL, 8.0 mmol) in ethyl acetate (120 mL) was slowly added a 1.0M solution of isopropyl chloroformate in toluene (5.1 mL) over the course of 10 minutes. The reaction was allowed to stir over night then was washed with brine, dried (MgSO4), and evaporated to obtain 1.3 g of yellow oil. LRMS (ESI) m/z 285.1 [(M+H)]+, calc'd for C14H24N2O4: 284.35.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1OC)([O-:3])=[O:2].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>>[CH:19]([NH:23][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH2:21][CH3:22])[CH3:20]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCC(C)N
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
In accordance with a more specific aspect of the present invention, a process is provided for producing N-sec-butyl-4-tert-butyl-2,6-dinitroaniline. The process may be broadly described as: (1) reacting 4-tert-butylphenol with dimethyl sulfate to produce 4-tert-butylanisole (a methylation reaction); (2) reacting the 4-tert-butylanisole with nitric acid, a reacting the 4-tert-butylanisole with nitric acid, a mixture of nitric acid and sulfuric acid or a mixture of nitric acid, sulfuric acid and oleum to produce 2,6-dinitro-4-tert-butylanisole (a nitration reaction); and (3) reacting the 2,6-dinitro-4-tert-butylanisole with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline (an amination reaction).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH:15][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:20]([Br:19])[CH:21]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NCC(=O)N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060mmol), diisopropylcarbodiimide (0.060mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CHCl3 1:1 (12 mL) and CH3OH (12 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-1-(4-chlorobenzyl)-3-[{N-(3-bromo-4-methylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1098) (11.6 mg, 50%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 466.0 (C21H23BrClN3O2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][N:12](C)[CH2:11][CH2:10][CH:9]=1.ClC(OC(Cl)C)=O>ClCCl.CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][NH:12][CH2:11][CH2:10][CH:9]=1
Reactant: CN1CCC=C(c2ccccc2Cl)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: Clc1ccccc1C1=CCCNC1
Reaction time: 2.5 h
Yield: 73.4 %

Procedure:
To a solution of the 5-(2-chlorophenyl)-1,2,3,6-tetrahydro-1-methylpyridine (5.9 g) in dichloromethane (60 ml) was added 1-chloroethyl chloroformate (5.1 ml) and the mixture was stirred for 2.5 h. The mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give brown oil. A solution of the obtained oil in methanol was refluxed for 2 h. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give 5-(2-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (2.4 g). A solution of 5-(2-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (155 mg), 2-chloro-1,6-dihydro-1-methyl-6-oxo-4-(pyrimidin-4-yl)pyrimidine (150 mg) and triethylamine (235 μl) in dimethylformamide (3 ml) was stirred at room temperature for 2 h. To the reaction mixture was added water (3 ml), and the precipitated crystals were collected by filtration to give the title compound (240 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH:8]([CH2:11][C:12](O)=O)[CH2:7][C:6]=2[CH:15]=1.F[C:17]1[CH:18]=[CH:19][C:20]2SCC(CI)CC=2[CH:28]=1.[C-]#[N:30].[Li+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH:8]([CH2:11][CH2:12][N:30]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:28]3)[CH2:7][C:6]=2[CH:15]=1
Reactant: Fc1ccc2c(c1)CC(CI)CS2
Reactant: O=C(O)CC1CSc2ccc(F)cc2C1
Reactant: [C-]#N
Agent: [Li+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)CC(CCN1CCCCC1)CS2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The starting material is prepared as follows: 6-Fluoro-3,4-dihydro-2H-1-benzothiopyran-3-ylacetic acid: A mixture of 3.8 g 6-fluoro-3-iodomethyl-3,4-dihydro-2H-1-benzothiopyran and 30 ml 0.5 M lithium cyanide in dimethylformamide is stirred at room temperature for 24 hours after which it is poured onto water. The product is extracted with ether. After drying over magnesium sulfate the solvent is removed in vacuo. This residue is refluxed in a mixture of 20 ml acetic acid and 20 ml 12 N HCl for 6 hours. The solvent is removed in vacuo, the residue is dissolved in 1 N NaOH and washed with ether. The aqueous phase is acidified with 3 N HCl and the product is extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo. The residue is triturated with ether/hexane and affords the title compound, m.p. 125°-135° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].CC(C(NCC(O)=[O:21])=S)C(N)=N.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[C:2]([OH:21])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: CC(C(=N)N)C(=S)NCC(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
In order to maintain xylose dehydrogenase expression during the fermentation, 0.5 mM ITPG was added for 24 hours after OD600 reached 10. Strains continued growing by the addition of glucose.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7]>C1COCC1.CO.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[C:6]([OH:7])=[O:5])(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Lithium hydroxide monohydrate (1.7 mmol) was added to a mixture of (1R,2S)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid methyl ester in THF (8 mL), methanol (8mL) and water (8 mL). Reaction stirred at room temperature overnight. Organic solvents were removed from the mixture in vacuo. Remaining aqueous was washed with ether (2×15 mL). Aqueous layer was made acidic to litmus paper with 1 N hydrochloric acid. Mixture was extracted with ethyl acetate (2×20 mL). Combined extracts were washed with brine (1×10 mL) then dried (magnesium sulfate), filtered and concentrated in vacuo. The product (208 mg) was obtained as a white solid in 80% yield: 1H NMR (300 Mz, CDCl3) δ 7.70 (d, 2 H, J=8.8), 7.48 (d, 4 H, J=8.8), 6.20 (d, 1 H, J=9.5), 3.41 (m, 1 H), 2.81 (dd, 1 H, Jd=4.4, Jd=4.8), 2.03 (m, 1 H), 1.80 (m, 1 H), 1.62 (m, 1 H), 1.44 (m, 2 H), 1.25 (m, 2 H); MS m/e 316 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:27][CH:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CNC3)c2)c2ccc(F)cc21
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 3-((4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Intermediate 37; 330 mg; 0.65 mmol) in DCM (10 mL) was added TFA (5 mL) dropwise. The reaction mixture was stirred for 0.5 hour and concentrated, neutralized with saturated aqueous Na2CO3 (50 mL), extracted with EtOAc (50 ml×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC to afford 265 mg (100%) of the title compound as a brown solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][C:22]=1[C:27](O)=[O:28]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:27]([C:22]3[NH:23][C:24]([CH3:26])=[CH:25][C:21]=3[CH3:20])=[O:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Product: Cc1cc(C)c(C(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)[nH]1
Yield: 58 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 3,5-dimethylpyrrole-2-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting 140°-141° C., in a 58% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:13])=[N:7][C:6]=2[CH:11]=1
Reactant: Fc1cc2nc(S)sc2cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2cc(F)c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A suspension (0° C.) of 300 mg (1.476 mmol) 5,6-difluoro-benzothiazole-2-thiol and 306 mg (2.214 mmol) potassium carbonate in 6 mL N,N-dimethylformamide under nitrogen, were added 110.5 μL (1.77 mmol) iodomethane. The mixture was stirred at 0° C. for 1 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 294 mg (91.7%) of the title compound as a solid. MS(m/e): 218.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][C@H:3]1[CH2:14][OH:15].C(N(CC)CC)C.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:16])[CH2:7][O:6][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:4][C@H:3]1[CH:14]=[O:15]
Reactant: CC1(C)COC(c2ccccc2)O[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)COC(c2ccccc2)O[C@H]1C=O
Yield: 74.6 %

Procedure:
Following the general procedure for oxidation reactions of Description 7, 40.2 g (181.9 mmol) of [(4R)-5,5-dimethyl-2-phenyl-1,3-dioxan-4-yl]methan-1-ol (7a) in 1,100 mL of dichloromethane (DCM) in the presence of 126.8 mL (92.1 g, 0.910 mol) of triethylamine and 103.3 mL (113.8 g, 1.456 mol) of dimethylsulfoxide (DMSO) was reacted with 86.9 g (0.55 mol) of sulfur trioxide pyridine complex to afford 38.3 g (96% yield) of the crude title compound (7b). Purification by silica gel column chromatography using mixtures of methyl tert-butyl ether (MTBE) and hexane (Hxn) as eluent (MTBE/Hxn=1:9→MTBE/Hxn=1:6) provided 29.9 g (75% yield) of the title compound (7b) as a colorless liquid. Rf=0.58 (MTBE/Hxn=1:2). 1H NMR (400 MHz, CHCl3): δ=1.04 (s, 3H), 1.27 (s, 3H), 3.69 (d, J=11.6 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.97 (d, J=1.2 Hz, 1H), 5.56 (s, 1H), 7.35-7.44 (m, 3H), 7.54-7.58 (m, 2H), 9.66 (d, J=1.6 Hz, 1H) ppm. MS (ESI) m/z: 221.0 (M+H)+, 242.9 (M+Na)+. The analytical data for the compound was consistent with that given in the literature (Ito et al., Synthesis, 1993, 137-140).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH:11]([C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])O)=[N:7][CH:6]=1)=[O:4].S(=O)(=O)(O)O.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH:28]([NH:31][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[N:7][CH:6]=1)=[O:4])([CH3:30])[CH3:29]
Reactant: CCCCc1noc(C)c1C(O)Cc1ncc(C(=O)OC)s1
Reactant: CC(C)N
Agent: O=S(=O)(O)O
Product: CCCCc1noc(C)c1/C=C/c1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Yield: 32.6 %

Procedure:
2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-thiazole-5-carboxylic acid methyl ester (30 mg, 0.092 mmol) was stirred with concentrated sulfuric acid (0.1 mL) for 30 min, then the reaction mixture quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated, then dissolved in toluene (0.5 mL) and isopropylamine (22 mg, 0.37 mmol) and TBD (13 mg, 0.092 mmol) added. The reaction mixture was then heated at 90° C. for 15 h and then the reaction mixture was concentrated then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (10 mg, 34%) as a pale yellow oil. MS: m/e=334.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(Br)cnc1C1=CCOCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1C1=CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinamine (0.17 g, 0.67 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (54.9 mg, 1.37 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(2-pyridinyl)quinoline (0.22 g, 0.74 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the brownish residue was treated with isopropanol and warmed to 45° C. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as mostly N-(5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br-].[CH2:20]1[CH2:24]OC[CH2:21]1>>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:24][CH:20]=[CH2:21])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Agent: [Br-]
Product: C=CCC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution (E)-N-(1,4-dioxaspiro[4.5]decan-8-ylmethylene)-2-methylpropane-2-sulfinamide (1.91 g, 6.99 mmol), prepared in the previous step, in dry THF (48 mL) was treated with a solution of allylmagnesiumm bromide (10.5 mL, 21 mmol, 2N in THF) dropwise at ambient temperature under argon. After the complete addition, the reaction mixture was allowed to stir at room temperature and for 3 hours and then quenched at 0° C. by the cautious addition of saturated ammonium chloride solution. After extraction with ethyl acetate, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-5% MeOH/Ethyl Acetate) to afford the product as a mixture of disatereomers.