Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][C:25]1[CH:26]=[C:27]([SH:32])[CH:28]=[CH:29][C:30]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][C:25]1[CH:26]=[C:27]([S:32][C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(S)cc1C
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(C)c(C)c3)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To a solution of the compound of Example 32A (40 mg, 0.12 mmole) in 2.5 mL of dimethylformamide was added 3,4-dimethylthiophenol (17 mg, 0.12 mmole), followed by potassium carbonate powder (20 mg, 0.14 mmole). The mixture was heated at 100° C. for 20 h. The solvent was removed using N2 gas flow. Water (5 mL) was then added to the residue, the resulting precipitate was collected through filtration, washed with cold water, and air dried to give the title compound (42 mg, 81%) as light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H), 2.23 (s, 3H), 2.27 (s, 3H), 3.45 (br, m, 2H), 3.63 (br, m, 6H), 6.79 (s, 1H), 6.82 (d, J=19 Hz, 1H), 7.18 (d, J=19 Hz, 1H), 7.24 (dd, J=4, 19 Hz, 1H), 7.27 (s, 1H), 7.34 (d, J=21 Hz, 1H), 7.56 (d, J=39 Hz, 1H), 8.32 (d, J=4 Hz, 1H). MS (APCI) (M+H)+ at m/z 440. FAB High Resolution MS calculated m/z for C23H26N3O4S (M+H)+: 440.1644. Observed m/z: 440.1646.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[O:16][C:7]1([CH2:11][CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:25]=[C:26]=[N:27][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[O:16][C:7]1([CH2:11][CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8]1)[CH2:6]/[C:5]/2=[N:27]\[C:26]#[N:25]
Reactant: CC(C)(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (200 mg, 0.60 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (1 M solution in DCM, 1.20 mmol) dropwise within 15 minutes. The mixture was stirred for 1 h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (244 mg, 1.31 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (30 g) and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-(6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (200 mg, crude), which was used for the next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13].CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH:9][C:12](=[O:13])[O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[CH2:5][CH2:4]1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC(F)(F)CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,4-difluorocyclohexanamine hydrochloride (Matrix scientific, 250 mg, 1.45 mmol) in DCM (5 mL) was added 4-nitrophenyl chloroformate (367 mg, 1.82 mmol) and DIEA (507 μl, 0.29 mmol). The resulting mixture was then stirred at RT for 16 h. Then, MeOH (2 mL) was added and the solvents were removed. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a yellow solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1>ClCCl>[OH:14][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:17]2([C:5]#[N:6])[CH2:20][CH2:19][CH2:18]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#CC1(Nc2ccc(CO)cc2)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
Trimethylsilyl cyanide (0.66 ml, 5 mmol) was added dropwise to a mixture of 4-aminobenzoic acid (0.492 g, 4 mmol) and cyclobutanone (0.35 g, 5 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 6 h and then concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane) to yield 36a (0.677 g, 3.36 mmol, 84%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)C(C)C)(C)C.[CH3:40][NH:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45]>CN(C)C=O.O>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][N:41]([CH3:40])[C:14](=[O:16])[CH2:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CNCCN(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-3-methylbutanoic acid (described in international publication number WO 2008/083347 A1) (5.74 g, 22.9 mmol) in N,N-dimethylformamide (150 ml) was added N,N-carbonyldiimidazole (4.45 g, 27.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. N,N-diisoproylethylamine (11.2 ml, 68.8 mmol) and N,N,N-trimethylethylenediamine (3.6 ml, 27.8 mmol) were added was added to the reaction mixture. The mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed two more times with water and dried over sodium sulfate. The dried organic layer was filtered and concentrated in vacuo. The crude product was purified on silica gel column chromatography (0 to 10% methanol in dichloromethane) to give 2.08 g (27% yield) of benzyl 4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl-4-oxobutan-2-ylcarbamate. 1H NMR (CDCl3) δ 7.34-7.26 (m, 5 H), 6.14 (s, 1 H), 5.04 (s, 2 H), 3.47 (t, J=5.3 Hz, 2 H), 3.02 (s, 3 H), 2.60 (s, 2 H), 2.59 (t, J=5.3 Hz, 2 H), 2.24 (s, 6 H), 1.46 (s, 6 H); MS (ESI+) calculated for C18H30N3O3: 335.23, Found: 336.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(O)c1
Yield: 87 %

Procedure:
A mixture of 3,5-dihydroxybenzoic acid (106 g, 0.69 mol), 1200 ml of methanol and 6 ml of concentrated sulfuric acid is added to a 2L, three-necked round-bottom flask equipped with a Soxhlet extraction apparatus, the thimble of the Soxhlet being packed with 4Å molecular sieves. The solution is stirred and heated at reflux for 24 hours and after removal of the methanol from the reaction solution under reduced pressure, the powder residue is washed with water and recrystallized from water to yield 87 percent of white, needle-like crystals: mp 167°-167.5° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15]1)([CH3:7])([CH3:6])[CH3:5].[C:30](=[O:33])([O-])[OH:31].[Na+].O.Cl>CS(C)=O>[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:15][CH2:16][N:17]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[NH:3][C:30](=[O:33])[O:31][N:27]=3)=[CH:28][CH:29]=2)=[O:21])[CH2:18][CH2:19]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(-c3noc(=O)[nH]3)cc2)CC1
Temperature: 40 °C
Yield: 78.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.04 g) in DMSO (10.0 mL) was stirred at 40° C. After stirred at 40° C. for 1 h, a mixture of 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}benzonitrile obtained in Example 16 (1.1 g) and sodium hydrogen carbonate (1.26 g) was added to the mixture. After stirred at 90° C. for 1 h, the reaction mixture was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in THF (30.0 mL), added to a mixture of 1,1′-carbonyl bis-1H-imidazole (0.568 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.522 mL) and the resulting reaction mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was poured into 1 M HCl water solution and extracted with ethyl acetate. The combined organics were washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure to provide the title compound (1.01 g, 78%) as a solid.
Reaction SMILES: N[C:2]1C(C(OC)=[O:11])=NC(I)=C(N)N=1.[C-]#N.[Na+].O.[NH2:18][C:19]1[C:20]([C:28]([OH:30])=[O:29])=[N:21][C:22]([C:26]#[N:27])=[C:23]([NH2:25])[N:24]=1.[NH2:31][C:32]1[C:33]([C:41]([OH:43])=[O:42])=[N:34][C:35]([C:39]#[N:40])=[C:36]([NH2:38])[N:37]=1>CN(C)P(N(C)C)(N(C)C)=O>[OH2:11].[NH2:18][C:19]1[C:20]([C:28]([O:30][CH3:2])=[O:29])=[N:21][C:22]([C:26]#[N:27])=[C:23]([NH2:25])[N:24]=1.[CH3:2][O:42][C:41]([C:33]1[C:32]([NH2:31])=[N:37][C:36]([NH2:38])=[C:35]([C:39]#[N:40])[N:34]=1)=[O:43]
Reactant: COC(=O)c1nc(I)c(N)nc1N
Reactant: N#Cc1nc(C(=O)O)c(N)nc1N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1nc(C#N)c(N)nc1N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl 3,5-diamino-6-iodo-2-pyrazinoate (370 mg., 0.0012 mole), cuprous cyanide (215 mg., 0.0024 mole) and hexamethylphosphoramide (10 ml.) are combined and heated at 100° C. for 15 minutes. After cooling to 25° C. the reaction mixture is added to aqueous sodium cyanide solution, stirred at 25° C. for 1 hour and extracted with CHCl3. The CHCl3 layer was washed with dilute NaCN solution, then with H2O, and dried (MgSO4). After evaporation of the CHCl3, the residual oil was treated with hexane to give 75 mg. of methyl, 3,5-diamino-6-cyano-2-pyrazinoate hemihydrate melting at 284°-5° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([F:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:25]([O:24][C:20](=[O:23])[CH:21]=[CH:22][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:19])=[CH:12][C:13]=1[F:18])[CH3:26]
Reactant: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A suspension of 9.72 g (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (30 mmol), 6 g ethyl acrylate (60 mmol), 10.2 ml DIPEA (60 mmol), 112 mg palladium acetate (3 mmol), and 1.57 g triphenylphosphine (6 mmol) in 10 ml DMF were stirred at 130° C. for 48 h. The reaction was monitored by TLC. The DMF was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography, using a 7/3 N-hexane/ethyl acetate mixture as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1
Reactant: c1cn[nH]c1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.73 g, 4 mmol), pyrazole (0.408 g, 6 mmol), Cu2O (0.057 g, 0.4 mmol), salicylaldoxime (0.219 g, 1.6 mmol), and Cs2CO3 (2.60 g, 8 mmol) in CH3CN (8 mL) was refluxed for 6 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (0.370 g, 25% yield) as a white solid: mp 187-189° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.72 (3H, s), 3.93 (3H, s), 6.55 (1H, dd, J=1.5, 2.3 Hz), 7.60 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.77 (3H, m), 7.84 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=2.6 Hz). Anal. Calcd for C17H16FN5O4: C, 54.69; H, 4.32; N, 18.76. Found: C, 54.58; H, 4.40; N, 18.67.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>[Pd].[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc(I)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc(Br)cn1

Procedure:
Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodide under inert conditions in an appropriate solvent and base e.g. DMF/Et3N with ethynyl-trimethyl-silane using a palladium catalyst e.g. Pd(PPh3)4 at room temperature gives 2-Bromo-5-trimethylsilanylethynyl-pyrazine. This material can be used without further purification and reacted to form 6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine using 0-(mesitylenesulfonyl)hydroxylamine to form the N-amino adduct. This can then be cyclised by reacting with base e.g. K2CO3 to form pyrazolopyrazine core (Scheme 6).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=O)C.O>C(OCC)C>[C:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([CH:21]=[O:20])[CH2:24]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 56.5 %

Procedure:
A 1.2 M solution of diisobutylaluminum hydride in toluene (30.8 ml, 36.9 mmol) was added at −78° C. to a solution of (3R)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (4.13 g, 16.1 mmol) in diethyl ether (30 ml). The reaction mixture was stirred for 2.5 h at −78° C. Water (9.6 ml) was added dropwise. The reaction mixture was warmed to room temperature. The precipitation was removed by filtration through a plug of celite. The celite was washed with tert-butyl methyl ether (3×100 ml). The liquids were combined and dried over magnesium sulfate. The solvent was removed in vacuo, to give 1.94 g of crude (3R)-3-formylpiperidine-1-carboxylic acid tert-butyl ester, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:16])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[S:26])[NH2:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCCCCCCCCCCC(N)=O
Solvent: C1CCOC1
Product: COCCCCCCCCCCCC(N)=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 127.3 %

Procedure:
To the title product from Example 12 (1.0 g, 5 mmol) in 70 mL of anhydrous tetrahydrofuran was added 2,4-bis (4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide [Lawesson's Reagent] (1.0 g, 2 mmol). After stirring at room temperature for 1 day, the solvent was removed by rotary evaporator and the resulting residue waspurified by chromatography on silica gel using 30-70 ethyl acetate-hexane as eluant to give the title compound (625 mg) as a white solid, m.p. 86.8°-89.2° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.C(N(CC)CC)C.[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44]>[I-].OCCC1SC=[N+](C)C=1C.CCO>[O:26]=[C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2)[CH2:44][CH2:43][C:42]([O:46][CH3:47])=[O:45]
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C=CC(=O)OC
Agent: Cc1c(CCO)sc[n+]1C
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCCl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 7 h
Yield: 23.6 %

Procedure:
To a mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 80 mg, 0.195 mmol), 5-(2-hydroxyethyl)-3,4-dimethylthiazolium iodide (11.12 mg, 0.039 mmol), 1,2-dichloroethane (1 mL), EtOH (1.000 mL), triethylamine (0.082 mL, 0.585 mmol) and methyl acrylate (0.053 mL, 0.585 mmol) was bubbled with nitrogen for 1 min. and then sealed in a 1-dram vial. The mixture was heated at 75° C. for 15 h. Additional 5-(2-hydroxyethyl)-3,4-dimethylthiazolium iodide (30 mg) and methyl acrylate (0.053 mL, 0.585 mmol) were added and the mixture was stirred at 75° C. for 7 h. The solvents were removed under reduced pressure. The residue was treated with water (2 mL) and extracted with dichloromethane. The combined dichloromethane extracts were dried (sodium sulfate) and concentrated. Flash chromatography purification (4 g silica gel column, 20→100% dichloromethane in heptanes) afforded methyl 4-oxo-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (23 mg, 0.046 mmol, 23.76% yield) as a glassy solid.
Reaction SMILES: O=C1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4](=[O:24])O1.Cl.[CH:26]1([CH2:31][O:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([CH2:31][O:32][NH:33][C:4](=[O:24])[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=2[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NOCC1CCCC1
Reactant: CS(=O)(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Agent: Cl
Product: CS(=O)(=O)Nc1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added methanesulfonyl chloride (280 mg) and the reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining solid yellow material was dissolved in a mixture of hot EtOAc (50 ml) and DMF (4 ml). On cooling a solid material formed, that was isolated by filtration and dried under vacuum, affording N-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-methanesulfonamide. Step 2: This anhydride intermediate was converted into the title compound by reaction with O-cyclopentylmethyl-hydroxylamine hydrochloride (see preparation 66), using general procedure 1A. 13C-NMR (DMSO-d6) δ 166.8, 152.9, 152.6, 148.3, 132.4, 127.9, 115.2, 114.8, 113.3, 111.4, 110.1, 79.4, 45.0, 41.5, 37.6, 28.9, 24.9.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[N+](C)(C)C.C(O)(=O)C(C)C.[C:18](=[O:28])([S:26][CH3:27])[O:19][O:20][CH:21](Cl)[CH:22]([CH3:24])[CH3:23]>CCOC(C)=O>[C:18](=[O:28])([S:26][CH3:27])[O:19][O:20][CH:21]([O:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)[O-]
Reactant: CSC(=O)OOC(Cl)C(C)C
Agent: C[N+](C)(C)C
Solvent: CC(C)C(=O)O
Solvent: CCOC(C)=O
Product: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Temperature: 80 °C
Yield: 67.7 %

Procedure:
In a third step (Step C), to a 3 L three neck round bottom flask equipped with a mechanical stirrer and Teflon-coated thermocouple was added compound (13) (1672 g, 9 mol), isobutyric acid (264 g, 1.5 mol), and compound (12) (1050 g, 5.76 mol). The reaction mixture was heated to 80° C. for 12 h, monitoring the reaction progress by 1H NMR. The reaction mixture was cooled to 20° C., diluted with EtOAc (1 L) and washed with water (2×1 L), saturated NaHCO3 (1×2 L) and water (1 L). The organic phase was separated and concentrated under reduced pressure to afford O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) (905 g, 3.9 mol, 65%) as a colorless liquid. 1H NMR (CDCl3, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H), 2.05 (m, 1H), 2.35 (s, 3H), 2.6 (m, 1H), 6.7 (d, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1COCC1>[C:19]([O:18][C:8]1([CH3:7])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Yield: 39 %

Procedure:
The procedure of Comparative Example 1 was repeated with the proviso that under the cooling conditions, 24 ml of pyridine was slowly dropwise added to a mixture of 22.6 g (0.136 mole) of 2-methyl-2-adamantanol, 130 ml of THF and 26.6 g of methacrylic chloride. The raw product was purified on a column of silica gel to obtain 12.1 g of the target product, i.e., 2-methyl-2-adamantyl methacrylate, (yield: 39.0%). It was confirmed that the product contained a remarkable amount of impurities.