Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:27]#[N:28])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2CC1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 3-(tert-butoxycarbonyl)-7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (4.78 g, 12.1 mmol), zinc cyanide (1.42 g, 15.6 mmol) and tetrakis-triphenylphosphine palladium (0) (1.4 g, 1.2 mmol, 10 mol %), in dry dimethylformamide (50 ml) was stirred at 100° C. for 3 h under argon. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (120 ml) and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate (100 ml), then water (2×50 ml), then brine (50 ml). The organic layer was dried over sodium sulfate and evaporated in vacuo to give brown oil, which was purified by chromatography on silica gel with 20-100% ethyl acetate-hexane elution to give the title compound (0.765 g, 23%) as a brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:23](=[O:24])[C:22]2[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:21]=2[Cl:20])[CH2:8][CH2:7]1)=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride (6.7 g, 34.7 mmol) in dry THF (90 ml) under nitrogen atmosphere was added triethylamine (12 ml, 86.8 mmol). The suspension was cooled to 0° C. and 2-chloro-5-(trifluoromethyl)benzoyl chloride (8.85 g, 36.4 mmol) in dry THF (40 ml) was added dropwise over 20 minutes. The resulting thick, colourless slurry was stirred at 0-5° C. for 30 minutes and then allowed to warm to room temp and stirred at room temp for 1 hour. The reaction was quenched by the dropwise addition of water (5 ml) in THF (45 ml) to give a clear solution. This was diluted with water (100 ml) and ethyl acetate (300 ml). The biphasic mixture was stirred for 5 minutes then the organic phase was separated and washed successively with water (100 ml), saturated sodium bicarbonate (100 ml) and saturated brine (100 ml), dried (MgSO4), filtered and evaporated to give a colourless solid; [M+H]+364.
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:22]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1F
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A well stirred suspension of 3.6 g (0.012 mole) of 1,3-dihydro-3-hydroxy-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10°, at which temperature all of the solid went into solution. The reaction mixture was poured into 400 ml of ice water, and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-heptane to give 3.0 g (83%) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 174°-175° (dec.); 1H nmr (DMSO-d6) δ 5.90 ppm (d, J = 57 Hz, 1H), 7.3-7.7 ppm (m, 6H), 8.07 ppm (d, J = 2.5 Hz, 1H) and 8.45 ppm (d, d, J = 9.0, 2.5 Hz, 1H); 19F nmr (DMSO-d6) δ -161.4 ppm (d, J = 57 Hz).
Reaction SMILES: CC([O-])(C)C.[Na+].Cl[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].Br[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][O:24][C:17]1[C:16]2[NH:10][C:9]3[C:8](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:21]=2[C:20]([O:22][CH3:23])=[CH:19][CH:18]=1
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc(OC)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1[nH]c1ccccc12
Temperature: 170 °C
Yield: 54.2 %

Procedure:
Following a published procedure (Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403-9410), NaOtBu (0.754 g, 7.84 mmol), Pd(OAc)2 (0.014 g, 0.06 mmol), and [HPtBu3][BF4](0.023 g, 0.078 mmol) were suspended in dry toluene (5 mL) in a microwave vial. 2-Chloroaniline (0.165 mL, 1.567 mmol) and 2-bromo-1,4-dimethoxybenzene (0.240 mL, 1.598 mmol) were then added, and the vial was sealed. The reaction was then heated in the microwave reactor at 170° C. for 4 h, allowed to cool, and then quenched by addition of 1M HCl. The aqueous phase was extracted with CH2Cl2, the organic layer was dried over Na2SO4, filtered and condensed. The crude mixture was purified by chromatography (SiO2, 0-10% EtOAc/Hexane) to afford the title product (0.193 g, 55%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].O=[C:17]1[CH2:22][CH2:21][C:20]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)([C:23]#[N:24])[CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[S:27]1[CH:28]=[CH:29][C:25]([C:20]2([C:23]#[N:24])[CH2:21][CH2:22][C:17]3([O:15][CH2:12][CH2:13][O:14]3)[CH2:18][CH2:19]2)=[CH:26]1
Reactant: N#CC1(c2ccsc2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CC1(c2ccsc2)CCC2(CC1)OCCO2
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Catalytic quantities of para-toluene sulfonic acid and ethyleneglycol (13.3 g: 0.21 mole) were added to 4-oxo-1-thiophen-3-yl-cyclohexanecarbonitrile (22 g; 0.107 mole) dissolved in toluene (500 ml). The reaction mixture was stirred for about 2 hours under reflux. On completion of the reaction (reaction monitored by thin layer chromatography), the toluene phase was separated, washed with sodium hydrogen carbonate solution (200 ml), dried (sodium sulfate) and concentrated under vacuum. 25 g 8-thiophen-3-yl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (95%; colorless solid) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:79])[C@H:71]([CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76])[NH2:72]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:72][CH:71]([CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76])[C:70]([O:69][CH3:68])=[O:79])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.34 mmol) in 10 ml of anhydrous DMF were added HATU (156 mg, 0.41 mmol) and N,N-diisopropylethylamine (175 mg, 1.36 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (108 mg, 0.51 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give dimethyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as white solid. Yield: 120 mg, 59%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH:38]([NH2:41])([CH3:40])[CH3:39]>C1COCC1>[CH:38]([NH:41][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])([CH3:40])[CH3:39]
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 80 °C
Reaction time: 21 h
Yield: 57.9 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.433 g, 0.807 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 15 hours. Additional isopropylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. for 21 hours. It was allowed to cool to room temperature, and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.25% ammonium hydroxide/2.5% methanol in chloroform. Drying at 63° C. in vacuo for 30 minutes yielded isopropyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl}-amine as a yellow semi-solid 0.198 g, 57.9%). This was dissolved in chloroform, and ethereal hydrochloride was added. The precipitate was filtered and dried at 85° C. in vacuo for 13 hours to give the hydrochloride as an off-white solid (0.180 g): MP: 274-6° C. (dec).; Mass Spectrum (+EI, [M+H]+) m/z 424.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:23][CH3:24])=[CH:8][CH:7]=1)=[N+]=[N-]>CO.[Pd]>[CH2:23]([C:13]1[N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:11][CH:10]=2)[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:14]=1)[CH3:24]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN)cc1
Reaction time: 4 h
Yield: 103 %

Procedure:
To a solution of 1-[4-(2-azidoethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole (960 mg, 3.0 mmol) in methanol (50 mL) was added 10% Pd—C (50 mg). The resulting mixture was stirred for 4 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated to afford 900 mg (94%) of the title compound as colorless amorphous: MS (ESI) m/z 292 [M+H]+1H-NMR (CDCl3) δ1.26 (2H, t, J=7.5 Hz), 2.72 (3H, q, J=7.7 Hz), 2.84 (2H, t, J=6.6 Hz), 3.01-3.06 (2H, br), 7.20-7.40 (9H, m), 7.81 (2H, dd, J=7.1, 1.2 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]=[CH2:12].[Li]CCCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[CH2:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[CH:20]=[O:21])[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1cc(F)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of 1-bromo-2-(but-3-en-1-yl)-4-fluorobenzene (0.5 g, 2.183 mmol) in tetrahydrofuran (10 mL) at −78° C. was added BuLi (1.048 mL, 2.62 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.204 mL, 2.62 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then warmed up to rt and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 10% EtOAc/hexane to obtain 2-(but-3-en-1-yl)-4-fluorobenzaldehyde (0.35 g, 90%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.88 (dd, J=8.6, 6.1 Hz, 1H), 7.08 (td, J=8.3, 2.6 Hz, 1H), 7.05-6.96 (m, 1H), 6.00-5.73 (m, 1H), 5.12-4.99 (m, 2H), 3.22-3.09 (m, 2H), 2.49-2.34 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[N:9][CH:10]=1.[BH4-].[Na+].CO.C(Cl)(Cl)Cl>CO>[OH:1][CH:2]([C:19]1[N:20]=[C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:22][C:23]=1[CH3:24])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[N:9][CH:10]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CC2SC(=O)NC2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1C(O)COc1ccc(CC2SC(=O)NC2=O)nc1

Procedure:
200 mg (0.47 mmol) of 5-((5-(2-oxo-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy)-2-pyridyl)methyl)thiazolidin-2,4-dione (Compound No. I-2a-1) was dissolved in 5 ml of methanol dehydrated with molecular sieve. To this solution, was added 21.5 mg of sodium borohydride, and the resultant solution was stirred at room temperature for 1 day. The reaction was terminated with a saturated aqueous solution of ammonium chloride, and the reaction mixture was extracted with chloroform. The reaction product thus obtained was washed with brine, and was dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off under a reduced pressure to obtain a residue, and the residue thus obtained was subjected to silica gel column chromatography (eluent: 10%--methanol/chloroform) to obtain 203 mg (quantitative) of pale brown powder of the aimed product (Compound No. I-2a-3).
Reaction SMILES: CC1C(C=CC2CCC=CO2)=C(C)ON=1.C(=O)(O)[O-].[Na+].[CH3:21][C:22]1[C:26]([CH:27]=[CH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH:31]([O:35]CC)[O:30]2)=[C:25]([CH3:38])[O:24][N:23]=1.[H][H].CC1C(CCC2CCCC(OCC)O2)=C(C)ON=1.S(=O)(=O)(O)O>S(=O)(=O)(O)O.[Pd].O1CCOCC1.C(OCC)(=O)C.C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH:31]([OH:35])[O:30]2)=[C:25]([CH3:38])[O:24][N:23]=1
Reactant: CCOC1CCCC(C=Cc2c(C)noc2C)O1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC1CCCC(CCc2c(C)noc2C)O1
Agent: Cc1noc(C)c1C=CC1CCC=CO1
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1CCC1CCCC(O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g. (4.88 mmoles) of 3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl) isoxazole, prepared as described in Example 5 above, in 10 ml. of ethanol was added 5 drops of 1N sulfuric acid. The solution was stirred at room temperature overnight, poured into excess saturated aqueous sodium bicarbonate solution, and extracted with ether. The ether extracts were washed with water and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave 1.25 g. of pale yellow liquid whose infrared spectrum indicated that formation of racemic 3,5-dimethyl-4-(6-ethoxytetrahydropyran-2-ylvinyl) isoxazole was complete. This material was taken up in 10 ml. of ethyl acetate. To this solution was added 25 mg. of 10 percent palladium on carbon and the resulting mixture was hydrogenated at room temperature and atmospheric pressure. After 2 hr., one equivalent of hydrogen had been consumed and uptake ceased. The catalyst was removed by filtration and washed with fresh ethyl acetate. Solvent removal from the filtrates gave 1.28 g. of racemic 3,5-dimethyl-4-(6-ethoxytetrahydropyran-2-ylethyl)-isoxazole as a colorless oil whose infrared spectrum indicated that the hydrogenation was complete. This crude acetal was taken up in 20 ml. of dioxane. To the flask was added 10 ml. of 1N sulfuric acid and the resulting solution was stirred at room temperature for 4 hr. It was then poured into excess saturated aqueous sodium bicarbonate solution and extracted with ether. The ether extracts were washed with saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave racemic 3,5-dimethyl-4-(6-hydroxytetrahydropyran-2-ylethyl)-isoxazole as a viscous oil. The crude hemiketal was taken up in 25 ml. of 1,2-dichloroethane, degassed and placed under nitrogen. To the flask was added 7.5 g. of manganese dioxide and the resulting suspension was stirred at room temperature overnight. The manganese dioxide was removed by filtration and washed with fresh solvent. Solvent removal from the filtrates gave a pale yellow resin which was crystallized from ether at -20° C. to give the desired acetone as a white solid of m.p. 60°-62°. A similarly prepared sample was shown by its infrared and nmr spectra, mixture melting point, and thin layer chromatographic behavior to be identical with the material prepared as described above in part A.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.Cl.N([O-])=O.[Na+].[I-:27].[Na+].C(=O)([O-])O.[Na+]>CC(C)=O.O>[I:27][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(I)cn1
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a solution of 5-amino-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (7.10 g) in acetone (200 ml)-water (50 ml) was added dropwise concentrated hydrochloric acid (7.46 g) under ice cooling, and then solution of sodium nitrite (1.83 ) in water (10 ml) was added dropwise. The mixture was stirred for 10 minutes. To the mixture was added a solution of sodium iodide (4.40 g) in water (20 ml) under ice cooling. The mixture was stirred at 15°-20° C. for 2 hours. To the reaction mixture was added water, and the mixture was neutralized with a solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography. From the fraction eluted with ethyl acetate-hexane (1:9, v/v), crystals (6.65 g, 67%) of 5-iodo-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine were obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms. Melting point: 129°-130° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
1.0 g of 4-hydroxy-1-indanone, 1.07 g of 2-chloro-5-nitropyridine and 5 g of anhydrous potassium carbonate were dissolved in 10 ml of N,N-dimethylformamide (DMF) and the mixture was stirred at room temperature for 17 hours. After the completion of the reaction, 50 ml of water was added to the reaction solution and the solution was extracted with ethyl acetate. After the organic (ethyl acetate) layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to obtain the titled compound (1.36 g, pale yellow powder).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41].[CH3:42][NH:43][CH3:44]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH3:44])[CH3:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41]
Reactant: CNC
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(N(C)C)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reaction time: 72 h

Procedure:
To the compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.075 g, 0.129 mmol) in THF (4 mL) was added a 1.0 M solution of dimethylamine in THF (0.322 mL, 0.322 mmol). The mixture was stirred under argon for 3 days. The completed reaction mixture was diluted with EtOAc and the organic phase washed with water, brine (2×), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with 1% MeOH/CH2Cl2 to afford the title compound as a white solid. mp 257.8-264.3° C.; LC-MS m/z 547 (M+H)+, 2.24 min (ret. time).
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[O:9]C)[CH3:3].ClCl.[OH-].[Na+]>CO.O>[CH3:3][C:2]1[O:1][CH:6]=[CH:7][C:8](=[O:9])[C:4]=1[OH:5]
Reactant: COc1ccoc1C(C)O
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1O
Temperature: 90 °C

Procedure:
2-(1-hydroxyethyl)-3-methoxy-furan (0.350 g, 2.5 mmole) in 4 ml of methanol and 1 ml of water was added to a solution of 2 ml of methanol and 5 ml of water as chlorine gas (2.5 mmoles) was added to the well stirred reaction. The temperature of the reaction was kept below -10° C. at all times. Following the addition the reaction was heated to 90° C. for 3 hours. After cooling, the reaction was adjusted to a pH 2.2 with 50% NaOH solution, the reaction was extracted with chloroform and the chloroform concentrated to yield maltol.