Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][C@H:4]1[C:12]2[C:11]([C:13]3[S:17][C:16]([C:18]([O-:20])=[O:19])=[CH:15][CH:14]=3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([O:21]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:5]1>C1COCC1.O>[OH:21][C@H:6]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:13]3[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=3)[C:12]=2[C@H:4]([CH3:3])[CH2:5]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc(C(=O)[O-])s3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)O)s3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide (6 mg, 0.146 mmol) was added to a solution of 5-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate (32 mg, 0.073 mmol) in THF (0.5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. THF was removed under reduced pressure, and 1N HCl (5 mL) was added. The reaction mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid. The crude mixture was used directly in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)=[CH:5]OCC.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[C:3](=[O:20])[C:23]3[C:22](=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:21][CH:5]=2)=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: Nc1cccnc1
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Yield: 65.1 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.60 g (2.27 mmol) of 3-ethoxy-2-(4-methoxy-3-methyl-benzoyl)-acrylic acid methyl ester, 0.214 g (2.27 mmol) of 3-aminopyridine, and 15 mL of diphenyl ether to yield 0.435 g of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(cc1N1CCOCC1)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cc(N3CCOCC3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[H-].[Na+].[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>C1COCC1>[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:21][CH:20]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: COCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOCc1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of tetraethylene glycol monomethyl ether (2.00 g, 9.61 mmol) in THF (15 mL) at room temperature was added NaH (276.7 mg, 11.53 mmol). The reaction mixture was stirred for 30 min, followed by the addition of 1,4-bis(chloromethyl)benzene (2.01 g, 11.5 mmol). The reaction mixture was stirred at room temperature overnight and subsequently the solvent was evaporated. The reaction mixture was then dissolved in CH2Cl2 and washed with water. The organic phase was dried with Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography to give the desired compound (2.56 g, 7.40 mmol, 77%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.26-7.40 (m, 4H), 4.55 (s, 2H), 4.54 (s, 2H), 3.69−3.56 (m, 14H), 3.53−3.50 (m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.7, 136.8, 128.7, 128.0, 72.8, 71.9, 70.7, 70.6, 70.5, 69.6, 59.1, 46.1; MS (ESI) m/z calculated for C22H35N6O11 [M+H]+ 347.1 found [M+H2O]+ 364.2.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([CH2:10][O:11][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[C:12]([OH:14])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N—BOC-D-serine (2.00 g, 9.75 mmol) in DMF (25 ml) was cooled to 0° C. under nitrogen atmosphere and sodium hydride (60% in mineral oil) (0.82 g, 20.47 mmol) was added portionwise over 15 minutes. After stirring at 0° C. for 30 minutes, 4-fluorobenzyl bromide (1.82 g, 9.75 mmol) in DMF (5 ml) was added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (100 ml) and water (50 ml). The aqueous phase was separated and washed with DCM (2×50 ml). The organic washings were discarded. The aqueous layer was acidified with 5% citric acid aqueous solution and back-extracted with DCM (2×100 ml). The combined organic portions were washed with brine (50 ml), dried (MgSO4) and concentrated in vacuo to yield the title compound as pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:14]([Mg]Br)[CH3:15]>C1COCC1>[CH2:14]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1)[CH3:15]
Reactant: CC[Mg]Br
Reactant: Clc1ccc(-c2ccccc2)nc1
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
5-Chloro-2-phenylpyridine (16 g, 84 mmol) and Ni(dppe)Cl2 (0.891 g, 1.687 mmol) were added to 300 mL of THF and the reaction mixture was degassed with nitrogen for 20 min. before being cooled to 0° C. Ethylmagnesium bromide (169 mL, 169 mmol) was added dropwise over a period of 60 min. and the reaction mixture stirred for and additional 3 h at before warming to room temperature overnight. The reaction mixture was recooled to 0° C. and quenched with 250 mL of water, extracted with EtOAc and the organic layer dried over sodium sulfate and filtered. The crude material was chromatographed on silica with 95/5 hexane/EtOAc to give 2.9 g (19%) of 5-ethyl-2-phenylpyridine as a white solid.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:26])[CH2:7][CH2:8][C:9]1[C:10](=[O:25])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH2:12][CH:13]=1.Cl>C1COCC1>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH:13]=[C:9]([CH2:8][CH2:7][C:6]([OH:26])=[O:5])[C:10]1=[O:25]
Reactant: COC(=O)CCC1=CCN(Cc2ccc(OC)cc2OC)C1=O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CC=C(CCC(=O)O)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
10.8 mg of LiOH.H2O solution (0.25 mmol) was added to 0.86 ml of THF solution containing 55 mg of 3-[1-(2,4-dimethoxy benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (0.17 mmol) in a dropwise manner at 0° C. The reaction mixture was stirred for 2 hrs at 0° C. and 5% HCl was added to pH 1. Then the mixture was extracted three times with 10 ml of ethyl acetate, the organic layer was washed with 15 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 41 mg of 3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid (16f) (yield: 80%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:38])([C:34]([F:37])([F:36])[F:35])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:38])([C:34]([F:35])([F:37])[F:36])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)c1
Reaction time: 2 h

Procedure:
To a solution of ((2R,5R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester in CH2Cl2 (0.3 ml) was added TFA (0.6 ml) and the reaction mixture was kept at 25° C. for 2 h. The reaction was added to cold 10% aqueous K2CO3 solution and the product extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide 5-cyano-3-methyl-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide as a colorless foam. The title compound was converted into its hydrochloride salt by dissolving the free base in CH2Cl2, adding 1 eq of 2N HCl in Et2O, evaporation to dryness, followed by crystallization from CH2Cl2-Et2O to provide the title compound as a white solid: HPLC RtH5=0.957 min; ESIMS: 450 [(M+H)+]; 1H NMR (600 MHz, DMSO-d6): 11.0 (s, 1H), 9.60 (d, 2H), 9.04 (s, 1H), 8.41 (s, 1H), 7.96 (m, 1H), 7.83 (dd, 1H), 7.33 (dd, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 2.56 (s, 3H), 1.73 (s, 3H), 1.70 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][N:4]([CH2:10][CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:27](=[O:45])([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)OC1C=CC([N+]([O-])=O)=CC=1>C(OCC)(=O)C>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][N:4]([CH2:3][C@H:2]([NH:1][C:27]([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)=[O:45])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][C@H:11]([NH:19][C:27]([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)=[O:45])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CN(CC(N)Cc1ccccc1)CC(N)Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The product from Example 7C (0.34 g) was treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (0.63 g, 1.99 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (10 mL). The mixture was stirred at 60° C. under a N2 atmosphere overnight. The mixture was diluted with ethyl acetate (50 mL), extracted with 10% aqueous K2CO3 (3×20 mL), washed with water (20 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (ethyl acetate:hexanes, 2:1) to provide the two title compounds combined and a third separated product. The mixture of (S,S) and (R,R) enantiomers were obtained as a colorless amorphous solid. Rf=0.32 (ethyl acetate); 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.75 (s, 2H), 7.30-7.11 (m, 10H), 5.53 (brs, 2H), 5.23 (d, J=12.9 Hz, 2H), 5.16 (d, J=13.2 Hz, 2H), 3.91 (m, 2H), 2.90-2.79 (m, 2H), 2.68 (dd, J=7.5, 13.6 Hz, 2H), 2.42 (t, J=12 Hz, 2H), 2.26 (dd, J=1, 12 Hz, 2H), 1.99 (d, J=13.9 Hz, 1H), 1.87 (d, J=14.2 Hz, 1H), 0.71 (s, 9H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([C:5]([NH2:7])=[NH:6])[CH2:4][CH2:3]1.[C:8]([CH2:10][C:11](OCC)=[O:12])#[N:9].CO.C[O-].[Na+]>CO>[NH2:9][C:8]1[N:7]=[C:5]([CH:2]2[CH2:4][CH2:3]2)[N:6]=[C:11]([OH:12])[CH:10]=1
Reactant: CCOC(=O)CC#N
Reactant: N=C(N)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1cc(O)nc(C2CC2)n1
Temperature: 25 °C

Procedure:
A mixed solution of cyclopropanecarboxamidine hydrochloride (0.30 g), ethyl cyanoacetate (0.27 ml) and methanol (1.5 ml) was added to 28% sodium methoxide methanol solution (2.0 ml) under ice-cooling. After heating under reflux for 1 hr, the mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was adjusted to pH 5 with water and acetic acid. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.30 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([NH:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCOCC1
Product: Clc1ncc(Br)c(NC2CCOCC2)n1
Yield: 83 %

Procedure:
In the reaction of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) with tetrahydropyran-4-ylamine (144 mg, 1.42 mmol) according to procedure 2, the desired product is obtained in 83% yield (320 mg) after chromatographic purification (silica gel, ethyl acetate/hexane with ethyl acetate: 0-100%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:24][CH2:23][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=1)[NH:14][C:13]([C:16]1[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=1)=[CH:12]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Reaction time: 3 h
Yield: 29 %

Procedure:
2-[7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-5-ylmethyl]-isoindol-1,3-dione (27 mg, 0.07 mmol) prepared in Example 64 was dissolved in ethanol (3 mL). Hydrazine hydrate (0.6 mL, 0.11 mmol) was added thereto, and the mixture was stirred for 3 h at 80°. After completion of the reaction, the reaction mixture was distilled under reduced pressure, and purified by column chromatography to give the title compound (7 mg, Yield 37%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH2:15]=[O:16].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([CH2:15][OH:16])[C:3]1=[O:13]
Reactant: CC1(C)CN(c2ccccc2)NC1=O
Reactant: C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2ccccc2)N(CO)C1=O
Temperature: 25 °C

Procedure:
4,4-Dimethyl-1-phenyl-3-pyrazolidone (152 g) was dissolved in 600 ml of acetic acid. To the solution as prepared above, 97 g of an aqueous solution containing 37% of formaldehyde was dropped with stirring at room temperature. The resultant mixture was stirred for 2 hours. At the end of the time, the solvent was distilled away under reduced pressure. To the residue thus obtained, 100 ml of toluene was added, and water was separated at the toluene azeotrope under reduced pressure. A mixture of 900 ml of hexane and 700 ml of ethyl acetate was added to the residue as obtained above which was then dissolved therein by heating. The resultant solution was allowed to cool to room temperature. Crystals precipitated were collected by filtration to obtain 120 g of 4,4-dimethyl-2-hydroxymethyl-1-phenyl-3-pyrazolidone.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27](O)(=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:27]([NH:2][NH:1][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(NN)c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(NNC(C)=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (2.0 g) and acetic acid (20 ml) is stirred at room temperature for 96 hours. After the reaction is complete, to the mixture are added methylene chloride and an aqueous potassium carbonate solution. The methylene chloride layer is separated, concentrated under reduced pressure, and the residue is crystallized from chloroform to give 1-[2-(2-acetylhydrazino)pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.84 g), which is listed in Table 10.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:42][CH2:41][C:32]2([O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[CH2:31][CH2:30]1.C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([C:6]1[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]([CH:29]2[CH2:42][CH2:41][C:32]3([O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]3)[CH2:31][CH2:30]2)[C:2](=[O:1])[C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:55][N:54]=[N:53][N:22]=2)=[CH:13][CH:14]=1)[CH2:24][CH3:25]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.026 g), azidotrimethylsilane (1.2 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.06 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH:18](O)[CH3:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:21])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCOC(=O)CCN(CCC(C)O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C=CCCCN(CCC(=O)OCC)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-3-(3-hydroxybutylamino)propionate (1.06 g, 3.66 mmol) in dichloromethane (DCM)(15 mL) was added Dess-Martin periodinate (1.17 g, 4.03 mmol). The mixture was stirred for 2 hours, then, a mixture of a saturated aqueous NaHCO3 solution and Na2S2O3 was added. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was dissolved in THF (10 mL), then a Wittig reagent, which was prepared from methyltriphenylphosphonium bromide (1.57 g, 4.4 nmmol) and 1N-tert-BuOK solution in THF (4.4 mL), in THF (10 mL) was added to the solution at 0° C. The mixture was stirred for an hour at room temperature, then quenched by a saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:10) to give ethyl N-(tert-butoxycarbonyl)-3-(4-pentenylamino)propionate (487 gm, 1.71 mmol, 46.6%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:3]1=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[C:12]([C:14]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[O:15])[S:13][C:3]1=2
Reactant: CN1CCNCC1
Reactant: Cn1c2ccccc2c2cc(C(=O)Cl)sc21
Product: CN1CCN(C(=O)c2cc3c4ccccc4n(C)c3s2)CC1
Reaction time: 336 h
Yield: 64.7 %

Procedure:
Preparation as for (30) from (26) (0.96 g) and N-methylpiperazine (0.46 g), stirring for 14 days, rinse up on silica gel column using dichloromethane/-methanol (9/1) as eluent. Precipitation as the oxalate salt gave (31) (0.78 g), m.p. 219.1°-219.5° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[Cl:19][C:20]1[CH:29]=[C:28](I)[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[Cl:19][C:20]1[CH:29]=[C:28]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(I)cc1Cl
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1Cl
Yield: 82.7 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.2 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.6 g (5 mmol) of methyl 2-chloro-4-iodobenzoate, 1.7 g (83%) of the expected ester was obtained in the form of a brown oil.
Reaction SMILES: [F:1][C:2]([F:18])([CH:7]([O:12]C(=O)C(C)=C)[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].[CH3:19][O:20][CH2:21]CO.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:18][C:2]([F:1])([CH:7]([OH:12])[CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([O:5][CH2:6][CH2:19][O:20][CH3:21])=[O:4]
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OC
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 105.2 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 25 g of 2-methoxyethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 8 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 23.9 g (yield 73%) of crude 2-methoxyethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.