Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:26][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1cccc(Oc2ncccn2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1cnc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)nc1
Yield: 17.2 %

Procedure:
3-(2-Pyrimidinyloxy)benzaldehyde (0.67 g, 3.35 mmol) and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (0.49 g, 3.33 mmol) were processed as described in Example 106A. The residue was purified by flash chromatography (silica gel, 6:4 ethyl acetate:hexanes to 1:1 ethyl acetate:hexanes) to provide the title compound (190 mg, 19% yield).
Reaction SMILES: C([O:3][C:4](=[O:62])[CH:5]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][C:57]([O:59]CC)=[O:58])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:39]2[CH:47]=[CH:46][C:42]3[O:43][CH2:44][O:45][C:41]=3[CH:40]=2)[CH2:18][C:19]([C:26]2[C:27](=[O:38])[N:28]([CH3:37])[C:29]([CH3:36])=[CH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[CH:20]=1)[CH3:7])C.[OH-].[Na+]>>[O:43]1[C:42]2[CH:46]=[CH:47][C:39]([C:17]3[CH2:18][C:19]([C:26]4[C:27](=[O:38])[N:28]([CH3:37])[C:29]([CH3:36])=[CH:30][C:31]=4[C:32]([F:33])([F:34])[F:35])([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)[CH:20]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:6]([CH3:7])[CH:5]([O:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[CH2:55][CH2:56][C:57]([OH:59])=[O:58])[C:4]([OH:62])=[O:3])[CH:16]=3)=[CH:40][C:41]=2[O:45][CH2:44]1
Reactant: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOC1=CC(c2ccsc2)(c2c(C(F)(F)F)cc(C)n(C)c2=O)CC(c2ccc3c(c2)OCO3)=C1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)c(C2(c3ccsc3)C=C(OCCCCCCC(C)C(Oc3ccccc3CCC(=O)O)C(=O)O)C=C(c3ccc4c(c3)OCO4)C2)c(=O)n1C
Yield: 81.1 %

Procedure:
A similar procedure as described in Example 1, step 3 was used, starting from 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(1,6-dimethyl-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-5-thiophen-3-yl-phenoxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (15 mg, 0.018 mmol) and 1.0 N aqueous sodium hydroxide (2 mL) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(1,6-dimethyl-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-5-thiophen-3-yl-phenoxy]-hexyl}-(2-(2-carboxy-ethyl)-phenoxy)-butyric acid (12 mg, 86%) as an amorphous off-white solid: ES(+)-HRMS m/e calculated for C40H42F3NO9 (M+H)+ 738.2885, found 738.2884.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:11](Cl)(=[O:13])[CH3:12]>C(Cl)Cl>[C:2]1([CH2:1][NH:8][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzylamine (98.1 g) in methylene chloride (100 ml) was added an aqueous solution (200 ml) of sodium hydroxide (44 g). While further stirring the mixture, acetyl chloride (78 ml) was added at 15-20° C. over 1 hr. This reaction mixture was stirred at room temperature for 30 min and extracted with chloroform (100 ml×2). The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a white solid (160 g). The obtained solid was crystallized from hexane: ethyl acetate (2:1, 750 ml) to give the title compound (125.7 g) as white crystals, m.p.=61-62° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([C:18]([NH2:20])=[O:19])[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].O=O.C(=O)([O-])[OH:24].[Na+]>O.[Pt]>[C:18]([C:13]1[N:12]=[CH:11][N:10]([C@@H:1]2[O:7][C@H:6]([C:8]([OH:24])=[O:9])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:14]=1[C:15](=[O:16])[NH2:17])(=[O:19])[NH2:20]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1C(N)=O
Reactant: O=C([O-])O
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ncn([C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H]2O)c1C(N)=O
Reaction time: 48 h

Procedure:
20 g. of 1-β-D-ribofuranosyl-imidazole-4,5-dicarboxamide [see, for example, J. Chem. Soc. 1949, 232] are dissolved in 2 litres of water at 80° C. Platinum (obtained by hydrogenating 10 g. of platinum oxide) is added. Oxygen is blown into the suspension with vigorous stirring. The temperature is held at 80° C. 8.6 G. of sodium hydrogen carbonate are added in several portions so that the mixture always remains alkaline. After 2 days, the catalyst is filtered off, the filtrate concentrated to 100 ml. and acidified with trifluoroacetic acid while cooling with ice-water. The crystallizing solution is left to stand overnight in a refrigerator and the product is then filtered off. 12.4 G. of 1-desoxy-1-(4,5-dicarbamoylimidazol-1-yl)-β-D-ribofuranuronic acid are obtained.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18](=[O:22])[C:19]([OH:21])=[O:20])([O-:10])=[O:9].C(O)=O>>[OH:22][C@@H:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])[C:19]([OH:21])=[O:20]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)[C@@H](O)Cc1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 138.1 %

Procedure:
Into 0.27 ml (19 mmol) of triethylamine was dissolved 3 mg (0.0048 mmol) of [RuCl((S,S)-TsDPEN)(p-cymene)] to prepare a solution, and to the solution were added 1.0 g (4.8 mmol) of o-nitrophenyl pyruvic acid and 0.54 ml (14 mmol) of formic acid, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 2 ml of water, and then 1 g of concentrated hydrochloric acid was gradually dropwise added under ice cooling, and pH of the solution was adjusted to 2. Extraction was performed twice with 10 ml of ethyl acetate, and then the organic phase was washed with 2 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 1.4 g (yield 97%, 95% ee) of (2S)-hydroxy-3-(o-nitrophenyl)propanoic acid was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.Cl.[CH2:30]([OH:33])[CH2:31][OH:32]>C(OCC)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:4]([NH:8][S:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=3)(=[O:10])=[O:11])=[N:5][CH:6]=[N:7][C:2]=2[O:32][CH2:31][CH2:30][OH:33])=[CH:23][CH:24]=1
Reactant: OCCO
Reactant: O=S(=O)(Nc1ncnc(Cl)c1-c1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
A solution of 0.046 g of Na in 1.5 ml of absolute ethylene glycol was treated with 0.216 g of N-[6-chloro-5-(p-chloro-phenyl)-4-pyrimidinyl]-α,α,α-trifluoro-p-toluenesulfonamide with the exclusion of moisture and heated at 100° C. for 3 hours, thereafter cooled to room temperature and treated with 2.3 ml of 1N HCl. The mixture was taken up in ethyl acetate, the organic extracts were washed with water, dried and evaporated under reduced pressure. The precipitate remaining behind was recrystallized from CH2Cl2, isopropyl ether and n-hexane and yielded N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-α,α,α-trifluoro-p-toluenesulfonamide, melting point 160°-162° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([Cl:30])[N:18]=3)([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:35]>C1COCC1.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([Cl:30])[N:18]=3)([O:14][CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
To a solution of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.54 g, 10.02 mmol) in THF (100 mL) was added NaH (481 mg, 12.02 mmol, 60% dispersion in mineral oil) and the mixture allowed to stir for 5 min before the addition of iodomethane (750 μL, 12.02 mmol) and 15-Crown-5 (10 drops). The resulting mixture was allowed to stir for 2.5 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O and the aqueous layer further extracted with 2-methyl THF. The combined organic phases were dried (Na2SO4) and concentrated in vacuo affording 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (4.30 g, 92%). LCMS (method A): RT 4.05 min, [M+H]+ 467.2
Reaction SMILES: Cl[C:2]1[C:3]2[C@:10]3([CH2:25][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[O:26]=[C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[C@@:10]21[CH2:25][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH:17]=[C:12]1[CH2:11]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (6S)-4′-chloro-6′-oxo-5,6′,7,7′-tetrahydrospiro [cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylate (200 mg, 0.537 mmol) in dry ethyl acetate (5.37 mL) was added triethylamine (299 μL, 2.15 mmol) and palladium on carbon (571 mg, 10%, 0.537 mmol). The reaction was placed on a Parr apparatus at 50 psi hydrogen gas. After 16 h, the reaction mixture was filtered under a nitrogen atmosphere through Celite®, washing with ethyl acetate. The filtrate was concentrated to give the title compound, along with one equivalent of triethylamine hydrochloride. MS: m/z=339.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]1)=O>>[CH2:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:44][CH2:45]1)[CH3:50]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: CCN1CCN(C(=O)CCl)CC1
Product: CCN1CCN(CCOc2ccc(CN(c3cc(OC)ccc3C3CCc4cc(O)ccc4C3)C(C)C)cc2)CC1
Yield: 52.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(4-ethylpiperazin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/C#Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC/C=C/C#Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
In 4 ml of toluene were dissolved 480 mg (1.79 mmol) of ethyl (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynoate, and 2.38 ml (3.58 mmol) of a 1.5M diisobutyl aluminum hydride-toluene solution were added to the solution with stirring at 0° C. After 10 minutes, ice was added to the mixture and the insolubles were removed by filtration using Celite. After the organic layer was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to obtain 353 mg (yield: 87%) of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=O.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=[N:15][S@:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ncccn1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N=Cc1ncccn1
Temperature: 50 °C
Yield: 80.5 %

Procedure:
A mixture of 2-pyrimidine-carboxaldehyde (11.5 g, 107 mmol), (S)-(−)-2-methyl-2-propanesulfinamide (12.9 g, 107 mmol) and potassium hydrogensulfate (14.5 g, 107 mmol) in toluene (57 ml) was heated at 50° C. overnight. After decanting the solution, the solid residue is washed 3 times with dichloromethane, the washings combined with the decanted solution and solvents are evaporated in vacuo to give 18.2 g (81%) of (S)-2-methyl-propane-2-sulfinic acid 1-pyrimidin-2-yl-methylideneamide. LC/MS (method 3): Rt=1.29 min; m/z=212.09 (M+H+).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15](N4CCNCC4)[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH2:7][CH2:6]1>S(=O)(=O)(O)O>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15]([OH:2])[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 ml of 70% nitric acid in 10 ml of 98% sulfuric acid was added in portions 1.0 g (3.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, keeping the temperature between 25°-30° C. The resulting solution was stirred at room temperature for 18 hours and poured onto 40 g of ice. The mixture was stirred at room temperature for 24 hours, concentrated in vacuo, the pH adjusted to 12 with aqueous sodium hydroxide, and filtered through a fiber glass pad. The filtrate was acidified to pH 3.5 with 6.0M hydrochloric acid, the resulting precipitate removed by filtration, washed with water then ether and dried in vacuo to give 0.23 g of the title compound, mp 325°-327° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1O[C:7]([O:10]CC)=[CH:8][N:9]=1)([CH3:4])[CH3:3].[C:13](#[N:16])[CH:14]=[CH2:15]>>[C:13]([C:14]1[CH:15]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:9]=[CH:8][C:7]=1[OH:10])#[N:16]
Reactant: CCOc1cnc(C(C)(C)C)o1
Reactant: C=CC#N
Product: CC(C)(C)c1cc(C#N)c(O)cn1
Temperature: 20 °C
Yield: 36.9 %

Procedure:
A neat mixture of 2-(1,1-dimethylethyl)-5-ethoxyoxazole (17 g., 0.1 mole) and acrylonitrile (6.1 g., 0.11 mole) is stirred and heated at 70°-75° C. for 16 hours. The resulting dark reaction mixture is cooled to 20° C. and chromatographed on silica gel (600 g.). Elution with 1% methanol in chloroform (4.35 l.) yields recovered 2-(1,1-dimethylethyl)-5-ethoxyoxazole (10.7 g., 63% recovery). Continued elution with the same eluant (300 ml.) affords impure product (3.2 g.). Further elution with the same eluant (2.5 l.) gives the desired product as a solid (6.5 g., 37%), m.p. 185°-195° C. Two recrystallizations of the latter from methanol-water (1:1; v:v) provides an analytical sample of 4-cyano-6-(1,1-dimethylethyl)-3-pyridinol as colorless crystals (4.5 g., 26%), m.p. 201°-202° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[C:19]2[CH:20]=[CH:21][C:22](=[O:24])[O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][C:22](=[O:24])/[CH:21]=[CH:20]/[C:19]1[C:14]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:15][CH:16]=[CH:17][C:18]=1[OH:23]
Reactant: O=c1ccc2c(C#CCCCCOC3CCCCO3)cccc2o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Yield: 59.2 %

Procedure:
A solution of 1.09 g (3.3 mmol) of rac-5-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]-2H-1-benzopyran-2-one and 1.8 mL (7.9 mmol) of 25% methanolic sodium methoxide in 5 mL of methanol was stirred and refluxed for 24 hr and then concentrated under reduced pressure. The residue was treated with 1N hydrochloric acid and worked-up with ethyl acetate in the usual manner (the organic extracts were additionally washed with saturated aqueous sodium bicarbonate). The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexane-ether. There was obtained 0.7 g (59%) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester as a yellow oil. Trituration of a sample prepared in this way with hexane gave a colorless solid, mp 66°-67.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:21]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH2:34](OC(OCC)OCC)C>>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:23][CH:22]=[C:21]([O:24][CH:25]5[CH2:26][CH2:27][N:28]([CH:31]6[CH2:33][CH2:32]6)[CH2:29][CH2:30]5)[CH:20]=4)[N:1]=[CH:34]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1N
Reactant: CCOC(OCC)OCC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described in Example 1, 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy] benzamide was reacted with triethylorthoformate. There was thus obtained the title compound (0.063 g); NMR Spectrum: (DMSOd6) −0.01 (m, 2H), 0.12 (m, 2H), 0.27 (m, 2H), 0.40 (m, 2H), 1.34 (m, 3H), 1.65 (m, 2H), 1.84 (s, 3H), 2.18 (m, 2H), 2.53 (m, 3H), 4.28 (m, 1H), 7.23 (m, 2H), 7.29 (s, 1H), 7.43 (d, 1H), 7.53 (s, 1H), 7.60 (d, 1H), 7.89 (s, 1H), 8.14 (s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([OH:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc2ccccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc4ccccc34)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (97 mg) and commercially available 1-naphthol (340 mg) were mixed and stirred at 150° C. for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate (3/1) and then with chloroform/methanol (100/1), and further purified by thin layer chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to obtain 57 mg of the title compound (yield: 40%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:33]=[CH:32][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Ethyl 4-(2-(6-morpholinopyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzoate (150 mg, 0.33 mmol) was dissolved in anhydrous tetrahydrofuran (1.5 mL) and lithium aluminum hydride 2.0 M tetrahydrofuran (0.25 mL, 0.50 mmol) solution was slowly added at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was diluted with ethyl ether (2.0 mL). The remaining lithium aluminum hydride was removed by adding water very slowly. After adding magnesium sulfate, the mixture was concentrated by filtering. The resultant target compound (130 mg, 95% yield) was used in the following reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1)#[N:2]>C1COCC1.[Ni].CCOC(C)=O>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1
Reactant: CNC(=O)Nc1cc(C#N)ccn1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1cc(CN)ccn1
Yield: 233.6 %

Procedure:
A solution of 1-(4-cyano-pyridin-2-yl)-3-methyl-urea (12.0 g, 11.4 mmol) in THF (80 mL) was treated with Raney nickel (0.5 g) placed under a hydrogen atmosphere (atmospheric pressure) for 8 hours at rt. The reaction mixture was diluted with EtOAc, filtered over Celite® and concentrated in vacuo. The residue was purified by chromatography on silica gel (Gradient elution: 100% CH2Cl2 to 85%/15% CH2Cl2/MeOH) to give 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea (4.8 g) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:23])=[O:22]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(S(=O)(=O)c2ccccc2Br)c2ccccc12
Reaction time: 0.5 h

Procedure:
A stirred solution of 1H-indole-3-carboxaldehyde (1 g, 6.89 mmol), in DMF (25 mL) was treated with sodium hydride (0.357 g, 60% in mineral oil, 8.95 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with 2-Bromobenzene sulfonyl chloride (1.8 mL, 8.25 mmol), stirred at room temperature for 3-5 hrs. After the completion of reaction (T. L. C.), the reaction mixture was quenched with 25 mL ice-cold water and diluted with 25 mL ethyl acetate. The organic phase was separated, washed sequentially with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel, EtOAc/Hexane, 2/8) to afford the title compound as an off-white foam, which was latter identified by IR, NMR and mass spectral data.