Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C([Li])CCC.[O:23]=[C:24]([CH3:30])[CH2:25][CH2:26][CH2:27][C:28]#[N:29]>O1CCCC1.C(OCC)C>[OH:23][C:24]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[CH:10]=1)([CH3:30])[CH2:25][CH2:26][CH2:27][C:28]#[N:29]
Reactant: CC(=O)CCCC#N
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 7.5 grams (0.025 mole) of 3-(4-trifluoromethylphenyl)phenyl bromide in 100 mL of tetrahydrofuran was cooled to about -78 ° C., and 10.0 mL (0.025 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78 ° C. for about one hour. After this time a solution of 2.8 grams (0.025 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was diluted with diethyl ether and partitioned between an aqueous dilute solution of hydrochloric acid and diethyl ether. The organic layer was separated and dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 1:1 ethyl acetate and hexane as the eluant. The product-containing fractions were concentrated under reduced pressure, yielding about 3.0 grams of 5-hydroxy-5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([O:5][CH2:6]1)[C:3](=[O:9])[O:2]2.O1C=CC[CH2:12][CH:11]1C([O-])=O.[Na+].C(I)C>CN(C)C=O>[O:5]1[CH:6]=[CH:1][CH2:8][CH2:7][CH:4]1[C:3]([O:2][CH2:11][CH3:12])=[O:9]
Reactant: O=C([O-])C1CCC=CO1
Reactant: O=C1OC2CCC1OC2
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC=CO1

Procedure:
The synthesis of 2,5-dioxabicyclo[2.2.2]octan-3 one was achieved through a three step reaction sequence as illustrated below: ##STR3## Sodium 3,4-dihydro-2H-Pyran-2-carboxylate was esterified with ethyl iodide in dimethylformamide to afford ethyl 3,4-dihydro-2H-pyran-2-carboxylate. Subsequent hydroboration with a borane solution in tetrahydropyran at 0° C., followed by oxidation with a sodium dichromate-sulfuric acid aqueous solution and subsequent treatment with sodium hydrogen sulfite gave ethyl 5-hydroxytetrahydropyran-2-carboxylate as a stereoisomer mixture. The hydroxytetrahydropyran ester was heated in a dilute solution in the presence of a catalytic amount of p-toluenesulfonic acid, any ethyl alcohol being liberated was removed through a Soxhlet extractor containing type 5A molecular sieves. Column chromatographic separation of the reaction products and subsequent repeated recrystallization gave the bicyclic lactone as colorless crystals; the overall yield was approximately 20%.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:21]3[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=34)=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:21]3[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=34)=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Br)ccc23)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Cc4ccccc4)ccc23)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.1 %

Procedure:
Bubble nitrogen gas through 1 mL of THF for 10 minutes. Add benzyl magnesium chloride (2M in THF, 0.12 mL, 0.24 mmol), zinc chloride (1M in diethyl ether, 0.26 mL, 0.26 mmol). Bubble with nitrogen gas for 15 minutes. Add Pd(PPh3)2Cl2 (4 mg, 0.006 mmol), 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (0.05 g, 0.12 mmol). Stir at room temperature for 48 hours. Quench with aqueous saturated NH4Cl solution. Evaporate the solvent in vacuo. Add methylene chloride. Filter the mixture and concentrate the filtrate in vacuo. Chromatograph the residue on silica gel (elute with 50% ethyl acetate/hexanes then 100% ethyl acetate). Final purification by preparative HPLC affords the title compound 20 mg (40%) as a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I.O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a vigourosly stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.07 g, 10.3 mmol) in DMF (25 mL) was added a 60% sodium hydride dispersion in mineral oil (500 mg, 12.5 mmol). After stirring for 20 min, methyl iodide (0.9 mL, 14.5 mmol) was added and the resulting mixture stirred for 48 h before being added to a mixture of water and brine (250 mL, 1:1). Extraction with ethyl acetate (4×50 mL), washing of the combined extracts with brine (100 mL) and drying (MgSO4) gave, after concentration, a residue which was purified via flash chromatography (silica gel, ethyl acetate/hexane, 1:1) to give the title compound as a colourless oil. δH (CDCl3): 1.50 (9H, s), 1.52, 1.88 (4H, 2m) 3.12 (2H, ddd), 3.18 (1H, m), 3.19 (3H, s), 3.77 (2H, m); Rf0.33 (ethyl acetate/hexane: 1/1).
Reaction SMILES: [Cl:1][C@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(O)C.C(Cl)Cl>[Cl:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](Cl)C[C@H]1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 42 %

Procedure:
A solution of 144 mg of (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoic acid in 2 ml of absolute ethanol was combined with 6.4 mg of pyridine p-toluenesulfonate and agitated for 5 days at room temperature under argon. The reaction mixture was then diluted with 100 ml of methylene chloride, washed twice with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as the eluent, thus obtaining 42.5 mg of the desired carboxylic acid as a highly viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([O-])=O.CO>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7]
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1N
Reaction time: 5 h

Procedure:
Nitro compound 20 (2.24 g, 7.14 mmol) and Pd/C (220 mg) was dissolved in EtOAc (50 mL) and MeOH (20 mL) and stirred vigorously under H2 atmosphere (1 atm). After 5 h, the Pd/C was filtered off over a pad of celite and florisil to leave pure aniline compound 21 in quant. yield (1.98 g) over two steps.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12](Br)[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:25]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Reactant: Nc1ccc(-c2nc(Br)cnc2N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2nc(-c3ccnc(N4CCOCC4)c3)cnc2N)cc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A suspension of the compound prepared in Example 12 (7.6 g), Pd(PPh3)4 (3.3 g), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (8.3 g), and Na2CO3 (9.1 g, 85 mmol) in a 3 to 1 mixture of dioxane/water (280 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. overnight, at which time LC/MS indicated the reaction was complete. The mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution (200 mL) and extracted with EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The crude product was obtained as a brown oil which was precipitated from DCM (50 mL) to give a dark yellow solid. The solid was filtered and triturated with a 1 to 1 solution of DCM/EtOAc (3×50 mL) to give the title compound (8.4 g) having the following physical data as a light yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:22][O:23][CH2:24][CH2:25]Br>O1CCCC1>[CH3:22][O:23][CH2:24][CH2:25][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)CCCC1
Temperature: -70 °C
Yield: 65 %

Procedure:
To a 3 L 3-necked round-bottomed flask equipped with a thermometer and dropping funnel were added diisopropylamine (136 mL, 0.98 mol) and tetrahydrofuran (750 mL). The solution was stirred under nitrogen and cooled in an ice-bath. Through the dropping funnel was added n-butyllithium (2.5 M in hexanes; 376 mL, 0.94 mol), and the solution was allowed to stir at 0° C. for 30 min and then cooled to −70° C. Through the dropping funnel was added a solution of cyclopentanecarboxylic acid, methyl ester (83.04 g, 0.65 mol) in tetrahydrofuran (135 mL). The solution was stirred at −70° C. for 1 h and then a solution of 2-bromoethyl methyl ether (55.5 mL, 0.59 mol) in tetrahydrofuran (135 mL) was added. The solution was stirred at −70° C. for 1 h and then the cooling bath was removed. The solution was stirred at room temperature overnight, then poured into saturated ammonium chloride solution (2 L) and extracted with ether (3×500 mL). The combined ether layers were washed with saturated brine (6×400 mL), dried (Na2SO4), filtered, evaporated, and distilled under vacuum to give 1-(2-methoxyethyl) cyclopentanecarboxylic acid, methyl ester (71.39 g, 59%) as a pale yellow liquid (bp 94-102° C. at 8 mm). This was dissolved in a mixture of tetrahydrofuran (340 mL), methanol (340 mL) and 1 M sodium hydroxide solution (425 mL). The mixture was stirred and heated at 55-60° C. for 24 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. Water (400 mL) was added and the solution was extracted with ether (2×200 mL). The aqueous layer was acidified to pH 1 with 1 N HCl (500 mL), and extracted with ether (300 mL, then 2×200 mL). The combined ether layers were washed with saturated brine (2×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(2-methoxyethyl)cyclopentanecarboxylic acid (63.68 g, 97%) as a yellow liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:17][C:18]1[N:19]=[C:20]([C:24]2[N:28]([CH2:2][C:3]3[C:8]([O:9][CH3:10])=[N:7][C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:5][N:4]=3)[CH:27]=[CH:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1nc(-c2ccccc2)cnc1CCl
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2)cnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A mixture of 2-chloromethyl-3-methoxy-5-phenyl-pyrazine (70 mg, 0.30 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (48 mg, 0.294 mmol) and K2CO3 (123 mg, 0.9 mmol) in DMF (5 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (2 mL) and extracted with DCM (3×10 mL). The combined organic layers are dried and solvent removed. PTLC separation (10% MeOH in DCM) gives 91 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-3-methoxy-5-phenyl-pyrazine as an oil. 1H NMR (CDCl3) 8.41 (s, 1H), 8.08 (dd, 1H), 7.95–7.99 (m, 2H), 7.80 (dd, 1H), 7.42–7.49 (m, 3H), 7.22 (s, 1H), 7.15 (s, 1H), 6.77 (dd, 1H), 5.98 (s, 2H), 4.08 (s, 3H). B. 3-Methoxy-5-phenyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazine (Compound 2) 1. Synthesis of 2-(1H-imidazol-2-yl)-thiazole
Reaction SMILES: CN(C)C(=O)C.[F:7][C:8]1[C:16]([F:17])=[C:15](C(O)=O)[C:14]([F:21])=[C:13]([F:22])[C:9]=1[C:10]([OH:12])=[O:11]>O>[F:7][C:8]1[C:16]([F:17])=[CH:15][C:14]([F:21])=[C:13]([F:22])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1c(F)c(F)cc(F)c1F
Temperature: 20 °C
Yield: 98 %

Procedure:
N,N-Dimethylacetamide (14.0 parts) and 2,3,5,6-tetrafluoroterephthalic acid (2.91 parts) was heated at 70° C. for 4 hours before cooling to 20° C. adding water (7 parts) and cooling to 5° C. The precipitated solid was collected by filtration and washed with cold water and dried, the aqueous filtrates were evaporated under vacuum and the resultant solids combined to give 2,3,5,6-tetrafluorobenzoic acid (98%). 1,2,4,5-tetrafluorobenzene (2%) was also formed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[C:26](OCC)(=O)CC(C)=O.ClC1C=CC=CC=1C=O.ClC1C=C(F)C=CC=1C=O>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][C@@H:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:5]=1[C:3]([O:2][CH2:1][CH3:26])=[O:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: O=Cc1ccc(F)cc1Cl
Agent: O=Cc1ccccc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccccc1Cl

Procedure:
The title compounds were prepared in analogy to Example 86 starting from methyl 2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a (100 mg) and ethyl (4R)-6-(bromomethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 102a (215 mg). The crude product was purified by silica gel chromatography first, and then by preparative HPLC to give Example 102 (27 mg), and Example 103 (21 mg). Ethyl (4R)-6-(bromomethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 102a was prepared in analogy to compound C with procedures shown in Example 1 by using ethyl acetoacetate and 2-chloro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde in the three component reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)C)c12
Reaction time: 8 h

Procedure:
Methyl 4-(4-fluoro-2-isopropoxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (451 mg) and lithium hydroxide (865 mg) was dissolved in a mixture of THF: methanol:water (1:1:1; 100 ml) and was stirred at room temperatruer overnight. Then the mixture was acidified with conc. HCl, the resultant precipitate was filtered, dried and triturated with diisopropyl ether to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.ClCCCl.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
Into a mixture of 1.0 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one, 42 μl of boron trifluoride-diethyl ether complex and 40 ml of 1,2-dichloroethane, 0.4 ml of ethyl diazoacetate (purity: 90%) was dropped at room temperature over 2 hours. After dropping, the reaction mixture was further stirred for two hours, and then subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give 1.10 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(ethoxycarbonylmethoxy)pyridine:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[F:22][C:23]([F:30])([F:29])[C:24]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)=[O:25]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
Intermediate 42 (100 mg, 0.33 mmol) was dissolved in dry THF (1 mL), ethyl trifluoroacetate (30 μl 0.39 mmol) was added and the reaction was refluxed for 18 hours. The reaction was cooled to RT, evaporated and the residue chromatographed from EtOAc to give compound 53 (49 mg, 37%) as a white solid: Mp 150-154° C. 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 6.27 (d, J=7.6 Hz, 1H), 4.15 (d, J=13.1 Hz, 1H), 3.80 (d, J=11.1 Hz, 2H), 3.38 (t, J=11.9 Hz, 1H), 3.11 (t, J=12.1 Hz, 1H), 1.94 (t, J=15.2 Hz, 2H), 1.46-1.34 (m, 2H). Purity 100%. HRMS calculated for C15H15F6N3O3+H+ 400.1096. found (ESI(+), [M+H]) 400.1078.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[OH:14][NH2:15]>N1C=CC=CC=1.C(O)C>[C:1](=[N:15][OH:14])([C:4]1[CH:5]=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cnc2ccsc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1cnc2ccsc2c1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a solution of 6-acetylthieno[3,2-b]pyridine (3.78 g, 21.3 mmol) in pyridine (40 ml) and ethanol (40 ml), under a nitrogen atmosphere, was added hydroxyl amine hydrochloride (5.0 g, 72 mmol). After the reaction mixture was heated at 80° C. for three hours, the solvents were removed under reduced pressure on a rotary evaporator and the residue was diluted with ice water to give crystalline product. This solid was collected by filtration and dissolved in ethyl acetate/methanol, dried over anhydrous sodium sulfate and filtered through charcoal. The solvents were evaporated to give pure product (3.15 g, 77% yield) which was used as is. A small portion was recrystallized from methanol for microanalysis, m.p 210°-213° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10]CC2C=CC=CC=2)=[C:5]([CH3:18])[N:4]=1.[OH-].[K+].C(O)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:18])[C:6]([OH:10])=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)c(OCc2ccccc2)c(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1nc(C)c(O)c(C)n1

Procedure:
The 2-methoxy-4,6-dimethyl-5-benzyloxy pyrimidine 0.7 g (2.7 mmol) is dissolved in 10 ml of ethanol with 0.3 g (5.4 mmol) of KOH. The whole is refluxed for 11 hours, and after cooling the reaction is diluted with 20 ml of water and brought to pH 5 with glacial acetic acid. The mixture is extracted into ethyl acetate (3×25 ml), dried over Na2SO4 and stripped in vacuo. The resulting solid is purified by column chromatography on silica gel using 9:1 hexane:ethyl acetate as eluent. The yield is 0.4 g (98%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5]CCOC(O)C)#N.[C:12](#[N:15])[CH:13]=[CH2:14].[CH2:16]([OH:22])[CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[C:4]([O:22][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:14][CH2:13][C:12]#[N:15])(=[O:5])[CH:3]=[CH2:1]
Reactant: CC(O)OCCOCCC#N
Reactant: C=CC#N
Reactant: OCCOCCO
Product: C=CC(=O)OCCOCCOCCC#N

Procedure:
Following the procedures described in Example 1, cyanoethoxyethoxyethanol (bp 144°-151° C./2 mm Hg) is prepared from diethylene glycol and acrylonitrile, acrylation of which gives the desired product.