Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43]O)=[CH:38][C:37]=1[CH3:45].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[C:37]([CH3:45])[CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1cc(CCO)ccc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)c(C)c3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 2-(4-fluoro-3-methylphenyl)ethanol (0.066 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 7 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluoro-3-methylphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0374 g, 0.062 mmol, 72.4% yield) as glassy paste. 1H NMR (500 MHz, CDCl3) δ 7.12-7.17 (m, 2H), 7.06-7.12 (m, 2H), 6.95-7.00 (m, 3H), 6.08 (s, 1H), 4.14-4.30 (m, 4H), 3.19 (d, J=11.2 Hz, 1H), 3.09 (t, J=7.0 Hz, 2H), 2.87 (t, J=12.0 Hz, 1H), 2.61 (s, 3H), 2.30 (d, J=1.9 Hz, 3H), 2.25-2.29 (m, 1H), 2.20 (s, 3H), 2.06 (t, J=11.7 Hz, 1H), 1.52-1.58 (m, 1H), 1.33-1.42 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.16-1.20 (m, 1H), 1.05-1.10 (m, 1H), 0.90 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=605.3.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C@@H:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCC[C@H]1CC[C@@H](c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCO)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2S,5S)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin2-yl] butyric acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and purification by column chromatography yielded the title compound as a colorless oil, MS: m/e=392.3 (M+H+) and [α]D20=−80.1° (c=1.0870 in chloroform).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.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.C1(C)C=CC=CC=1>[C:9]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: Brc1ccc(Br)nc1
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: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(-c2ccc(Br)cn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
2,5-dibromopyridine (15.85 g, 66.0 mmol) was weighed into a reaction vessel in an argon stream and prepared into a solution by the addition of toluene (300 mL). 4-benzoylphenylboronic acid (18.86 g, 83.0 mmol), tetrakis(triphenylphosphine)palladium(0) (3.05 g, 2.6 mmol) and a 1.41 M aqueous sodium carbonate solution (100 mL) were added thereto, and the mixture was stirred at 90° C. for 8 hours. From the obtained reaction mixture, the solid was collected by filtration. This solid was washed with cold toluene and cold diethyl ether in this order. This solid was dissolved in a toluene/chloroform mixed solvent (volume ratio: 2/1) and purified by silica gel column chromatography. The eluate was evaporated to dryness, and the obtained residue was dissolved in a chloroform/ethanol mixed solvent (volume ratio: 9/2) and recrystallized several times to obtain 2-(4′-benzoylphenyl)-5-bromopyridine (3.00 g, 8.87 mmol) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)O)=O)=[CH:4][CH:3]=1.[CH:19]([NH:22][C:23]([NH2:25])=[S:24])([CH3:21])[CH3:20]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:25]=[C:23]([SH:24])[N:22]([CH:19]([CH3:21])[CH3:20])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: CC(C)NC(N)=S
Solvent: CN(C)C=O
Product: CC(C)n1c(S)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 30 g (0.121 mole) of 4,4'-difluorobenzoin, 14.3 g (0.121 mole) of N-isopropylthiourea and 100 ml DMF was heated at reflux through molecular sieves for five hours. The mixture was cooled to room temperature and the crystalline product was collected, washed with DMF/water, then water, then dried to give 22.7 g of 4,5-bis(4-fluorophenyl)-1-isopropylimidazole-2-thiol as a pale yellow solid, mp 308°-312°.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1)[CH3:2].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1([C:14]([OH:16])=[O:15])[CH2:5][CH2:6][C:7](=[O:8])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC1(C(=O)O)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC1(C(=O)O)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of the 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylic acid in 1,4-dioxane (20 mL) was added HCl (6N) (7.53 mL, 45.2 mmol) and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-ethoxy-4-oxocyclohexanecarboxylic acid (0.777 g, 4.17 mmol, 65% yield over 2 steps) as a red oil. 1H NMR (500 MHz, CHLOROFORM-d) δ=3.59 (q, J=7.0 Hz, 2H), 2.66-2.55 (m, 2H), 2.42-2.33 (m, 4H), 2.24-2.15 (m, 2H), 1.31 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9]O)=[C:6]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])=[C:6]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethanol (2.80 g, 9.66 mmol), phthalimide (1.56 g, 10.6 mmol) and triphenylphosphine (2.79 g, 10.6 mmol) were dissolved in THF (105 mL) and the solution was cooled at 0° C. DIAD (2.09 mL, 10.6 mmol) was added dropwise and the mixture was stirred 23° C. for 1 hour. The solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 10 to 50% ethyl acetate in hexane to afford the title compound (3.50 g, 86%). LC/MS: Rt=2.12 min, ES+ 419 (AA standard).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.Cl>[C:1]([NH:4][CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1cccc(CC(CCC(=O)OC(C)(C)C)NC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(CC(CCC(=O)O)NC(C)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl 4-acetylamino-5-(3-methoxyphenyl)valerate (508 mg) in 1,4-dioxane (2 ml), 4N hydrogen chloride in 1,4-dioxane (4 ml) was added and the solution was stirred for 1 hour. The solution was poured into ice water (6 ml) and the pH of the solution was adjusted to 12 with sodium hydroxide solution. The solution was washed successively with diisopropyl ether and ethyl acetate and the pH of the solution was adjusted to 1 with 6N hydrochloric acid. The solution was extracted with ethyl acetate and the extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 4-acetylamino-5-(3-methoxyphenyl)valeric acid (362 mg).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8]C)=[O:6])#[N:3].[CH:10](I)([CH3:12])[CH3:11]>CO>[CH:10]([CH:4]([C:2]#[N:3])[C:5]([O:7][CH3:8])=[O:6])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)I
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C#N)C(C)C
Temperature: 25 °C
Yield: 79.4 %

Procedure:
In 20 ml of absolute methanol was dissolved 520 mg of metallic sodium, and 2.12 g of ethyl cyanoacetate was added thereto with stirring at room temperature, after which 4.0 g of isopropyl iodide was added dropwise over a period of 10 minutes. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 3 hours, refluxed for 1 hour, subjected to a conventional post-treatment, and then distilled under reduced pressure to obtain 2.1 g of methyl α-isopropylcyanoacetate.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].B(F)(F)F.CCOCC.[Br:17][C:18]1[CH:19]=[C:20]2[C:30](=[CH:31][CH:32]=1)[O:29][C:23]1[CH:24]=[N:25][C:26]([Cl:28])=[CH:27][C:22]=1[C:21]2([CH:34]([CH3:37])[CH2:35][OH:36])O.C(=O)(O)[O-]>C1COCC1.CCOC(C)=O>[N:1]([C:21]1([CH:34]([CH3:37])[CH2:35][OH:36])[C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:23]=2[O:29][C:30]2[C:20]1=[CH:19][C:18]([Br:17])=[CH:32][CH:31]=2)=[N+:2]=[N-:3]
Reactant: CC(CO)C1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CO)C1(N=[N+]=[N-])c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 66 °C
Yield: 61.8 %

Procedure:
Azidotrimethylsilane (1.432 mL, 10.79 mmol) and borontriflouride etherate (1.368 mL, 10.79 mmol) were added sequentially to a solution of 7-bromo-3-chloro-5-(1-hydroxypropan-2-yl)-5H-chromeno[2,3-c]pyridin-5-ol (2000 mg, 5.40 mmol) in THF (50 mL). The reaction mixture was heated to 66° C. After 12 h reaction time, additional azidotrimethylsilane (1.432 mL, 10.79 mmol) and borontriflouride etherate (1.368 mL, 10.79 mmol) were added and the reaction mixture was continued to be heated to 65° C. After 24 h reaction time, additional azidotrimethylsilane (1.432 mL, 10.79 mmol) and borontriflouride etherate (1.368 mL, 10.79 mmol) were added and the reaction mixture was continued to be heated to 65° C. After 32 h reaction time, the reaction mixture was cooled to rt and aqueous saturated bicarbonate solution was added carefully, followed by EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (10-55% EtOAc/hexanes). 2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)propan-1-ol (1.32 g, 85% purity) was isolated of a white solid and taken onto the next step without further purification.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:26](OCC)=O)=[N:12]2)=[CH:7][C:6]=1[CH3:31].C([NH2:34])=O>>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:26]#[N:34])=[N:12]2)=[CH:7][C:6]=1[CH3:31]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)c(C)c2)n1
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc(-n2nc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of sodium methoxide (169 mg) and ethyl 1-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate (420 mg) in formamide (5 ml) was warmed at 110° C. for 30 minutes. The reaction mixture was poured into ice-water (50 ml) and the precipitate was collected by filtration, and washed with water and dried in vacuo. To an ice-cooled solution of POCl3 (0.23 ml) in dimethylformamide (3 ml) was added the residue by small portions under nitrogen atmosphere. After 2 hours, the mixture was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo. The resulting residue was purified by column chromatography on silica gel using chloroform and was recrystallized from ethanol to afford 1-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (297 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][O:10]C)[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([CH2:9][OH:10])[C:7]=1[CH3:8]
Reactant: COCc1ncnc(Cl)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
4-Chloro-5-methyl-6-[(methyloxy)methyl]pyrimidine (Intermediate 49, 2.14 g, 12.40 mmol) was dissolved in DCM (105 ml), cooled in an ice bath and treated with 1M boron tribromide in DCM (13.64 ml, 13.64 mmol). The resulting mixture was stirred for 1 hour, allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by adding water and diluted with DCM. The DCM layer was separated, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a yellow solid (1.70 g) m/z (ES+) 159 (M+1), title compound is 49% pure by LCMS. Also contains (6-bromo-5-methyl-4-pyrimidinyl)methanol, m/z (ES+) 203, 205 (M+1) (49% by LCMS)
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[CH3:25][C@@H:26]([CH2:35][CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>C(O)C>[CH3:25][C@@H:26]([CH2:35][CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Reactant: CC[C@H](C)CCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCC[C@@H](C)CC)cn2)cc1
Yield: 29.7 %

Procedure:
KOH (0.8 g) was added to a solution of 5-hydroxy-2-(4-octyloxyphenyl)pyrimidine (4 g) dissolved in ethanol (20 ml), followed by adding (S)-8-methyldecyl bromide (3.2 g) prepared according to the method disclosed in the literature (Mol. Cryst. Liq. Cryst., 1984, Vol. 114, pp. 237-247), keeping the mixture under reflux for 6 hours, allowing the resulting material to cool down, extracting it with toluene, washing the resulting organic layer with 2N-NaOH aqueous solution, further washing with water until the washing water became neutral, distilling off low-boiling components in the organic layer and recrystallizing the residue from ethanol to obtain the captioned compound, (S)-5-(8-methyldecyloxy)-2-(4-octyloxyphenyl)pyrimidine (1.8 g). Its phase transition points were as follows: ##STR12##
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21]([O:23]C)=[O:22])(=[O:18])=[O:17])=[O:14])[N:3]=1.C(O)C.[OH-].[K+]>O.Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])(=[O:17])=[O:18])=[O:14])[N:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture containing 5 g of methyl 2-[[(4-methylquinazolin-2-yl)aminocarbonyl]aminosulfonyl]benzoate, 20 ml of ethanol, 2.5 ml of water and 2.5 g of potassium hydroxide is stirred at ambient temperature and pressure for 18 hours. The mixture is then diluted with water and 20 ml of concentrted hydrochloric acid added with stirring. The resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[CH3:8][C:9]1([CH3:15])[CH2:13][CH2:12][NH:11][C:10]1=[O:14].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>COC1CCCC1.[Cu]I>[CH3:8][C:9]1([CH3:15])[CH2:13][CH2:12][N:11]([C:2]2[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=2)[C:10]1=[O:14]
Reactant: CC1(C)CCNC1=O
Reactant: Cn1ccc(I)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: COC1CCCC1
Product: Cn1ccc(N2CCC(C)(C)C2=O)n1
Yield: 91.5 %

Procedure:
A solution of 3-iodo-1-methyl-1H-pyrazole (200 mg), 3,3-dimethylpyrrolidin-2-one (109 mg), copper(I) iodide (73 mg), N1,N2-dimethylethane-1,2-diamine (0.083 mL) and tripotassium phosphate (408 mg) in cyclopentyl methyl ether (4 mL) was stirred overnight at 120° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](C)=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:19])=[C:11]([CH2:12][OH:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccccc2)cc1CO
Reaction time: 2 h

Procedure:
To a solution of 3-(benzyloxy)-2-methylbenzoic acid (300 mg) in THF (10 mL) was added a 1.0 M solution of borane-THF complex in THF (1.85 mL) over 30 min. After stirring for 2 hr, methanol (20 mL) was added dropwise to the reaction mixture over 20 min. Methanol (10 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure to give the title compound (280 mg) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]1([C:6]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[N:8](C3CCCCO3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:6]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1=C(c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)CCC1
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2n[nH]c3cnc(-c4cccnc4)cc23)CCC1
Reaction time: 6 h
Yield: 38.1 %

Procedure:
A mixture of 35 mg (0.10 mmol) of 3-cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine in 4 ml of trifluoroacetic acid was stirred for 6 hours. The mixture was concentrated in vacuum, the residue partitioned between saturated aqueous solution of NaHCO3 and ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 10 mg (38%) of 225. ESI MS m/z 263.0 (M+1). 1H NMR (400 MHz, DMSO): 13.59 (s, 1H), 9.39 (s, 1H), 9.14 (s, 1H), 8.53-8.600 (m, 3H), 7.50 (dd, J=7.9, 4.8 Hz, 1H), 6.88 (s, 1H), 2.91 (t, J=6.6 Hz, 2H), 2.64 (s, 2H), 2.04-1.94 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](OCC)=[O:13])[C:5]2[O:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.B.[H-].[H-].[H-].[H-].[Li+].[Li+].[Li+].[Li+].CO.Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[O:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1
Reactant: CCOC(=O)c1cc(Cl)cc2nc(S)oc12
Agent: B
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CO
Product: OCc1cc(Cl)cc2nc(S)oc12
Reaction time: 2 h
Yield: 69.6 %

Procedure:
5-Chloro-7-ethoxycarbonyl-2-mercaptobenzoxazole (280 mg) was dissolved in diethyl ether (20 mL), and the mixture was added with lithium tetrahydride borane (100 mg). The mixture was stirred at 35 C.° for 2 hours. The reaction mixture was added with methanol and 1 N hydrochloric acid, and volatile components were evaporated under reduced pressure. This procedure was repeated 3 times. The resultant product was purified by silica gel chromatography (methanol:methylene chloride=1:20) to obtain the title compound (163 mg).
Reaction SMILES: O([Si](C)(C)C)[K].[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH3:8]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:13][CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: C[Si](C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCC/C=C/c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Following General Procedure II, a mixture of KOSiMe3 (570 mg, 4.0 mmol, 2.0 equiv), (E)-21 (379 mg, 2.2 mmol, 1.1 equiv), ethyl-4-iodobenzoate (2.0 mmol) and Pd(dba)2 (58 mg, 0.1 mmol, 0.05 equiv) was stirred at room temperature for 15 min, and then was filtered through SiO2. Purification by column chromatography (SiO2, Hexane/Ethyl Acetate, 50/1) and Kugelrohr distillation afforded 413 mg (84%) of (E)-154f as colorless oil.