Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[N:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The synthesis was performed with reference to the known literature (Tetrahedron, Vol. 29, p. 359, 1973). A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0419 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.125 g, 91%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]([F:69])([F:68])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59]([CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)(=[O:61])=[O:60].C(OC(N1CCC(SC2C=CC=CC=2C(F)(F)F)CC1)=O)(C)(C)C.OO.Cl>CN(C=O)C.O>[O:27]=[C:25]([N:65]1[CH2:64][CH2:63][CH:62]([S:59]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[C:52]([F:68])([F:51])[F:69])(=[O:61])=[O:60])[CH2:67][CH2:66]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)C1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(S(=O)(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 26.9 %

Procedure:
DIPEA (88 mg, 0.68 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (36 mg, 0.15 mmol) in DMF (1 mL) followed by HOBt (20 mg, 0.15 mmol) and EDCI.HCl (39 mg, 0.2 mmol). After 2 minutes 4-(2-trifluoromethyl-benzenesulfonyl)-piperidine hydrochloride (250 mg, 1.0 mmol) (prepared from 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester by means of oxidation with hydrogen peroxide and subsequent hydrolysis of the N-protection group with hydrochloric acid) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected. The solid obtained was purified by column chromatography (using 60-120 silica gel and 5% MeoH in DCM as eluent) to afford 21 mg (29.6% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzenesulfonyl)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 521.14, 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (m, 5H), 7.7 (d, 2H), 7.5-7.3 (m, 3H), 7.1 (s, 1H), 4.5 (d, 1H), 4.2-4.0 (m, 2H), 4.0 (d, 1H), 3.7-3.5 (t, 1H), 3.1 (t, 1H), 2.7 (m, 1H), 1.9-1.7 (m, 2H), 1.7 (m, 1H), 1.5 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[C:13]([NH:15][CH:16]([CH2:21][C:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]1[O:14][C:21]([C:22]2[C:30]3[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:15]=1)[CH:32]([CH3:34])[CH3:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1c[nH]c2c(Br)cccc12)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc([C@@H](NC(=O)OCc2ccccc2)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Yield: 109.4 %

Procedure:
Dichlorodicyanoquinone (340.8 g, 1,500 mmol) was added to a stirred solution of the title compound of Example 4 (361.4 g, 681 mmol) dissolved in tetrahydrofuran (15 L) and heated to reflux for 6 hours at which time HPLC indicated complete reaction. The reaction was concentrated to ¼ its volume and diluted with ethyl acetate (12 L). The resulting black solution was washed three times with saturated aqueous NaHCO3 (5.5 L). The organic layer was dried over sodium sulfate and concentrated to give the title compound as a black solid (392 g, 100% yield). 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[OH:6][CH:7]1[O:11][C:10](=[O:12])[CH:9]=[CH:8]1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl>[OH:12][CH:10]1[CH:9]2[CH:8]([C:5]3[CH2:4][C:3]2=[CH:2][CH:1]=3)[C:7](=[O:6])[O:11]1
Reactant: O=C1C=CC(O)O1
Reactant: C1=CCC=C1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(O)C2C3=CC=C(C3)C12
Temperature: 20 °C
Reaction time: 17 h

Procedure:
244 ml of cyclopentadiene were slowly added to a mixture of 208 g of 5-hydroxy-2(5H)-furanone, 350 mg of hydroquinone and 1.05 liters of chloroform while keeping the temperature at 45°-47° C. and the mixture was stirred at 20° C. for 17 hours and was evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was heated to reflux with stirring and was cooled and vacuum filtered. The solid was dissolved in methylene chloride and the solution was treated with activated carbon and evaporated to dryness under reduced pressure. The residue and isopropyl ether was heated to reflux with stirring and was cooled and vacuum filtered to obtain 325.7 g of racemic 1-hydroxy-3-oxo-1,3,3a,7a-tetrahydro-4,7-methanoisobenzofuran melting at 105° C.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[C:11]([CH3:22])=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[Cl:9][C:10]1[C:11]([CH3:22])=[C:12]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)/C=C/c1cccc(Cl)c1C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a solution of trimethylsulfoxonium iodide (0.157 g, 0.712 mmol) in 1 mL DMSO was added NaH (60% in mineral oil) (0.032 g, 0.807 mmol) portion-wise. The mixture was stirred at room temperature for 30 min, and then a solution (E)-methyl 3-(3-chloro-2-methylphenyl)acrylate (0.1 g, 0.475 mmol) in 1 mL DMSO was added in one portion. The reaction was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.042 g, 39% yield) as a clear colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (d, J=7.8 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 3.79-3.75 (m, 3H), 2.55 (ddd, J=9.1, 6.7, 4.5 Hz, 1H), 2.45 (s, 3H), 1.81 (dt, J=8.4, 4.9 Hz, 1H), 1.64-1.57 (m, 1H), 1.30 (ddd, J=8.4, 6.7, 4.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[N:19]([CH2:23][CH2:24][O:25][CH3:26])[C:20](=O)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[C:10]2[N:19]([CH2:23][CH2:24][O:25][CH3:26])[C:20]([CH3:21])=[N:16][C:11]=2[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(C(C)=O)c1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COCCn1c(C)nc2cc(Br)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
A mixture of N-[2-(benzyloxy)-4-bromo-6-nitrophenyl]-N-(2-methoxyethyl)acetamide (11.7 g, 27.7 mmol, Step 2) and iron powder (7.74 g, 139 mmol) in acetic acid (150 mL) was refluxed with stirring for 5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was poured onto water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 1:1) to afford the title compound as a pale green solid (9.74 g, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:13])[CH3:12]>C1C=CC=CC=1>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 20 g. of 4-hydroxybenzoic acid in 200 ml. of benzene and 40 ml. of acetyl chloride is refluxed for 3 hours. Solvent and excess acetyl chloride are evaporated. The mixture is dissolved in methanol (150 ml.) and water (20 ml.) added; after 15 minutes, addition of more water results in the precipitation of 4-acetoxy benzoic acid, m.p. 192°-193° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].C([O-])(=O)C.[Na+].CC(OC)(C)C>CCO.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=[N:18][O:16][CH3:17])[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: CON
Reactant: CCOC(=O)CC(=O)[C@H](C)[C@H](C)CC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCO
Product: CCOC(=O)CC(=NOC)[C@H](C)[C@H](C)CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
(4R,5R)-4,5-Dimethyl-3-oxo-heptanoic acid ethyl ester (21.23 g, 106 mmol) was dissolved in 200 mL of EtOH and added to 10.6 g (127 mmol) of methoxylamine-HCl and 10.6 g (127 mmol) of sodium acetate solids. The slurry was stirred at room temperature for 48 hours. MTBE (200 mL) and 100 mL of water were added, and the resulting phases were separated. The organic phase was washed with 100 mL of water and was evaporated to yield a two-phase mixture. Hexanes (100 mL) were added and the phases were separated. The aqueous phase was extracted with 50 mL of hexanes and the combined organic phases were washed with 50 mL of water, dried over magnesium sulfate, and evaporated to give 21.24 g (87.4% yield) of the titled compound as a clear yellow oil: 1H NMR (CDCl3, 399.77 MHz) δ 0.84-0.88 (m, 6H), 1.07 (d, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.4-1.6 (m, 2H), 2.24 (m, 1H), 3.08 (d, J=15.8 Hz, 1H), 3.19 (d, J=15.8 Hz, 1H), 3.80 (s, 3H), 4.10-4.2 (m, 3H). Low resolution mass spec: nominal m/e calc'd for C12H23NO3 (M+H)+: 230. Found: m/e 230.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>C(O)(=O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:35]2)=[CH:30][CH:29]=1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3)c2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 3 of Preparation 4 and 4-chlorophenylhydrazine hydrochloride (106.0 mg, 0.59 mmol) were added to acetic acid (3.0 mL). The reaction mixture was stirred at 120° C. for 8 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 163.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:28]([Cu])#[N:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:9]2=[C:10]([C:28]#[N:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 508 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.FC(F)(F)S(O[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reactant: OB(O)c1ccccc1F
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2F)CCC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
2-Fluorobenzeneboronic acid (4.48 g) and tetrakis(triphenylphosphine)palladium (740 mg) were added to a solution of ethyl 2-trifluoromethanesulfonyloxycyclopent-1-enecarboxylate obtained in Preparation Example 3-(1) in toluene. Then, ethanol (100 mL) and a 1 N sodium carbonate solution (32 mL) were added to the reaction solution, followed by replacement of the reaction atmosphere with nitrogen. The reaction solution was heated to 85° C. and stirred overnight. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.60 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:24]([N:4]1[C:3]([CH2:1][CH3:2])=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: CCc1nc2ncnc(-c3c(C)cc(C)cc3C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCn1c(CC)nc2c(-c3c(C)cc(C)cc3C)ncnc21
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A solution of 8-ethyl-6-(2,4,6-trimethylphenyl)purine (200 mg, 0.75 mmol) in anhydrous dimethylfomamide (5 mL) was cooled to 0° C., and treated with sodium hydride dispersion in mineral oil (72 mg 50% w/w, 1.50 mmol). After 1 hour, bromobutane (0.10 mL, 0.90 mmol) was added by syringe, and the mixture was allowed to stir for 12 hours. It was poured into ethyl acetate (120 mL), and was washed with water (3×120 mL) and brine (100 mL). The aqueous layers were back-extracted in sequence with ethyl acetate (120 mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the title product as a viscous oil (64.2 mg, 0.20 mmol, 27%). TLC RF 0.20 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.96 (1H, s), 6.95 (2H, s), 4.25 (2H, t, J=7.5 Hz), 2.93 (2H, q, J=7.7 Hz), 2.32 (3H, s), 2.04 (6H, s), 1.91-1.86 (2H, m), 1.50-1.38 (2H, m), 1.39 (3H, t, J=7.7 Hz), 1.01 (3H, t, J=7.5 Hz). MS (NH3-CI): m/e 325 (3), 324 (23), 323 (100).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O>[Br:21][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c(Br)c1
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a stirred mixture of 3-amino-4-(trifluoromethyl)benzoic acid (Matrix Scientific, 2.05 g, 10 mmol) in aqueous HBr (48% in water, 20 mL) and H2O (67 mL) at 0° C. is added NaNO2 (0.828 g) in small portions over 15 min. After stirring the solution for 30 minutes the mixture is added dropwise to a solution of CuBr (2.5 g) in aqueous HBr (48% in water, 40 mL) and H2O (100 mL). The mixture is stirred at 75° C. for 2 hours, then room temperature for 16 hours. The mixture is treated with 20% NaOH to raise the pH above 10 and then filtered through celite. The resulting solution is acidified with 6 M HCl to pH 1 and extracted with dichloromethane (3×100 mL). Organic layers are collected, dried over Na2SO4, filtered and concentrated to give 3-bromo-4-(trifluoromethyl)benzoic acid (2.30 g, 85.5% yield). LCMS m/z=269.1, 271.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:16](=[O:28])[CH:15]=[N:14]2)=[CH:8][C:7]=1[CH3:29].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:34][O:33][C:32]1[C:2]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:3][C:4]([O:5][C:6]2[C:11]([CH3:12])=[CH:10][C:9]([N:13]3[C:18](=[O:19])[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:16](=[O:28])[CH:15]=[N:14]3)=[CH:8][C:7]=2[CH3:29])=[CH:30][CH:31]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)n(COCC[Si](C)(C)C)c3=O)cc2C)cc1Br
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)n(COCC[Si](C)(C)C)c3=O)cc2C)cc1-c1ccccc1
Temperature: 80 °C
Yield: 83.8 %

Procedure:
To a solution of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazine-3,5-dione (36 mg) of EXAMPLE 6 in degassed DMF (1.1 ml) were added sequentially tetrakis(triphenylphosphine)-palladium(0) (7.5 mg), phenylboronic acid (24 mg) and 2M aqueous sodium carbonate (0.13 ml). The resulting mixture was heated at 80° C. under nitrogen for 45 h, then additional portions of tetrakis(triphenylphosphine)palladium(0) (7.5 mg), phenylboronic acid (24 mg) and 2M aqueous sodium carbonate (0.13 ml) were added followed by further heating for 18 h. The reaction was diluted with water (4 ml) and extracted with ethyl acetate, then chloroform. The organic layers were washed with brine, dried and concentrated to afford the crude product (43 mg). Purification using silica gel chromatography gave the title compound (30 mg). MS Calc. 546:; Found 545 (M−1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14](OCC)=[O:15])=[C:12]([C:19]([F:22])([F:21])[F:20])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:19]([F:22])([F:21])[F:20])[S:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Temperature: -60 °C

Procedure:
Into a 25-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate (80 mg, 0.24 mmol, 1.00 equiv), toluene (2 mL). This was followed by the addition of DIBAL-H(25% in toluene) (0.690 g, 5.00 equiv) dropwise with stirring at −60° C. The resulting solution was stirred for 2 h at 28° C. The reaction progress was monitored by LCMS. The reaction mixture was cooled to 0° C. with a water/ice bath. The reaction was then quenched by the addition of 20 mL of water/NH4Cl. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×30 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by TLC-plate (EA: PE=4:1). This resulted in 0.056 g (80%) of [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H12F3NOS, 288.1 (M+H). found 288.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@@H:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].Cl.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([C:11]([C@@H:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC(=O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-((1R)-4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester 506 (219 mg, 0.438 mmol) was dissolved in THF (3.5 mL) and treated with 4M HCl (1.75 mL, 7.01 mmol). The reaction mixture was heated to 45° C. and stirred 2 h. Ethyl acetate was added and the organic layer was separated then washed with water, sodium bicarbonate (sat aq), water, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to 0.190 g (95% yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester 507 as a white foam.