Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18]C)=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>ClCCl>[C:40]([NH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:16]([OH:18])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)(=[O:42])[CH3:41]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2c(-c3ccc(C)c(C)c3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in dichloromethane (DCM) (549 μl) was treated with Et3N (15.96 μl, 0.115 mmol) and acetic anhydride (8.11 μl, 0.086 mmol), and then stirred for 3 hours. The mixture was quenched with sat. NaHCO3, extracted with DCM, washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(7-(acetamidomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetic acid (21.6 mg, 0.045 mmol, 85% yield) as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm, 8.37 (s, 1 H), 7.47 (t, J=7.3 Hz, 1 H), 7.39-7.29 (m, 1 H), 7.24 (d, J=7.2 Hz, 1 H), 7.13 (dd, J=8.4, 12.6 Hz, 1 H), 7.09-6.98 (m, 1 H), 6.11 (br. s., 1 H), 5.34 (s, 1 H), 4.63-4.45 (m, 2 H), 3.69 (s, 3 H), 2.36 (s, 3 H), 2.31 (s, 3 H), 2.05 (s, 3 H), 1.10-0.96 (m, 9 H); LCMS (m/z) ES+=465 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([CH2:18][C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.C[N:31](C)C=O>>[CH:1]1([C:7]2[CH:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:31]=[C:9]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC(CC(=O)c1ccco1)C1CCCCC1)c1cccc(O)c1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1cccc(-c2cc(C3CCCCC3)cc(-c3ccco3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-cyclohexyl-1-(3-hydroxyphenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin (2.7 g, 1.90 mmol), NH4OAc (1.7 g), and AcOH (1.7 mL) in dimethylformamide (30 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 3-(4-cyclohexyl-6-furan-2-yl-pyridin-2-yl)-phenol; 1H NMR (DMSO-d6) d 1.42 (m, 4H), 1.71 (m, 2H), 1.85 (m, 4H), 2.64 (m, 1H), 6.67 (dd, J=3.3, 1.5 Hz, 1H), 6.85 (dd, J=8.1, 1.8 Hz, 1H), 7.18 (d, J=3.3 Hz, 1H), 7.29 (m, 1H), 7.57 (m, 3H), 7.63 (s, 1H), 7.85 (s, 1H), 9.54 (s, 1H); IR (KBr) 1607 cm−1; MS [M+H]+ m/z=320. Anal. calcd for C21H21NO2.0.6 C4H8O2: C, 75.52; H, 6.94; N, 3.77; Found: C, 75.72; H, 6.72; N, 3.55.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH2:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1CCc2cc(Br)ccc21)OCc1ccccc1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (23.57 mmol, 5 g) in ethyl acetate (40 mL) was added potassium carbonate (47.1 mmol, 6.52 g) as a solution in water (40.0 mL). The whole was stirred vigorously before benzyl chloroformate (25.9 mmol, 3.65 mL, 4.42 g) was added and stirring continued overnight. The reaction was quenched with more water and was extracted with DCM (2×). The organic layers were separated and dried using a hydrophobic frit, and were concentrated in vacuo to give desired product as a brown solid (5.5 g, 15.9 mmol, 67.4%). 1H NMR (400 MHz, CDCl3) δ 1.82 (m, 1H) 2.60 (m, 1H) 2.85 (m, 1H) 2.90 (m, 1H), 4.95 (d, 1H) 5.18 (m, 3H) 7.18 (d, 1H) 7.34 (m, 7H).
Reaction SMILES: [IH:1].[CH2:2]([N:4]=[C:5](SC)[NH:6][NH2:7])[CH3:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[IH:1].[NH2:7][NH:6][C:5]([NH:4][CH2:2][CH3:3])=[N:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CCN=C(NN)SC
Agent: I
Solvent: O
Product: CCNC(=NCc1ccccc1)NN

Procedure:
A solution of 25.0 g. of methyl N-ethylthiocarbazimidate hydroiodide and 10.2 g. of benzylamine in 150 ml. of water is heated on a steam bath for one hour and then evaporated under reduced pressure. The residue is dissolved in ethanol, treated with activated charcoal, filtered and evaporated under reduced pressure. The residue is dissolved in methylene chloride and the solution is passed through hydrous sodium magnesium silicate and concentrated under reduced pressure, giving the desired product as a residual red oil.
Reaction SMILES: [Na].[OH:2][C:3]1([C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:7][C:6]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:5]=2[NH:4]1.[N+]([O-])([O-])=O.[Ag+:29]>>[OH:2][C:3]1([C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:7][C:6]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:5]=2[NH:4]1.[Ag:29]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: O=[N+]([O-])c1cc(C(F)(F)F)cc2c1NC(O)(C(F)(F)C(F)F)N2
Agent: [Na]
Product: [Ag]

Procedure:
In procedures similar to those reported in the preceding example, 2-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-4-nitro-6-(trifluoromethyl)benzimidazoline sodium salt was reacted with silver nitrate, yielding 2-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-4-nitro-6-(trifluoromethyl)benzimidazoline, silver salt, as a white powder, m.p. >350° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[CH2:23][C:22](=[O:25])[CH2:21][CH2:20]4)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: COc1ccc(-c2cnc(Nc3cccc4c3CC(O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 10C for the product of Example 1I. 1H NMR (DMSO-d6) δ 8.98 (s, 1H), 7.59 (d, 1H, J=7.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.20 (s, 1H), 7.08 (t, 1H, J=7.6 Hz), 7.00 (d, 2H, J=8.8 Hz), 6.82 (d, 1H, J=7.4 Hz), 4.79 (d, 1H, J=4.1 Hz), 3.93 (m, 1H), 3.78 (s, 3H), 2.74-2.98 (m, 4H), 1.85 (m, 1H), 1.63 (m, 1H); MS (ESI+) m/z 337 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1>C(Cl)(Cl)Cl.C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][NH:32][CH2:22][C:23]2[CH:31]=[CH:30][C:29]3[O:28][CH2:27][O:26][C:25]=3[CH:24]=2)=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(CO)cnc1-c1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCn1c(CNCc2ccc3c(c2)OCO3)cnc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Hydroxymethylimidazole 103 (0.82 g) is dissolved in chloroform (10 mL) and treated with thionyl chloride (1 mL). The solution is heated to 50° C. for 30 min, cooled and evaporated. The residue is washed with benzene and evaporated to give the intermediate chloromethyl hydrochloride as a white powder which is taken up in acetonitrile (30 mL). This is added dropwise to a solution of piperonylamine (5 mL) in acetonitrile (10 mL). The reaction is allowed to stand overnight and then evaporated. The residue is taken up in ethyl acetate and washed with water. The organic layer is dried (Na2SO4) and concentrated. Purification on silica gel (10% MeOH/CHCl3) provides the product as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.79 (3H, t, J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.56 (2H, m, J=7.4 Hz), 3.75 (4H, s), 4.04 (2H, dd, J=8 Hz), 5.92 (2H, s), 6.76 (2H, m), 6.84 (1H, s), 6.97 (1H, s), 7.38–7.44 (3H, m), 7.53–7.56 (2H, m).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[N:14]([CH2:26][C:25]4[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=4)[N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc(-c2ccc3occc3c2)n[nH]c1=O
Reactant: Fc1ccc(CCl)cc1
Product: O=C(O)c1cc(-c2ccc3occc3c2)nn(Cc2ccc(F)cc2)c1=O
Yield: 73.4 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride, to thereby yield the title compound as a yellow powder (yield: 73.4%).
Reaction SMILES: [F:1][C:2]([F:14])([C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(OCC)(=O)C.CCCCCC>ClCCl.O>[CH3:22][S:23]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:14])([F:1])[C:10]([F:11])([F:12])[F:13])(=[O:25])=[O:24]
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
7,7,8,8,8-Pentafluorooctan-1-ol(25 g, 113 mmol) was dissolved in dichloromethane (250 ml), triethylamine(47.4 ml, 339 mmol) and methanesulfonylchloride(17.6 ml, 227 mmol) were added dropwise under cooling to 0° C., and the resulting mixture was stirred for 1 hour. The reaction solution was diluted with water, extracted twice with dichloromethane(200 ml), washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/n-hexane=1/10, v/v) to give 30 g(100 mmol, Yield 89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH:40]([F:42])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH2:36][C:37]#[N:38])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.C=O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH:40]([F:41])[F:42])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH2:35][CH2:36][C:37]#[N:38])[CH3:45])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: N#CCCNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCC#N)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amide (31.1 g, 52.0 mmol) in DCM (500 mL) was treated with 37% aqueous formaldehyde solution (21.3 mL, 286.2 mmol). On complete addition the reaction was cooled in an ice bath before the addition of sodium triacetoxyborohydride (44.1 g, 208.2 mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 1.5 hours, after which, the reaction was filtered and the filtrate diluted with methanol. The mixture was diluted with methanol and loaded onto a pad of Isolute® SCX-2 which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The basic fractions were combined and evaporated. The resultant residue was purified by flash column chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Appropriate fractions were combined and evaporated. The resultant residue was recrystallized from ethyl acetate to afford the title compound as a pale brown solid (30.7 g, 96%). LCMS (Method 5) [M+H]+=612.2, RT=2.84 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=7.0, 1.6 Hz), 8.70-8.67 (m, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.63 (dd, 1H, J=8.8, 2.7 Hz), 7.56 (d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=7.0, 4.2 Hz), 7.26 (t, 1H, J=73.4 Hz), 5.22-5.24 (m, 2H), 4.38 (d, 1H, J=12.9 Hz), 3.96 (d, 1H, J=13.5 Hz), 3.06 (t, 1H, J=12.7 Hz), 2.62-2.65 (m, 6H), 2.22 (s, 3H), 1.72 (d, 2H, J=11.9 Hz), 1.34-1.40 (m, 2H).
Reaction SMILES: CN([CH:4]=[C:5]([C:14](=[O:16])[CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])C.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O-]CC.[Na+].[Na].Cl>C(O)C.O>[C:6]([C:5]1[C:14](=[O:16])[CH:15]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:23][CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(=CN(C)C)C(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c(C(=O)c2ccccc2)co1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of this enamine (19.0 g) and diethyl oxalate (23.7 ml) in ethanol (120 ml) was added to a solution of sodium ethoxide prepared by dissolving sodium (3.0 g) in ethanol (60 ml). The solution was stirred for 6 hours at room temperature than acidified with 5 M hydrochloric acid solution (100 ml). The mixture was allowed to stand overnight and was then cooled and diluted with water (300 ml) to give pale crystals of ethyl 5-benzoyl-4-oxo-4H-pyran-2-carboxylate (mp 84°-86° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11])[CH3:8]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.62 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.48 g, yield: 62.8%). mp: 80-82° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.19 (t, J=7.3 Hz, 3H), 2.59 (s, 3H), 3.34 (dq, J=6.1 and 7.3 Hz, 2H), 5.72 (s, 1H), 6.60-6.85 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:26]=[CH:27][CH:28]=2)=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+].Cl>CO>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1[N:14]=[C:13]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of methyl 3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)phenyl)propanoate (240 mg) in methanol (2.0 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (1.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (181 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:1]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2cccc(C)c2)c1-c1ccccc1

Procedure:
m-Toluidine (5 mmol, 0.5 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4 (sodium sulfate), the solids were separated, and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 92.5° C.-94.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.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>[CH3:21][Si:20]([C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1)([CH3:22])[CH3:23]
Reactant: C#Cc1ccc(OC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.72 g (0.0054 mole) of p-methoxyphenylacetylene, 1.51 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.0102 g (0.0053 mmole) of CuI, 0.102 g (0.146 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 10 ml of THF and 10 ml of triethylamine. The light orange brown mixture was stirred at room temperature under nitrogen for 3 days. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 10 ml of chloroform and the solution was washed two times with water (10 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.5 g (98.7% yield) of solid was obtained. 1HNMR: 0.28 ppm (s, 9H); 3.85 ppm (s, 3H); 6.90 ppm (d, 2H); 7.45 ppm (s, 4H); 7.48 ppm (d, 2H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH2:17]([O:20][C:21]1[C:22](/[C:35](/[CH2:43][CH3:44])=[C:36](/[F:42])\[C:37](OCC)=[O:38])=[CH:23][C:24]2[C:25]([CH3:34])([CH3:33])[CH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]=2[CH:30]=1)[CH2:18][CH3:19]>C1COCC1>[CH2:17]([O:20][C:21]1[C:22](/[C:35](/[CH2:43][CH3:44])=[C:36](/[F:42])\[CH2:37][OH:38])=[CH:23][C:24]2[C:25]([CH3:33])([CH3:34])[CH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]=2[CH:30]=1)[CH2:18][CH3:19]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of diisobutylaluminum hydride and hexane (40 mL, 1 M, 40 mmol) was added to a stirring solution of ethyl (E)-3-(3-n-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enoate (Intermediate 8, 3.52 g, 9.36 mmol) in THF (60 mL) at −78° C. under argon. The solution was stirred at −78° C. for 3 h, and the reaction was quenched at −78° C. by adding methanol. The solution was warmed to room temperature and stirred for 1.5 h. The solution was treated with 1 M aqueous HCl, and the products were extracted three times with ether. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound after purification by silica gel chromatography (15% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12](N)=[C:11]([CH3:17])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.N([O-])=O.[Na+].C(OC([S-])=[S:29])C.[K+]>O>[F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([SH:29])=[C:11]([CH3:17])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1S
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylaniline (20 g=70 mmol), add 50 ml 4 N HCl. Reflux 1 hr., cool to 0° C., and add over 1 hour NaNO2 (6.0 g=87 mmol) in 13 ml H2O. After 30 min., add to 45° C. solution of potassium ethylxanthate (14.3 g=83 mmol) in 40 ml H2O. Keep at 45° C. for 30 minutes, cook, and extract with ether. Dry and concentrate. Dissolve the oil in 100 ml EtOH, add potassium hydroxide (17.5 g) and reflux 1 hour. Concentrate, than add 50 ml water and 10 ml concentrated sulfuric acid. Add 0.5 g zinc dust and steam distill. Extract the distillate with ether, dry and concentrate. Recrystallize from hexane to obtain 4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylthiophenol, m.p. 62°-64° C.