Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:23])[CH:13]([OH:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:23])[CH:13]([O:22][C:30]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(F)c2ccccc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)c2ccccc12
Yield: 100.5 %

Procedure:
To a mixture of ethyl 6-(4-fluoro-1-naphthyl)-5-hydroxy-6-oxohexanoate (19.0 g), pyridine (5.50 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (10.8 g) with stirring under ice-cooling. After 16 hours of stirring at room temperature, the reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluoro-1-naphthyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (26.3 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1cccs1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cccs1
Temperature: 85 °C

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5 mmol) was dissolved in DMF (3 mL). Potassium phosphate (212.4 mg, 1 mmol), copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) were added. 2-(1-Bromoprop-1-en-2-yl)thiophene (121.8 mg, 0.6 mmol) was dissolved in DMF (2 mL) and added dropwise to the reaction mixture. Nitrogen was purged for 2 min and the reaction mixture was heated at 85° C. overnight (prolonged heating required in some cases). DMF was evaporated and water added to the reaction mixture. The precipitate obtained was filtered and purified by silica gel chromatography (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 20 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.55 (s, 1H), 7.42 (d, 1H), 7.38 (d, 1H), 7.20 (s, 2H), 7.10 (m, 2H), 4.50 (m, 2H), 3.70 (m, 2H), 3.10 (m, 5H), 2.0 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)=O)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:33]([NH2:35])[CH3:34])[CH:29]=[CH:30][C:31]=1[F:32].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:25][C:26]1[CH:27]=[C:28]([CH:33]([NH:35][CH:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:34])[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Reactant: CC(N)c1ccc(F)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Yield: 93.9 %

Procedure:
Following a similar procedure to that described in Example (1a), 700 mg of 3,4-dimethoxy-5-nitrophenyl 4-methoxyphenyl ketone, 854 mg of 1-(3,4-difluorophenyl)ethylamine hydrochloride, 1.84 ml of triethylamine, 0.29 ml of titanium tetrachloride, 616 mg of sodium cyanoborohydride and 0.19 ml of acetic acid were reacted, to obtain 950 mg of the title compound as a yellow oil.
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:13]=[CH:12][CH:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-]>CO.[Pd]>[CH2:8]([CH:5]([CH2:6][CH3:7])[CH:4]([NH2:1])[C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCC(CC)C(N=[N+]=[N-])c1ccnn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Yield: 92.7 %

Procedure:
5-(1-Azido-2-ethylbutyl)-1-(4-methoxybenzyl)-1H-pyrazole (0.750 g, 2.39 mmol) in MeOH (24 mL) with 5% Pd/C (75 mg) was hydrogenated under atm pressure for 24 h. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated to give 0.637 g (93%) of {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}amine as an oil.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH2:24]([C@@H:31]1[CH2:35][N:34]([C:36]2[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=2)[C:33](=[O:47])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C@@H:31]1[CH2:35][N:34]([C:36]2[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=2)[C:33](=[O:47])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(N2C[C@@H](Cc3ccccc3)NC2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2C[C@@H](Cc3ccccc3)NC2=O)sc1C(=O)O
Yield: 83 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with (R)-ethyl 2-(4-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 83% yield: MS (ES+) m/z 318.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([O:22]C)=[O:21])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+:25]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([O-:22])=[O:21])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.[Na+:25]
Reactant: COC(=O)c1cc(-c2cncc(Cl)c2)cnc1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1cc(-c2cncc(Cl)c2)cnc1-c1ccccn1
Temperature: 135 °C

Procedure:
To a solution of methyl 5″-chloro-2,2′:5′,3″-terpyridine-3′-carboxylate (12-3, 3.05 g, 9.36 mmol, 1.0 equiv) in THF/methanol (22 mL/4.5 mL) was added 10 N sodium hydroxide (1.124 mL, 11.2 mmol, 1.2 equiv) and the system was heated to 135° C. for 15 minutes in a microwave reactor. The reaction mixture was cooled, concentrated, and azeotroped with ethyl acetate (2×100 mL) and toluene (3×100 mL) to afford the desired product (12-4) as a white solid. ESI+MS [M+H]+ C16H10ClN3O2 calc'd 312.0. found 311.9.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1/[CH:13]=[CH:14]/[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1/[CH:13]=[CH:14]/[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(/C=C/C2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(/C=C/C2CCCN2)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a stirred solution of ethyl (E)-4-[2-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]ethenyl]benzoate (700 mg, 2.03 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL) and the resulting mixture was stirred for 3 hr. The mixture was concentrated and the residue was made basic by the addition of sat. NaHCO3. The mixture was extracted with CHCl3 (2×100 mL). The combined extracts were dried over Na2CO3 and concentrated in vacuo to give 434 mg (87%) ethyl (E)-4-[2-(2-pyrrolidinyl) ethenyl]benzoate as a brown oil. 1H-NMR (CDCl3) δ 1.39 (3 H, t, J=7.3 Hz), 1.52–2.06 (4 H, series of m), 2.93–2.99 (1 H, m), 3.07–3.13 (1 H, m), 3.74 (1 H, q, J=7.3 Hz), 4.37 (2 H, q, J=7.3 Hz), 6.34 (1 H, dd, J=15.6, 7.3 Hz), 6.54 (1 H, d, J=15.6 Hz), 7.41 (2 H, d, J=8.3 Hz), 7.97 (2 H, d, J=8.3 Hz).
Reaction SMILES: C(=O)([O-])O.[Na+].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:11][CH:10]=1.[O-]Cl.[Na+]>O.C(Cl)Cl.[Br-].[K+]>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:7]=[O:6])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC=O)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Yield: 75 %

Procedure:
(hh) (α) A solution of 5 mg (0.04 mmol) of potassium bromide and 20 mg (0.24 mmol) of sodium hydrogen carbonate in 10 ml of water was added at room temperature and while stirring to a solution of 0.270 g (0.58 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate [Example 29(h)] in 10 ml of methylene chloride under argon. The V reaction mixture was cooled to 0° C. and treated with 2 mg (0.01 mmol) of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO). Then, 1 ml (0.658 mmol) of Javelle water was sprayed into the reaction mixture while stirring continuously. After the addition the reaction mixture was stirred at 0° C. for about 30 minutes. For the working-up, 20 ml of a 1:1 mixture of methylene chloride and water were added, the reaction mixture was washed with 10 ml of saturated sodium chloride solution and the aqueous phase was back-extracted with 10 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with a 2:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 200 mg (75% of theory) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-oxo-ethyl)-phenyl]-piperidine-1-carboxylate as a foam; MS: 460 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]1=[O:28])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]1=[O:28])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(CC(C)C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(CC(C)C)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 93 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-isobutyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-isobutyl-3,4-dihydroquinoxalin-2(1H)-one (93%). [α]D25=−272° (c=0.010 G/ML, CHCl3); MS (ESI) m/z 371 ([M+H]+); MS (ESI) m/z 369 ([M−H]−); HRMS: calcd for C21H23FN2O3, 370.1693; found (ESI_FT), 371.17594; Anal. Calcd for C21H23FN2O3: C, 68.09; H, 6.26; N, 7.56. Found: C, 67.85; H, 6.24; N, 7.65.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=2)[CH:3]=1)#[N:20]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (91 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=80/20→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (147 mg, 60%) as a white powder.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:15]3=[N:14][C:13]=2[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:8][CH:7]=1)[C:3]([O-:5])=O.ClC(Cl)(Cl)[C:41]([N:43]=C=O)=[O:42].O>ClCCl.C(O)C>[O:24]1[CH2:23][CH2:22][N:21]([C:20]2[C:15]3[N:16]([C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH:2]5[O:1][C:41](=[O:42])[NH:43][C:3]5=[O:5])=[CH:7][CH:8]=4)=[C:13]([CH2:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:14]=3)[N:17]=[CH:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: O=C([O-])C(O)c1ccc(-c2c(CCc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: O=C1NC(=O)C(c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)O1
Temperature: 25 °C

Procedure:
A solution of compound 50c (0.15 g, 0.29 mmol) and 2,2,2-trichloroacetyl isocyanate (81 mg, 0.43 mmol) in dichloromethane (10 mL) was stirred at rt for 30 min and concentrated in vacuo. The residue obtained was dissolved in ethanol (10 mL), and TEA (87 mg, 0.86 mmol) was added. The reaction mixture was heated at reflux for 2 h and allowed to cool to rt. Water (10 mL) was added. The solids formed were collected by filtration and washed with Et2O (2×20 mL) to obtain the title compound 70 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.17 (d, J=8.4 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.70 (t, J=7.8 Hz, 1H), 7.54-7.48 (m, 3H), 7.37-7.31 (m, 3H), 6.27 (d, J=5.7 Hz, 1H), 5.27 (s, 1H), 3.90-3.73 (m, 4H), 3.68-3.56 (m, 4H), 3.34-3.28 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H26N6O4: 535.2 (M+H). Found: 535.2.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH:3]([OH:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:30][C:2]([CH3:1])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 4-{1-[4-(3,3-dimethyl-2-hydroxybutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzoic acid, Example 1, (0.50 g, 1.22 mmol) in CH2Cl2 (10 mL) is added a solution of the Dess-Martin reagent (0.57 g, 1.34 mmol) in CH2CL2 (10 mL) dropwise and stirred for 2 h. The reaction is diluted with EtOAc (100 mL), washed with 10% Na2SO3 (2×20 ml), 0.1 M HCl (20 ml), and H2O (20 ml). The organic layer is MgSO4 dried, and concentrated to give the title compound (0.48 g, 1.17 mmol, 95%).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10](C2C=CC=CC=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[Cl-].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][Zn+]>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:33]2[CH:30]=[CH:29][C:28]([C:27]([F:37])([F:36])[F:26])=[CH:35][CH:34]=2)[CH:11]=[C:12]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:27]([F:37])([F:36])[F:26])[CH:29]=2)[CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: FC(F)(F)c1cccc(C[Zn+])c1
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Agent: [Cl-]
Product: CC(C)CC(C(=O)O)c1cc(Cc2cccc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Nigishi coupling of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with 3-trifluoromethylbenzyl zinc chloride under the conditions described in Example 2; 1H NMR (400 MHz, MeOD) δ ppm 0.76-0.86 (m, 6 H), 1.36 (dt, J=13.51, 6.82 Hz, 1 H), 1.54-1.62 (m, 1 H), 1.80-1.91 (m, 1 H), 3.62 (t, J=7.83 Hz, 1 H), 4.05 (s, 2 H), 7.16 (s, 1 H), 7.33-7.44 (m, 6 H), 7.64 (q, J=8.56 Hz, 4 H); Calcd for C27H24F6O2 (M+Na) 517.17, Found 517.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]([N:18]=[C:19]=[O:20])=[O:17]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:19]([NH:18][C:16]([O:15][CH3:14])=[O:17])=[O:20])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)N=C=O
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(=O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 79.1 %

Procedure:
To 4-nitrobenzenesulfonamide (2.1 grams, 0.01 mole) in 100 milliliters dry toluene was added 1.2 grams (0.012 mole) methoxycarbonyl isocyanate. Three drops of pyridine were added. The mixture was refluxed for four hours. After cooling the precipitate was filtered off and washed with toluene. The solid material was dried. There was obtained 2.4 grams of the title compound, m.p. 150°-158° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15][CH3:16]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15][CH3:16]
Reactant: OCCCCl
Reactant: COc1c(F)cccc1CCl
Product: COc1c(F)cccc1COCCCCl

Procedure:
In an analogous manner to that described in (δ) 1-chloromethyl-3-fluoro-2-methoxy-benzene was reacted with 1-chloro-3-propanol to yield 1-(3-chloro-propoxymethyl)-3-fluoro-2-methoxy-benzene as a colorless liquid; MS: 232 (M)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:20])=O>O>[Cl:20][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCOC(CC)CCCCO
Solvent: c1ccncc1
Solvent: O
Product: CCOC(CC)CCCCCl
Temperature: 25 °C

Procedure:
The starting material prepared in Example 37, 5-ethoxyheptanol (238 g, 1.49 moles) is diluted in pyridine (128 g, 1.62 moles). The solution is stirred at room temperature and thionyl chloride (388 g, 3.22 moles) is added dropwise over 2 hours, after which time the reaction is heated in a 70° C. water bath for 2 additional hours. Water (700 ml) is added to the reaction and the organic layer separated. The aqueous layer is extracted with hexane (3×400 ml) and the extracts combined with the organic phase. The organic phase is then washed with a 10% sodium hydroxide solution (1000 ml). The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The remaining solvent is removed leaving a clear light yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (162 g, 1.13 moles), BP 96° C./9.5 cm Hg.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][S-:15].[Na+]>CN(C=O)C>[CH3:14][S:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: C[S-]
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a DMF solution (5 mL) containing 935.3 mg (4.87 mmol) of 4-fluoro-2-(trifluoromethyl)benzaldehyde was added sodium thiomethoxide (414.2 mg, 5.84 mmol). The mixture was stirred at 90° C. for 2 h, partitioned between EtOAc and water. The EtOAc extracts were washed with brine, dried over Na2SO4 and evaporated to afford desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Br-].[CH:10]1([Zn+])[CH2:13][CH2:12][CH2:11]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.ClCCl>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([CH:10]2[CH2:13][CH2:12][CH2:11]2)=[CH:7][N:6]=1
Reactant: [Zn+]C1CCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: ClCCl
Product: Clc1ncc(C2CCC2)cn1
Yield: 35.5 %

Procedure:
To a 100 mL recovery flask containing 5-bromo-2-chloropyrimidine (816 mg, 4.22 mmol) was applied vacuum then placed under a nitrogen atmosphere. To the flask was added dichloromethane (3 mL), PdCl2(dppf)-CH2Cl2 (172 mg, 0.211 mmol) and then cyclobutylzinc(II) bromide (8.44 mL, 4.22 mmol, 1.3 M in THF) over 1-2 minutes. The reaction was quenched at 2 hours with 20 mL of saturated aqueous NH4Cl and 50 mL EtOAc. The organic layer was washed with 20 mL each of saturated aqueous NaHCO3 and then NaCl, dried with MgSO4, filtered and concentrated to 0.88 g of yellow oil containing some solids. This was purified by flash chromatography (5-10% EtOAc in hexanes) to yield product (253 mg, 1.50 mmol, 36%) as a faintly pale yellow liquid with some small amount of crystalline material. MS (ESI) 169.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH2:19][OH:20])=[CH:14][CH:13]=3)=[N:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH:19]=[O:20])=[CH:14][CH:13]=3)=[N:2]1
Reactant: OCc1ccc2[nH]c(-c3n[nH]c4ccccc34)cc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]c(-c3n[nH]c4ccccc34)cc2c1
Reaction time: 5 h

Procedure:
To a stirred solution of the alcohol (6-2, 29 mg, 0.11 mmol) in tetrahydrofuran (2 mL) was added at the ambient temperature 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75 mg, 0.33 mmol). After 5 h stirring, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, 50% ethyl acetate in hexanes) afforded the desired product (6-3) as a light tan solid; 1H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 11.14 (s, 1H), 9.98 (s, 1H), 8.22 (d, 1H, J=8.4 Hz), 8.20 (s, 1H), 7.70–7.56 (m, 3H), 7.46 (t, 1H, J=7.8 Hz), 7.36 (s, 1H), 7.28 (t, 1H, J=7.8 Hz).