Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([SiH:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[Cl-].[NH4+].[CH3:11][CH2:12][CH2:13][CH2:14]C>C1COCC1>[CH2:11]([SiH:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])[CH2:12][CH2:13][CH3:14]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CCCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[SiH](C(C)C)C(C)C
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Diisopropylchlorosilane (13.1 mL, 76.8 mmol) was dissolved in THF (75 mL), and n-butylmagnesium chloride THF solution (0.84M, 100 mL, 84 mmol) was added dropwise thereto in a nitrogen atmosphere for 10 minutes. Subsequently, cuprous bromide (286 mg, 2.00 mmol) was added to the resultant mixture, followed by stirring at 65° C. for 8 hours. The reaction mixture was left to cool, and saturated aqueous ammonium chloride and n-pentane were added thereto. The formed organic layer was washed three times with water and once with saturated brine, and the thus-washed layer was dried over sodium sulfate anhydrate. The solvent was removed, followed by purification through distillation under reduced pressure, whereby the Compound 47a was obtained as a colorless liquid (boiling point; 50 mmHg, 93.2 to 95.5° C. fraction, 8.43 g, 64%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:11]([C:10]1[CH:19]=[CH:20][C:7]([CH2:6][O:5][CH2:4][CH2:3][NH:2][C:35]([NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])=[CH:8][CH:9]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCOCc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOCc1ccc(C(=O)c2ccccc2)cc1)Nc1ccccc1
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred suspension of (X) (3.49 g, 12 mmol) in dry DCM (10 ml) was added dry triethylamine (10 ml). After 0.25 h. stirring a solution of phenyl isocyanate (2.14 g, 18 mmol) in dry DCM (10 ml) was added in one portion. The mixture was stirred for a further 16 h. then quenched with water (10 ml). The organic layer was collected and washed sequentially with water, 2M HCl, and water. The organic layer was dried over MgSO4 and purified by flash chromatography on silica gel eluting with 2:1 petrol 40/60:ethyl acetate (Rf=0.1) to yield (XI) (3.01 g, 67%) as a white solid; m.p. 129-132° C.; δH (DMSO-d, 200 MHz) 3.39 (q, 2H, J=5.1 Hz, NHCH2), 3.58 (t, 2H, J=5.0 Hz, OCH2CH2), 4.65 (s, 2H, OCH2Ar), 6.32 (t, 1H, J=5.2 Hz CH2NHC(O)NHAr), 6.90 (t, 1H, J=7.3 Hz, 4″-H), 7.24 (t, 2H, J=7.4 Hz, 3″-, 5″-H), 7.44 (d, 2H, J=7.6 Hz, 2″-, 6″-H), 7.56 (m, 4H, 3-, 5-, 3′-, 5′-H), 7.70 (m, 5H, 2-, 4-, 6-, 2″-, 6″-H) 8.63 (s, 1H, CH2NHC(O)NHAr) ppm; δC (DMSO-d, 400 MHz) 39.9 (CH2CH2NH), 70.4 (CH2CH2O), 72.1 (ArCH2O), 118.4 (2″-, 6″-C), 121.9 (4″-C), 128.1 (2-, 6-, 2′-, 6′-C), 129.4 (3″-, 5″-C), 130.4, 130.6 (3-, 5-, 3′-, 5′-C), 133.5 (4′-C), 136.9, 138.0 (1-, 1″-C), 141.3 (4-C), 144.4 (1″-C), 156.1 (N(H)C(O)NH), 196.3 (Ar2C(O)) ppm; max 3431 (N—Hstr), 1724 ((R(H)N)2C═Ostr), 1658 (Ar2C═Ostr) cm−1; m/z 375 [M+H]+ (5%), 397 [M+Na]+ (10%), 433 [M+MeCN+NH4]+ (100%); found 375.1703, C23H23N2O3 requires 375.1709.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[C:23](O)=[O:24])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C1COCC1.C(OCC)C>[C:7]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[CH2:23][OH:24])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc2ccccc2c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A 1.0M solution of lithium aluminiumhydride in THF (10 ml, 10 mmol) was placed under an atmosphere of nitrogen and a solution of 1-phenyl-2-naphthalenecarboxylic acid (2.4 g, 10 mmol, Synthesis 1983, 105) in dry THF (10 ml) was added dropwise. When addition was complete the mixture was stirred for 30 minutes at ambient temperature and then 30 minutes at reflux. The reaction mixture was allowed to cool and carefully water (0.4 ml), 4N sodium hydroxide (0.4 ml) and water (1.2 ml) were added successively. The mixture was stirred at ambient temperature for 30 minutes, diluted with diethylether and filtered. The solvent was evaporated in vacuo and the residue was dissolved in toluene. After drying (MgSO4) the solvent was evaporated in vacuo to give 2.3 g of crude (1-phenyl-2-naphthyl)methanol.
Reaction SMILES: C([CH:5]([O:27][C:28]1[CH:29]=[N:30][NH:31][C:32](=[O:35])[C:33]=1[Cl:34])[C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][CH:7]=1)(C)(C)C.[F-:36].[K+]>C(#N)C>[C:6]([N:31]1[C:32](=[O:35])[C:33]([Cl:34])=[C:28]([O:27][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][F:36])=[CH:25][CH:26]=2)[CH:29]=[N:30]1)([CH3:26])([CH3:7])[CH3:5]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc(C(Oc3cn[nH]c(=O)c3Cl)C(C)(C)C)cc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)n1ncc(OCc2ccc(OCCCF)cc2)c(Cl)c1=O
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To a scintillation vial containing a suspension of Example 4F (4.5 mg, 8.64×10−3 mmol) in anhydrous acetonitrile (0.25 mL) was added a solution of potassium fluoride (1.6 mg, 4.07×10−2 mmol) and kryptofix (15.0 mg, 4.07×10−2 mmol) in anhydrous acetonitrile (0.25 mL). The vial was capped and lowered into a 90° C. oil bath. The reaction was allowed to stir for 40 minutes. The reaction was cooled and concentrated under reduced pressure. Preparatory thin layer chromatography [silica gel; eluent pentane-ethyl acetate (3:2)] provided the desired product (0.8 mg, 25%). 1H (CDCl3) δ(ppm): 1.62 (s, 9H); 2.14-2.20 (m, 2H); 4.09-4.11 (m, 2H); 4.60 (t, 1H); 4.68 (t, 1H); 5.24 (s, 2H); 6.92 (d, 2H); 7.32 (d, 2H); 7.72 (s, 1H); 19F (CDCl3, CFCl3 as internal standard) δ(ppm): −222.66 (t of t, J=28.2, −50.4).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH:7]([OH:18])[C:8]2[CH:13]=[CH:12][C:11]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CN(C)C1C=CC(C=O)=CC=1.C[Si](C)(C)C1C=CC(Cl)=CC=1.O=[Cr](=O)(O[Cr](=O)([O-])=O)[O-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([Si:14]([CH3:16])([CH3:15])[CH3:17])=[CH:10][CH:9]=2)=[O:18])=[CH:19][CH:20]=1
Reactant: CN(C)c1ccc(C(O)c2ccc([Si](C)(C)C)cc2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CN(C)c1ccc(C=O)cc1
Agent: C[Si](C)(C)c1ccc(Cl)cc1
Product: CN(C)c1ccc(C(=O)c2ccc([Si](C)(C)C)cc2)cc1

Procedure:
4-Dimethylamino-4'-trimethylsilylbenzhydrol prepared from 4-dimethylaminobenzaldehyde and 4-trimethylsilylchlorobenzene was oxidized by a Cornforth reagent, to yield 4-dimethylamino-4'-trimethylsilyl benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[CH:5]=[O:6].C1(C)C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:22]=[N:21][CH:20]=2)[CH:7]=[C:8]([Cl:10])[N:9]=1
Reactant: O=Cc1cc(Cl)nc(Cl)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1cc(-c2cnco2)cc(Cl)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
528 mg of 2,6-dichloroisonicotinaldehyde (this compound was prepared by the method described in J. Chem. Soc., Chem. Commun., 1998, 1567-1568) was dissolved in 10 ml of methanol, and 586 mg of p-toluenesulfonyl methyl isocyanide and 415 mg of potassium carbonate ware added, and the mixture was stirred at 50° C. for 30 minutes. The reaction solution was concentrated, and then diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 630 mg of the objective compound as white powder.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@H:24]([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:17]=[CH:18][CH:19]=1.CI.[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@:24]([CH3:1])([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF (1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes (800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50° C. After five minutes, the LDA solution was added dropwise to the other flask, and stirring continued for 14 hours at 50° C. Upon cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 60% to 80% over 25 minutes provided the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH3:19])[N:18]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:13][C:14]3[S:15][CH:16]=[C:17]([CH3:19])[N:18]=3)[N:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1csc(Nc2nccc3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=257.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-amino-4-methylthiazole.
Reaction SMILES: CC([O:4][C:5]([C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:18])=[CH:15][CH:16]=1)([CH3:9])[CH3:8])=[O:6])C.[OH-].[Na+].Cl>C(O)(C)C.O>[CH3:9][C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:16]=1)([C:5]([OH:6])=[O:4])[CH3:8]
Reactant: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 4 °C
Yield: 97.2 %

Procedure:
Fenofibrate (350. g, 0.970 mol) was suspended in 2 L of isopropanol. A solution of NaOH (77.6 g NaOH, 1.94 mol, 2 eq) in 1.8 L of water was added and the mixture heated to reflux for 2.7 hours. The solution was cooled to approximately 4° C. A solution of hydrochloric acid (697.2 g of a 10.03% solution, 69.90 g of HCl, 1.917 mol, 2 eq) was added maintaining the temperature at less than 5° C., and the product crystallized from solution. The crystallization can be optionally seeded with Form I fenofibric acid after approximately 50% of the hydrochloric acid is added. The slurry was warmed to 20° C. and mixed for 0.8 hours. The product was filtered, rinsed with 600 mL of 2:1 water:isopropanol, and then rinsed with 300 mL of water. The product was dried in a vacuum oven at 40° C. with a nitrogen purge for 14 hours, and then dried at 60° C. for 24 hours. The dry weight was 300.6 g, or 97.2% yield. 1H NMR (400 MHz, CD3OD) δ 7.72 (m, 2H), 7.71 (m, 2H), 7.52 (m, 2H), 6.95 (m, 2H), 1.66 (s, 6H); Anal. Calcd. for C17H15ClO4: C, 64.06; H, 4.74; N, Cl, 11.12. Found: C, 63.94; H, 4.64; Cl, 11.13.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([S:9][CH2:13][CH2:12][CH2:11][C:10]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C1CCCO1
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCSc1cccc(Br)c1
Temperature: 110 °C

Procedure:
3.74 g of sodium were dissolved in 77 ml of absolute ethanol under argon. The solution was treated dropwise with 25 g of m-bromothiophenol and heated to reflux. Thereafter, 12.4 ml of γ-butyrolactone were added and the reaction mixture was heated to 110° C. for 5 hours. The separated carboxylic acid sodium salt was removed by filtration, washed with a small amount of ether and dissolved in 300 ml of water. The solution was acidified to pH 2 with 1N HCl while cooling with ice, the free carboxylic acid was extracted with ether, the ethereal solution was dried and evaporated. There were obtained 33.1 g of 4-(m-bromophenylmercapto)butyric acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25](O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:17]([CH:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([NH:16][C@@H:13]1[C@@H:11]2[C@@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)(C)C(Cc1ccccc1)C(=O)O
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C)C(Cc1ccccc1)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-benzyl-3,3-dimethylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.08 (dd, J=7.4, 13.6, 1H), 7.46 (d, J=7.3, 1H), 7.44-7.40 (m, 1H), 7.38 (dd, J=7.6, 15.7, 2H), 7.34 (d, J=4.3, 2H), 7.31-7.23 (m, 4H), 4.36-4.29 (m, 1H), 3.59 (d, J=13.1, 0.5H), 3.53 (dd, J=13.2, 32.6, 1H), 3.40 (d, J=13.1, 0.5H), 3.25 (q, J=12.0, 1H), 2.79-2.67 (m, 2H), 2.48-2.42 (m, J=7.0, 1H), 2.41-2.23 (m, 3.5H), 2.20 (t, J=8.3, 0.5H), 2.12 (d, J=6.7, 0.5H), 2.06 (dd, J=5.9, 11.7, 0.5H), 1.88 (dd, J=5.8, 11.7, 0.5H), 1.74 (dd, J=9.4, 16.4, 0.5H), 1.60 (dd, J=7.0, 13.2, 0.5H), 1.51-1.42 (m, 0.5H), 1.37-1.21 (m, 2H), 1.15 (s, 9H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[NH:20][N:21]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Nc2cc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 200 °C

Procedure:
To a mixture of 4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983, 121-128)(0.53 g, 2.21 mmol) in diphenylether (5 mL) was added 3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the resulting mixture heated at 200° C. overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resulting precipitate was isolated by filtration. The crude solid was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-4 as a white solid: mp 242-244° C.; 1H NMR (DMSO) δ 2.27 (3H, s), 6.02 (1H, s), 7.47 (2H, d), 7.53-7.40 (2H, br m), 7.67 (1H, m), 7.92 (1H, m), 8.09 (2H, d), 8.48 (2H, m), 9.20 (1H, s), 12.17 (1H, br s); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:33]([O:35][CH3:36])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[C:33]([O:35][CH3:36])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(=O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Yield: 64.2 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy]pyrrolidine-2-carboxylic Acid, Methyl Ester (425 mg, 0.825 mmol) was oxidized as described in the preparation of 4-[N-dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (272 mg, 64%) as a pale yellow oil.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:16][N:15]=2)=[CH:9][CH:8]=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:35](=[O:38])[CH2:36][CH2:37][N:15]3[N:16]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[N:18]=[C:14]23)=[CH:11][CH:12]=1
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCC(=O)N3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (3 mL) and TEA (0.06 mL) were added to (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162 (44 mg), and the reaction solution was stirred at room temperature for 10 minutes. Acrylic acid chloride (0.01 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour and at 60° C. for two hours. TEA (0.03 mL) and acrylic acid chloride (0.01 mL) were added to the reaction solution at 60° C., and the reaction solution was stirred at 60° C. for four hours. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) and further purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28](=[O:34])[N:27]([CH2:35][CH2:36][O:37][CH3:38])[C:26]=2[CH:39]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[C:31]([CH3:32])([CH3:33])[CH2:30][CH2:29][C:28](=[O:34])[N:27]([CH2:35][CH2:36][O:37][CH3:38])[C:26]=3[CH:39]=2)=[N:3][CH:4]=1
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC#N)n3)cc21
Yield: 48 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenoxy]-acetonitrile and 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. Product isolated as a yellow foam (50 mg, 48%). mp: 235-238° C., MS (ESI+): 539.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.26 (s, 1H), 8.61 (s, 1H), 8.11 (s, 1H), 7.40 (m, 2H), 7.29 (d, J=9 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.06 (t, J=9 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 5.19 (s, 2H), 3.54 (q, 7 Hz, 2H), 2.07 (br m, 2H), 1.87 (br m, 2H), 1.20 (s, 6H), 1.12 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:29]([N:19]1[CH2:18][CH2:17][C@@:15]23[C:16]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]3)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(OC)c13
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of 700 mg (2.44 mmol) 4-methoxymorphinan-6-one.1H2O, 900 mg (6.51 mmol) anhydrous K2CO3 and 310 mg (2.56 mmol) allyl bromide in 20 ml dry DMF was stirred at 80° C. for 30 min. Then the mixture was cooled to room temperature, filtered, and the filtrate evaporated in vacuo. The resulting oil was partitioned between water and ether, the organic layer washed with brine, dried and evaporated to give an oil which was crystallized with u-hexanes. To 700 mg (93%) N-allyl-4-methoxymorphinan-6-one, m.p. 84°-86°, [α]D26 -114.6° (c 0.79, CHCl3), were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][N:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][N:34]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cn4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 2-bromo-5-methanesulfonyl-pyridine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1>[Pd].CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(Cl)cc3)c2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(CCc3ccc(Cl)cc3)c2c1
Yield: 31.1 %

Procedure:
N-{3-[2-(4-Chlorophenyl)ethyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 75 from 465 mg of N-{3-[(E)-2-(4-chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide, 47 mg of 10% palladium-on-charcoal and 8 ml of dimethylformamide. 145 mg of N-{3-[2-(4-chlorophenyl)-ethyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 215° C. (analysis C22H20ClN3O4S2 % calculated C, 53.92; H, 4.11; Cl, 7.24; N, 8.58; O, 13.06; S, 13.09. % found C, 52.86; H, 4.26; Cl, 7.72; N, 8.49; S, 12.52).