Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].[C@:9]12([C:22](OCC)=O)[CH2:14][C@H:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2>CC1CCCO1>[CH3:2][C:1]1[N:3]=[C:22]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[O:5][N:4]=1
Reactant: CCOC(=O)[C@]12C[C@H]1CN(C(=O)OC(C)(C)C)C2
Reactant: CC(N)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1noc([C@]23C[C@H]2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 56.5 %

Procedure:
2-Methyl-tetrahydrofuran (40 mL), acetamide oxime (0.93 g, 0.0125 mol) and sodium methoxide (1.1 g, 0.020 mol) were added to (1R,5R)-3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (142) (1.27 g, 0.0050 mol) and the mixture was heated to reflux for 3 hrs. Upon cooling the suspension was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic layer was washed with water (25 mL), saturated sodium chloride (25 mL) and dried over Na2SO4. The mixture was concentrated and the residue was chromatographed over 25 g of silica gel with 15-25% ethyl acetate/hexanes, to obtain 0.75 g of clear colorless oil. MS (ESI) m/z 304 [M+K]+. 1H NMR (CDCl3) δ 1.16-1.17 (m, 1 H), 1.46 (s, 9 H), 1.60 (s, 1 H), 1.72-1.75 (m, 1 H), 2.36 (s, 3 H), 3.49-3.51 (m, 1 H), 3.65-3.79 (dd, 1 H), 3.91-4.00 (m, 2 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28](O)=[O:29].Cl.[CH3:35][O:36][C:37]([C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][C@H:42]2[NH2:48])=[O:38]>C1COCC1.C(OCC)(=O)C>[CH3:25][CH:26]([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28]([NH:48][C@H:42]1[C:41]2[C:45](=[CH:46][CH:47]=[C:39]([C:37]([O:36][CH3:35])=[O:38])[CH:40]=2)[CH2:44][CH2:43]1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)C(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)CC(C)C(C)C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
HATU (0.872 g, 2.3 mmol, 1 eq) and TEA (0.647 ml, 4.6 mmol, 2 eq) were added to an ice-cooled solution of 3,4-dimethylpentanoic acid (300 mg, 2.3 mmol, 1 eq) in THF (26 ml), and stirring was carried out for 15 min. (3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.786 g, 3.5 mmol, 1.5 eq) was added to the reaction solution, and the mixture was then stirred overnight at RT. The reaction solution was diluted with ethyl acetate, washed with sat. sodium hydrogen carbonate solution and sat. NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1), the desired product was obtained. Yield: 87% (0.61 g)
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccccn2)CCNCC1
Reaction time: 0.67 h
Yield: 100 %

Procedure:
tert-Butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate (I-2, 5.45 g, 19 mmol) was dissolved in TFA/CH2Cl2 (1:1, 50 mL) at 0° C. After stirring 40 min, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 2 N NaOH in saturated aqueous NaCl (1:1, 80 mL) and extracted with EtOAc (5×200 mL). The combined extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) which was used immediately in subsequent reactions. A solution of 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) in CH2Cl2 (50 mL) at 0° C. was treated with i-Pr2NEt (10 mL) and n-EtSO2Cl (2,24 mL, 21 mmol). After stirring for 1 h at 0° C., the reaction mixture was treated with 2 N NaOH and stirred vigorously for an additional 1 h, before being extracted with EtOAc (4×200 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 1-ethylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (I-3) as a yellow-brown solid. Analytical LCMS: single peak (214 nm), 1.6501 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1ccc(-c2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (2.01 g) and ethyl 4-bromobenzoate (2.29 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[C:26]([O:27][CH3:28])=[CH:25][C:15]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][OH:24])=[O:17])=[C:14]([N+:29]([O-])=O)[C:13]=1[O:32][CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO.[Ni]>[NH2:29][C:14]1[C:13]([O:32][CH3:33])=[C:12]([O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:26]([O:27][CH3:28])=[CH:25][C:15]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][OH:24])=[O:17]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OCc1ccccc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Hydrazine hydrate (2.31 g, 72.2 mmol) was added dropwise to a solution of 125 (6.01 g, 14.4 mmol) in methanol (60 mL) gently refluxing over Raney nickel (1.1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the produce as a brown oil (3.97 g, 10.3 mmol, 73%): 1H NMR (270 MHz, CDCl3) δ1.6-2.2 (m, 4H), 3.5-3.8 (m, 4H), 3.8 (s, 3H), 3.9 (s, 3H), 4.4 (br s, 1H), 5.1 (s, 2H), 6.6 (s, 1H), 7.3-7.6 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ171.5, 144.9, 143.5, 141.9, 137.5, 134.6, 128.6, 128.5, 128.3, 128.2, 128.0, 115.1, 107.3, 75.1, 66.9, 61.0, 60.6, 60.4, 56.9, 50.9, 28.5, 24.9, 21.1, 14.2.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CCOCC.CO>[OH:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1
Reactant: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CCN2C[C@@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To 870 mg (1.63 mmol) of (+)-5-[[(2R, 4S)-4-benzoyloxy-1-(4-methoxy phenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1, 4]oxazepine in 15 ml of ether was added 460 mg (11.4 mmol) of NaOH in methanol (60 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, then water was added to the residue and the products were extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate) to give 680 mg (97.1%) of (+)-5-[[(2R, 4S)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as yellow amorphous.
Reaction SMILES: Br.[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:32][C:33]([NH:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:5])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(CN)c1ccc(O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CNC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 4.64 g of (±)-4-(2-amino-1-methylethyl)phenol hydrobromide, 100 ml of ethyl acetate, 6.92 g of potassium carbonate, 40 ml of water and 3.75 g of benzyloxycarbonyl chloride is stirred at room temperature overnight. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried, and then evaporated under reduced pressure to remove the solvent. 4.82 g of (±)-4-(2-benzyloxycarbonylamino-1-methylethyl)phenol are obtained as pale yellow oil.
Reaction SMILES: [CH:1](=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CCO.O.[Pd]>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1COc2ccc(OC)cc2C1=Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
3.1 g (9.1 mmol) of ethyl 4-benzylidene-6-methoxychroman-3-ylcarbamate were dissolved in 80 ml of EtOH and 910 mg (0.9 mmol) Pd/C were added. Then, 5.8 g (91 mmol) of ammonium formate dissolved in 20 ml of water were added and the mixture was warmed to 70° C. and stirred for 1.5 h. The mixture was cooled to room temperature. The catalyst was filtered off and washed with EtOH/water. The filtrate was concentrated in vacuo to remove EtOH. The aqueous concentrate was extracted with ethyl acetate (2×). The combined organic phases were dried over MgSO4 and the solvent was evaporated to yield 3.2 g (9.3 mmol, quant.) of the crude product.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:5][CH2:6][CH2:7][C@H:8]([OH:22])[C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12].[OH-].[Na+]>O1CCOCC1.O>[C:18]([O:17][C:15]([NH:14][C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@@H:8]([OH:22])[CH2:7][CH2:6][NH:5][C@H:4]([C:3]([OH:27])=[O:2])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@H](CC(C)C)NCC[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NCC[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Yield: 83 %

Procedure:
2 (700 mg) was dissolved in dioxane (8 ml), diluted with H2O (8 ml) and treated with four portions (2 ml each) of 1N NaOH (aqueous) over a 1.5 hour period. The aqueous dioxane was removed in vacuo and the white solid residue dissolved in H2O (10 ml). The product was precipitated by acidification with 1N HCl and collected by filtration to give 3 as a fine white powder (560 mg, 83% yield) after drying.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([CH2:66][CH2:67][NH-:68])=[CH:58]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([CH2:66][CH2:67][NH-:68])=[CH:58]1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCc1c[nH]c2ccccc12
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 92 mg of Z-Phe-His-OH, 79 mg of H-Leu-Val-Ile-2-(3-indolyl)-ethyl amide, 32 mg of HOBt and 44 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.34.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])[N:20]=[C:21]4[C:26]=3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]([F:30])([F:29])[F:28])[CH:13]=2)[CH:5]=1.COC(=O)C1C=CC(COC2C=CC(C3N(CC4C=CC=CC=4)N=C4C=3C=CC=C4C(F)(F)F)=CC=2)=CC=1.[CH2:79]([NH2:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1.C([Mg]Br)CCC>C1COCC1.CCOCC>[CH2:79]([NH:86][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])[N:20]=[C:21]4[C:26]=3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]([F:28])([F:30])[F:29])[CH:13]=2)[CH:5]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccc(Cl)cc3F)c2)c1
Agent: CCCC[Mg]Br
Agent: COC(=O)c1ccc(COc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1ccccc1)c1cccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccc(Cl)cc3F)c2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Fifty-seven milligrams (57 mg; 0.1 mmol) of 3-[3-(2-(4-chloro-2-fluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester (prepared similarly to that of 4-[4-(2-benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester in preparation of Example 2) were dissolved in 2 ml of dry THF followed by the addition of 110 μl of benzylamine (1 mmol). The reaction mixture was cooled to −30° C. and 450 μl of 2M solution of butylmagnesiumbromide in ether were added dropwise. Then the reaction mixture was stirred for 30 min at −30° C. and left overnight at 0° C. The reaction mixture was quenched with aq NH4Cl solution and product was extracted with EtOAc. Flash column chromatography (SiO2, dichloromethane as an eluant) afforded N-benzyl-3-({3-[2-(4-chloro-2-fluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}methyl)benzamide in 66% yleld.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].O[C:8]1[CH:17]=[CH:16]C=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12]C2=O>CCOCC>[CH2:14]=[C:9]1[CH2:10][CH2:11][CH2:12][C:3]2[C:2]([OH:5])=[CH:1][CH:16]=[CH:17][C:8]1=2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCc2c(O)cccc21
Agent: [K+]
Solvent: CCOCC
Product: C=C1CCCc2c(O)cccc21
Reaction time: 0.25 h

Procedure:
To a suspension of CH3PPh3I (897 mg, 2.22 mmol) in Et2O (10 mL) was added t-BuOK (249 mg, 2.22 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (300 mg, 1.85 mmol). The mixture was stirred at room temperature overnight, diluted with diethylether, and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The crude residue was purified by short column chromatography and was concentrated under reduced pressure to give 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol. A mixture of 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 5-methyl-5,6,7,8-tetrahydro-naphthalen-1-ol (110 mg, 36%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16]O)[S:14][CH:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[Br:24][CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:22])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1cc(-c2csc(CO)n2)cc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2csc(CBr)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 92 %

Procedure:
1.5 g (4.70 mmol) of intermediate 353.2, (2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol are dissolved in dichloromethane (30 ml). After adding CBr4 (2.02 g; 6.10 mmol), the reaction medium is cooled down to 0° C. PPh3 (1.48 g; 5.63 mmol) is added by fractions then the mixture is allowed to return to ambient temperature. The reaction medium is then poured into ice-cold water before being extracted with dichloromethane. The organic phase is washed with salt water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column (eluent: 30% of ethyl acetate in heptane), in order to produce a brown oil with a yield of 92%. This product is sufficiently pure to be able to be used directly in the following stage.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O>[CH2:13]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1cc(CO)occ1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of 17 g (0.12 mole) of kojic acid and 5.1 g (0.13 mole) of sodium hydroxide in 190 ml of 10:1 (by volume) methanol-water was added dropwise 17.5 g (0.14 mole) of benzyl chloride. After 4.5 hours at reflux, the mixture was allowed to cool and was poured into 200 ml of ice-water. The resultant solid was collected, washed with water, and dried, giving 22.4 g of analytically pure title compound, m.p. 128°-130°.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:23][CH3:24])[C@@H:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH2:23][CH3:24])[C@@H:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](O)c1nc(-c2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reaction time: 1 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to yield (290 mg, 0.83 mmol) of (S)-2-tert-butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol. (S)-2-tert-Butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C(#N)C.CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][C:9](=[O:10])[NH:11][C:14]2=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)CNCc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Temperature: 0 °C
Yield: 20.6 %

Procedure:
A mixture of 2-(4-bromobenzylamino)acetamide (1B3) (45.9 mmol, 11.2 g) and carbonyldiimidazole (68.8 mmol, 11.2 g) in acetonitrile (223 ml) was cooled to 0° C. with stirring and 4-dimethylaminopyridine (45.9 mmol, 5.60 g) was added. The mixture was stirred at 0° C. for 24 h and then heated at 80° C. for 18 h. The reaction mixture was diluted with water and the acetonitrile removed under reduced pressure. The mixture was acidified to pH 4 with aqueous HCl and the precipitate collected by filtration and dried in a vacuum oven to give 1-(4-bromobenzyl)imidazolidine-2,4-dione (1B4) 2.55 g (20.2%); 1H NMR (400 MHz, DMSOd6) δ 10.94 (bs, NH) 7.55 (d, 2H) 7.24 (d, 2H) 4.42 (s, 2H) 3.86 (s, 2H).
Reaction SMILES: C([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12)=C.C1[CH:15]2[CH:16]3[CH:20]=[CH:19][CH:18]([CH:14]2C=C1)[CH2:17]3.C(C1C=C(O)C(=CC=1)O)(C)(C)C>>[CH:6]1[C:5]2[CH:8]=[CH:9][C:10]([CH:20]3[CH2:19][CH:18]4[CH2:17][CH:16]3[CH:15]=[CH:14]4)=[CH:3][C:4]=2[CH:7]=1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=Cc1cccc2c1CC2
Agent: CC(C)(C)c1ccc(O)c(O)c1
Product: C1=Cc2cc(C3CC4C=CC3C4)ccc21
Yield: 42.9 %

Procedure:
A 100-ml autoclave with an agitator was charge with 10 g (77 mmol) of 4-vinylbenzocyclobutene, 4.6 g (35 mmol) of dicyclopentadiene, and 438 mg (2.6 mmol) of 4-tert-butylcatechol and was then tightly closed. The reactants were allowed to react at 170° C. for two hours while stirring at 300 rpm. The product was then cooled and removed from the autoclave. The product was diluted with toluene, and the resulting polyvinylbenzocyclobutene was precipitated in methanol. Polyvinylbenzocyclobutene was filtered out, and the solvent was removed. The residue was transferred to a distillation apparatus. The residue was distilled under reduced pressure (127° C., 5 mmHg) to yield 3.0 g (15 mmol, yield 20%) of 5-(4-benzocyclobutenyl)-2-norbornene as a colorless and transparent liquid. 1H NMR structural identification showed that the present example produced a compound having the formula (2).