Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(Cl)cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 90 °C

Procedure:
356 mg (1.52 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 73.1 mg (3.1 mmol) NaH is added. 250 mg-(1.54 mmol) 2-amino-4,6-dichloropyrimidine is then added and the solution stirred at 90° C. over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 mL 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 254 mg (46%). ESI-MS m/z 361.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Yield: 59.3 %

Procedure:
7.9 g of 4'-methyl-2-cyanobiphenyl, prepared in A), are dissolved in 100 ml of carbon tetrachloride in the presence of 7.3 g of N-bromosuccinimide and 0.3 g of benzoyl peroxide. The mixture is heated to reflux for 6 hours and the crystals are filtered off; the remaining solution is concentrated under vacuum and the residue is crystallised in ether to give 6.6 g of 4'-bromomethyl-2-cyanobiphenyl in the form of crystals of melting point 115°-118° C.
Reaction SMILES: O.NN.[N+]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][C:8]=1[CH:21]=[CH:22][N:23]1CCCC1)([O-])=O>CO.[Ni]>[CH2:14]([O:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:23][CH:22]=[CH:21]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1c(C=CN2CCCC2)cccc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: c1ccc(COc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine hydrate (4.6 g, 92 mmol, 85% solution) was added to a mechanically stirred mixture of 1-[2-[2-nitro-3-(phenylmethoxy)phenyl]ethenyl]pyrrolidine and N-methyl-N-[2-[2-nitro-3-(phenylmethoxy)phenyl]ethenyl]methanamine (20 g, 61.8 mmol, crude product obtained as described in Step 2) and Raney-Nickel (5 g) in methanol (500 mL), care being taken to keep the temperature at 45°-50° C. Two additional portions of hydrazine hydrate (4.6 g each ) were added after 30 and 60 minutes, respectively. The temperature was maintained at 45°-50° C. for 5 hours. After stirring overnight at room temperature, the mixture was filtered off (Celite) and the filtrate was concentrated in vacuo. The residue (dark liquid) was purified by flash-chromatography (on silica Merck-60, dichloromethane-light petroleum ether 1:1) to yield pure 7-benzyloxyindole as an oil that solidifies upon standing (2.3-3.03 g, 17-22%, based upon different runs). A sample was recrystallized from petroleum ether as white needles, m.p. 62°-63° C. (Dictionary of Organic Compounds Vol III, p 3077, m.p. 67°-68° C., ligroin).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C@H:5]([C:7]1[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[S:10][CH:11]=1)[OH:6]>O1CCCC1.O>[O:6]1[CH2:4][C@@H:5]1[C:7]1[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[S:10][CH:11]=1
Reactant: O[C@H](CBr)c1csc(C(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1nc([C@H]2CO2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.9 %

Procedure:
Aqueous sodium hydroxide (5N, 11 mL) was added to a solution of (1S)-2-bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanol (which was obtained in Example 103) (1.52 g, 5.5 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane. The organic extracts were washed with H2O and brine, and dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/dichloromethane 6/4) gave a clear oil (1.33 g, 74% yield); MS (ES) m/z: 196 (MH+); 1H NMR (400 MHz, CDCl3) δ 3.09 (m, 1H), 3.19(m, 1H), 4.11(m, 1H), 7.48 (s, 1H).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:40][CH2:41][CH2:42][CH2:43][NH:44]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CSc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)c2c(=O)[nH]ccc2n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)c2c(=O)[nH]ccc2n1

Procedure:
The compound was prepared from N-(3-{[2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl]amino}phenyl)-1-pyrrolidinecarboxamide using mCPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA sequences similar to that described for Example 1 (Scheme 2).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[CH:24][C:25]([CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:26][C:21]3=[N:20][N:19]=1)[CH:14]=[CH:13]2.Br[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CC(N(C)C)=O.CCOC(C)=O.O>[OH:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[CH:24][C:25]([CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:26][C:21]3=[N:20][N:19]=1)[CH:14]=[CH:13]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(CO)COc1cccc2ccc(-c3nnc4cc(CN5C(=O)c6ccccc6C5=O)ccn34)nc12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (0.513 g, 1.57 mmol) was added to a solution of 2-((3-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione (0.221 g, 0.524 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (0.350 g, 2.10 mmol) in DMA (2 mL). The reaction was sealed and heated at 100° C. and stirred for 30 minutes. The reaction was cooled to ambient temperature and diluted with EtOAc/H2O (2:1). The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting with a 20:1 mixture of DCM/MeOH), to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:27][N:15]4[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl.C(N(C(C)C)CC)(C)C.[F:38][C:39]([F:51])([F:50])[C:40]1[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][C:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:27][N:15]4[CH2:16][CH2:17][N:18]([S:46]([C:42]5[CH:43]=[CH:44][CH:45]=[C:40]([C:39]([F:38])([F:50])[F:51])[CH:41]=5)(=[O:48])=[O:47])[CH2:19][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:3][CH2:4]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Oc3cnc(C4(C)CC4)cn3)C[C@H]2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(c2cnc(O[C@@H]3C[C@H]4CN(S(=O)(=O)c5cccc(C(F)(F)F)c5)CCN4C3)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 206A (28 mg, 0.075 mmol) in 1,4-dioxane (1 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes, and the mixture was then concentrated and dried in vacuo. To the resulting colorless solid was added CH2Cl2 (0.75 mL), diisopropylethylamine (0.065 mL, 0.375 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (22.02 mg, 0.090 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% ethyl acetate in hexanes. The title compound was obtained as a colorless solid (10 mg, 28%). 1H NMR (300 MHz, CDCl3) δ ppm 0.72-0.81 (m, 2H), 1.07-1.17 (m, 2H), 1.48 (s, 3H), 1.72-1.88 (m, 1H), 1.92-2.05 (m, 1H), 2.12 (t, J=10.51 Hz, 1H), 2.33 (dd, J=9.92, 5.16 Hz, 1H), 2.38-2.63 (m, 3H), 2.94-3.07 (m, 1H), 3.65 (dd, J=10.31, 6.74 Hz, 1H), 3.72-3.82 (m, 1H), 3.86-3.98 (m, 1H), 5.23-5.35 (m, 1H), 7.70 (t, J=7.93 Hz, 1H), 7.87 (d, J=7.93 Hz, 1H), 7.96 (d, J=7.93 Hz, 1H), 8.00 (d, J=1.19 Hz, 1H), 8.01-8.04 (m, 1H), 8.05 (d, J=1.19 Hz, 1H); MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:18][C:12]1[S:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:9][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(Oc2csc(C3OCCO3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1sc(C2OCCO2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-(4-Phenoxy-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 109 (4.88 g, 19.7 mmol) and N-bromosuccinimide (3.85 g, 21.7 mmol) were dissolved in tetrahydrofuran (100 mL), and the solution was stirred for 4.5 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was silica gel-filtered to obtain 2-(5-bromo-4-phenoxy-thiophen-2-yl)-[1,3]dioxolane (5.48 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][N:12]=[C:11]([C:14]([O:16]CC)=[O:15])[C:10]=2C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].[OH-].O.Cl.[CH2:24]1COCC1>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[N:12]([CH3:24])[N:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1n[nH]c(-c2cccc(C#N)c2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(-c2cccc(C#N)c2)cc1C(=O)O
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of ethyl 5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylate (100 mg, 392 μmol, Eq: 1.00) in THF (5 ml) in MeOH (1.00 ml) was added LiOH 1M (2.35 ml, 2.35 mmol, Eq: 6). The mixture was stirred overnight. To the residue was added water and HCl 1N (pH:1), this aqueous phase was extracted two times with ethyl acetate, the resulting organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired compound (52 mg, 52.6%) as a yellow solid. MS (ISP): 228.1 (M+1).
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.Cl.[NH:7]1[CH2:10][CH:9]([OH:11])[CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[CH2:2][CH:3]([N:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH2:4]1
Reactant: OC1CNC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: OC1CN(C2COC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of oxetan-3-one (0.5 g, 6.94 mmol), azetidin-3-ol hydrochloride (1.140 g, 10.41 mmol) and 4 A molecular sieves (1.5 g) in dichloromethane (10 mL) was stirred at room temperature for 4 h. sodium triacetoxyborohydride (2.94 g, 13.88 mmol) was added and the reaction mixture was stirred at room temperature overnight. The ppt was filtered through a pad of celite and the filtrate was diluted with ethyl acetate (more ppt appeared) and filtered again. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 3-10% 2N ammonia in methanol/dichloromethane). 1-(oxetan-3-yl)azetidin-3-ol was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: -11 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
(2S,4S)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (70.0 g) was dissolved in tetrahydrofuran (700 mL) and then cooled to −11° C. To this solution, triethylamine (33.4 g) and ethyl chlorocarbonate (35.8 g) were slowly added and stirred at −15° C. for 30 minutes. Subsequently, 28% aqueous ammonia (73 mL) was added to the reaction mixture. After stirring at −10° C. for 40 minutes, a mixture of ethyl acetate and tetrahydrofuran (4:1, 1400 mL) and water (230 mL) were added and stirred. The reaction mixture was separated into organic and aqueous layers, and the aqueous layer was further extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1, 350 mL). The combined organic layers were washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude crystal was recrystallized from a mixed solvent of acetonitrile and diisopropyl ether to give the titled compound (57.7 g, white powder).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:35])([CH3:34])[C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.[NH:36]1[C:44]2[C:39](=[CH:40][C:41](B(O)O)=[CH:42][CH:43]=2)[CH:38]=[CH:37]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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]>[NH:36]1[C:44]2[C:39](=[CH:40][C:41]([C:2]3[CH:3]=[C:4]4[C:31](=[CH:32][CH:33]=3)[O:30][C:29]([CH3:35])([CH3:34])[C:25]3([CH2:28][O:27][CH2:26]3)[C:5]34[CH2:9][O:8][C:7]([NH2:10])=[N:6]3)=[CH:42][CH:43]=2)[CH:38]=[CH:37]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC(C)(C)C21COC1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(-c3ccc4[nH]ccc4c3)cc2C2(COC(N)=N2)C12COC2
Temperature: 100 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
A mixture of di-tert-butyl (6′-bromo-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (13.8 mg), indole-5-boronic acid (8.1 mg), PdCl2(dppf) (2.0 mg) and 1M aqueous K2CO3 (0.063 mL) in dioxane (0.25 mL) was stirred for 12 hours at 100° C. The mixture was filtered by using Chem Elut cartridges and washed with CHCl3. The filtrate was evaporated. The residue was purified with HPLC (Column: Waters SunFire™ Prep C18 OBD™ 5 micrometer, 19×100 mm; MeOH/0.1% aqueous HCOOH 11/89 to 95/5(v/v)) and afforded 6′-(1H-indol-5-yl)-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (4.5 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[O:27]1[C:31]2=[CH:32][CH:33]=[CH:34][C:35]([C:36](O)=[O:37])=[C:30]2[CH:29]=[CH:28]1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:36]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[O:27][CH:28]=[CH:29][C:30]=23)=[O:37])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2occc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with benzofuran-4-carboxylic acid (M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105).
Reaction SMILES: Br[C:2]([F:23])([F:22])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]23[O:17][CH2:16][C:13]([CH2:18][CH2:19][CH3:20])([CH2:14][O:15]2)[CH2:12][O:11]3)=[CH:5][C:4]=1[F:21].[F:24][C:25]1[CH:26]=[C:27]([OH:33])[CH:28]=[C:29]([F:32])[C:30]=1[F:31].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1.CCCCCCC>[F:22][C:2]([F:23])([O:33][C:27]1[CH:26]=[C:25]([F:24])[C:30]([F:31])=[C:29]([F:32])[CH:28]=1)[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]23[O:17][CH2:16][C:13]([CH2:18][CH2:19][CH3:20])([CH2:14][O:15]2)[CH2:12][O:11]3)=[CH:5][C:4]=1[F:21]
Reactant: CCCC12COC(c3cc(F)c(C(F)(F)Br)c(F)c3)(OC1)OC2
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCCC12COC(c3cc(F)c(C(F)(F)Oc4cc(F)c(F)c(F)c4)c(F)c3)(OC1)OC2
Temperature: 83.5 °C
Yield: 50.4 %

Procedure:
In a reactor under an N2-atmosphere, 10.0 g (25.1 mmol) 1-(4-(bromodifluoro-methyl)-3,5-difluorophenyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane, 4.5 g (30 mmol) of 3,4,5-trifluorophenol, 3.5 g (25 mmol) of potassium carbonate, 2.6 g (7.5 mmol) of tetrabutylphosphonium bromide, 50 ml of H2O and 5 ml of n-heptane were added, and the mixture was refluxed at 82-85° C. for 10 hours. After being cooled to room temperature, the mixture was added with 100 ml of toluene and 100 ml of water, the organic layer was separated, and then the water layer was subjected to extraction with toluene. The organic layer was collected, washed by an aqueous solution of sodium hydrogen carbonate and water in sequence, dried over anhydrous magnesium sulfate, filtered to remove insoluble substance, and concentrated at a reduced pressure. The residue was purified by a fractionation operation utilizing column chromatography, with a mixed solvent of heptane and ethyl acetate in a volume ratio of 1:4 (ethyl acetate:heptane) as an eluent solvent and silica gel as a filler. The product was further purified by recrystallization using isopropanol/ethyl acetate in a volume ratio of 80/20, so that 5.9 g of 1-(4-(difluoro(3,4,5-trifluorophenoxy)methyl)-3,5-difluorophenyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9]2)=[C:4]([O:17]C)[CH:3]=1.B(Br)(Br)Br.CO.Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9]2)=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(Cl)ccc1B1OCc2ccccc21
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(Cl)ccc1B1OCc2ccccc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 1,3-dihydro-1-(4-chloro-2-methoxyphenyl)-2,1-benzoxaborole as a white solid (AN-2551, 0.5 g, 1.93 mmol) in anhydrous methylene chloride (25 mL) at −78° C. Was added dropwise a solution of boron tribromide in methylene chloride (1.0 M, 1.93 mL, 1.93 mmol) under nitrogen. The mixture was stirred at −78° C. for 1 h and at room temperature for 4 h. Then the reaction flask was re-cooled to −78° C. and methanol (10 mL) was added. The reaction mixture was warmed to room temperature and 6N HCl (2 mL) was added. The mixture was evaporated to give a residue that was mixed with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The residue was purified by flash column chromatography eluted with a mixed solvent of hexanes and ethyl acetate (4:1, v/v) to provide the desired compound 1,3-dihydro-1-(4-chloro-2-hydroxyphenyl)-2,1-benzoxaborole as a white solid (0.32 g, 1.31 mmol) in 67.8% yield. M.p. 96-98° C.; 1H NMR (MeOH-d4, 300 MHz): δ 8.19 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.52-7.51 (m, 2H), 7.43-7.38 (m, 1H), 6.96-6.91 (m, 1H), 6.89-6.88 (m, 1H) and 5.41 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.Cl[C:30]([O:32][CH3:33])=[O:31]>C1COCC1.[Cl-].[Na+].O.C(Cl)(Cl)(Cl)Cl>[CH3:33][O:32][C:30]([C:4]1[CH:3]=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:12][CH2:13][O:14][CH3:15])=[O:31]
Reactant: COC(=O)Cl
Reactant: COCOc1ccc(F)c2ccccc12
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COCOc1c(C(=O)OC)cc(F)c2ccccc12
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.30 g of 4-fluoro-1-methoxymethoxy-naphthalene in 21 ml of dry THF was added 1.8 ml of TMEDA. The mixture was cooled to −18 to −22° C. (carbon tetrachloride bath) after which was added 2.46 ml of 1.6 M n-butyl-lithium. The mixture was stirred at −20° C. for 0.5 h after which it was cooled to −75° C. To the mixture was added a solution of 0.60 ml of methyl chloroformate in 6 ml of THF. The mixture was stirred at −75 to −78° C. for 0.5 h, poured into brine, extracted twice with ether, dried (sodium sulphate), filtered and concentrated to an orange oil. The oil was dissolved in dichloromethane and purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes to provide 0.162 g of 4-fluoro-1-methoxymethoxynaphthalene-2-carboxylic acid methyl ester as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8].[C-:16]#[N:17].[K+].ClCCl>C(O)C>[C:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])#[N:17]
Reactant: [C-]#N
Reactant: CCOC(=O)CNC(=O)CCCCCBr
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CCCCCC#N
Yield: 99 %

Procedure:
23.73 g (84.7·10-3 mol) of N-(6-bromohexanoyl)-glycine, ethyl ester are dissolved in 200 ml of ethanol, and 6.5 g (0.1 mol) of powdered potassium cyanide are added. The reaction mixture is brought to the reflux point and stirred under reflux for 15 hours. After concentration of the mixture under reduced pressure, the residue is taken up with dichloromethane and the organic phase is washed with aqueous sodium chloride solution. The organic phase is dried and concentrated under reduced pressure to give 19 g of the expected product (yield=99%).