Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].Cl>CCO>[CH3:17][C:14]([C:11]1[CH:10]=[C:9]([CH:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[OH:19])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:12]=1[OH:13])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(C(O)c2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Over a 25-minute period NaBH4 (1.89 g, 0.05 mole) is added to a solution of 3.1 g (0.01 mole) of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]phenylmethanone (C. D. Cook, JOC, 1960, p. 1429) in 50 mL absolute EtOH while maintaining the temperature at 10°-15° C. The reaction mixture is then allowed to come to room temperature for 1.5 hours. The reaction mixture is cooled t 0° and 4N HCl (12 mL) is slowly added. The white precipitate is filtered off and washed with H2O. It is taken up in Et2O and washed with saturated NaHCO3. After drying over Na2SO4 the Et2O is evaporated to dryness yielding an analytically pure olive colored product, 2.9 g (93%), m.p. 117°-119° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=O.OO.[Na+].[Cl-].[I:19]I>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[I-:19]
Reactant: II
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Product: [I-]
Reaction time: 8 h

Procedure:
In a second set of experiments, glucose oxidase (D-glucose:oxygen 1-oxidoreductase; EC 1.1.3.4) (1 mg/ml) and horseradish peroxidase (donor:hydrogen-peroxide oxidoreductase; EC 1.11.1.7) (0.5 mg/ml) made up in 10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.4, was loaded into the inner reservoir of the mechanical device. The device ring was closed and rinsed under distilled water. The device was then placed in a beaker containing approximately 20 ml 150 mM potassium iodide and 100 mg/ml glucose made up in distilled water. No formation of elemental iodine, evident by the appearance of the yellow triiodide complex, occurred in the external medium even after leaving the ring submerged in the solution over a period of approximately 8 hours. At the end of the experiment, the ring was squeezed about its outer circumference to distort its shape into an ellipsoid. This latter operation triggered the appearance of triiodide in the external medium (verified as elemental iodine by chloroform extraction and identification of its characteristic violet color in chloroform), indicating that egress of glucose oxidase and horseradish peroxidase had occurred as a result of distortion of the ring, presenting the enzymes formerly contained within the inner reservoir to the substrates in the external medium. This allows for elemental iodine to be formed via oxidation of glucose and subsequent peroxidation of iodide in the external medium.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=O.[C:24](=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=[CH2:24]
Reactant: O=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 43.6 %

Procedure:
2.83 g (8.0 mmol) of 2-(2,2,2-trifluoroethylthio)-4-(3-trifluoromethylpyrazolyl)benzaldehyde (Compound No. V-275 of the present invention) prepared in the same manner as in Example 8 (9), 2.85 g (8.0 mmol) of methyltriphenylphosphonium bromide and 1.38 g (10.0 mmol) of potassium carbonate were refluxed in a solvent mixture of 20 ml of dioxane and 0.3 ml of water with heating for 5 hours. After cooling down to room temperature, the insolubles were filtered off, and the dioxane was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.23 g of [2-ethenyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (yield 43.8%) as a pale yellow liquid (nD20 1.5328).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1)[CH2:2][CH3:3].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.CN(C)C(=O)C.C1(C)C=CC=CC=1>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]2[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])=[CH:26][CH:25]=1)#[N:34]
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate (30.7 g) obtained in Example 2 and 4′-(bromomethyl)biphenyl-2-carbonitrile (33.4 g) were dissolved in a mixture of acetone (45 ml) and N,N-dimethylacetamide (45 ml), followed by addition of potassium carbonate (29.3 g) to the reaction solution, and the reaction solution was stirred at 55° C. for 2 hours. The reaction solution was cooled to room temperature, followed by addition of water and toluene, and the organic layer was washed with water. The solvent was evaporated under reduced pressure to afford the title compound (53.8 g) as yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:26][C:27]([NH2:29])=[NH:28])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:35](OC(=O)CNC(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)=O)([CH3:38])([CH3:37])[CH3:36].O>CS(C)=O>[C:35]([O:24][C:23](=[O:25])[CH2:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:17][CH:16]=1)=[O:20])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCC(=O)O)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine trifluoroacetate ##STR60## NaH (34 mg, 60% dispersion in mineral oil, 0.85 mmol) was added to a stirred solution of guandine hydrochloride (80 mg, 0.84 mmol) in DMSO (2 mL) at 23° C. After 30 min, N-[(1,4-dichloro-7-isoquinolinyl)carbonyl]glycine t-butyl ester (120 mg, 0.34 mmol) was added and the resultant solution heated at 90° C. for 21 h. After cooling, the mixture was poured into water (30 mL), extracted with EtOAc, and then with CH2Cl2, and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel using CH2Cl2 -MeOH-0.880NH3 (90:10:1) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine t-butyl ester (25 mg, 0.07 mmol) as a yellow gum.
Reaction SMILES: OS(O)(=O)=O.[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>C(O)(=O)C>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH2:7][C:8]1=[CH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:28])=[CH:21][CH:22]=1
Reactant: O=C1CCOc2ccccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Concentrated H2SO4 (2 ml) was slowly added to a solution of 4-chromanone (2.00 g, 13.50 mmol) and methyl-4-formylbenzoate (2.11 g, 12.86 mmol) in glacial acetic acid. The reaction mixture was stirred 16 h at room temperature. The solvent was concentrated to half volume the resulting precipitate was filtered and rinsed with ethyl acetate to afford the title compound 260 (3.11 g, 82%) as a purple solid. 1H NMR: (DMSO) δ (ppm): 8.05 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 7.64-7.59 (m, 3H), 7.15 (dd, J=7.6, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 5.43 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:16]1[CH2:21][CH2:20][O:19][C:18]2[CH:22]=[C:23]([C:26](=[O:32])[CH2:27][CH2:28]N(C)C)[CH:24]=[CH:25][C:17]1=2>O1CCOCC1.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[O:16]1[CH2:21][CH2:20][O:19][C:18]2[CH:22]=[C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:15])[CH:24]=[CH:25][C:17]1=2
Reactant: CN(C)CCC(=O)c1ccc2c(c1)OCCO2
Reactant: O=Cc1ccccc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)c1ccc2c(c1)OCCO2)c1ccccc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
Triethylamine (3.61 mmol) and benzaldehyde (4.3 mmol) in dry dioxane (10 mL) was added to a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one (XVI) (5.4 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.43 mmol) in dioxane heated at 95° C. under nitrogen. The solution was further heated overnight at 95° C. The solution was cooled and excess solvent was evaporated under vacuum. The residue was partitioned between CH2Cl2 and water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in hexane gradient to yield 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-phenylbutane-1,4-dione 1 as a white solid (12% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 3.33-3.37 (m, 4H), 4.29 (m, 2H), 4.34 (m, 2H), 6.98 (m, 1H), 7.48 (m, 1H), 7.55 (m, 3H), 7.64 (m, 1H), 8.00-8.02 (m, 2H); ESIMS found C18H16O4 m/z 297 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[CH3:21][O:22][C:23](=[O:41])[C:24]([CH3:40])([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25].[F-].[Cs+]>COCCOC.O>[CH3:21][O:22][C:23](=[O:41])[C:24]([N:26]1[CH:30]=[C:29]([C:17]2[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[Cl:1])[CH3:11])[CH:18]=2)[CH:28]=[N:27]1)([CH3:40])[CH3:25]
Reactant: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)(C)n1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Temperature: 120 °C

Procedure:
To a solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (6.363 g, 14.901 mmol) and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]propionic acid methyl ester (4.6 g, 15.64 mmol) in DME (27 mL) was added a solution of CsF (6.79 g, 44.7 mmol) in water (9.3 mL). The reaction mixture was degassed 3 times with N2. Pd(dppf)CH2Cl2 was added and the reaction mixture was degassed 3 times with N2. The reaction was heated to 120° C. in the microwave (subsequent Pd was added in intervals of 30 minutes until the reaction was complete). Water was added and the reaction was extracted with EtOAc, dried over Na2SO4, and concentrated to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester. The crude product was purified by a silica gel column chromatography with a gradient of 25%-50% EtOAc/hexanes to provide 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester (1.46 g, 21% yield) with a Rf 0.11 (50% EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C:7]2[CH:6]=[CH:5][C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:2]([F:26])([F:25])[F:1])[CH:8]=2)=[CH:12][CH:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-phenyl]-methanol (162 mg, 0.4327 mmol, 1 eq.) in anhydrous DCM (5 mL) is added PPh3 (148 mg, 0.5625 mmol, 1.3 eq). The mixture is stirred at room temperature for 5 min. at which point the reaction is cooled to 0° C. To the reaction mixture at 0° C. is added a solution of CBr4 (187 mg, 0.5625 mmol, 1.3 eq.) in anhydrous DCM (2 mL). The reaction is allowed to slowly warm to room temperature and is stirred for 12 h. The reaction mixture is applied directly to silica gel chromatography (6:1 hexanes/EtOAc) to give 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]=[C:5]1[CH2:17][CH2:16][C:8]2([S:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[NH:9]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:26](Cl)(=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30].Cl>C(Cl)Cl>[CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]=[C:5]1[CH2:17][CH2:16][C:8]2([S:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[N:9]2[C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC2(CC1)N[C@@H](C(=O)O)CS2
Reactant: CC(C)CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC=C1CCC2(CC1)SC[C@H](C(=O)O)N2C(=O)CCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 8 ml of methylene chloride are dissolved 0.79 g of (3S)-8-(3-methylbutylidene)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 1.20 ml of triethylamine. Into the solution thus obtained are dropwise added a solution of isocaproyl chloride (prepared from 0.48 ml of isocaproic acid, 0.38 ml of oxalyl chloride and 5 ml of methylene chloride) in methylene chloride at 5-10° C., and stirred at ambient temperature for 2 hours. The whole was acidified to pH 2.0 with 2 mol/L HCl and extracted with CHCl3. The combined organic extracts were washed with water and brine, dried on MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography, [eluent; chloroform:methanol=9:1] to obtain 1.10 g of (3S)-8-(3-methylbutylidene)-4-(4-methylpentanoyl)-1-thia-4-azaspiro[4.5]-decane-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: C(O[CH:4](O)[CH2:5][C:6]1[C:18]([CH3:19])=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:20])[CH:7]=1)C.[NH2:22][C@@H:23]([CH3:33])[C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[OH:25]>[C].[Pd].O1CCCC1>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[C@@H:23]([NH:22][CH2:4][CH2:5][C:6]1[C:18]([CH3:19])=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:20])[CH:7]=1)[CH3:33]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)COc1cc(C)c(CC(O)OCC)cc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(C)c(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A suspension of ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10% palladium carbon (50% wet, 1.4 g), (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) and tetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and washed with water, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1.[F:54][C:55]([F:69])([F:68])[C:56]1[CH:57]=[C:58]([N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:59]=[CH:60][CH:61]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10](=[O:12])[N:65]1[CH2:64][CH2:63][N:62]([C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([C:55]([F:68])([F:69])[F:54])[CH:57]=2)[CH2:67][CH2:66]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 170.5 %

Procedure:
2.53 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester and 2.46 g of TOTU was dissolved in 15 ml of DMF. The, 3.29 ml of N-Methylmorpholine was added and the mixture was stirred for 30 min at RT. 1.72 g of 1-(3-Trifluoromethyl-phenyl)-piperazine was added and stirring was continued for 5 h. The mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic phase over sodium sulfate and evaporation of the solvents under reduced pressure afforded a brownish powder that was purified by chromatography over silica gel eluting with ethyl acetate/heptane 1:2 to 100% ethyl acetate to give 7 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1
Reactant: C1CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Yield: 91.5 %

Procedure:
A suspension of 0.5 g (2.9 mmol) of 6-chloro-3-nitro-2-picoline, of 0.73 ml (8.69 mmol) of pyrrolidine and of 0.8 g (5.79 mmol) of potassium carbonate is heated at 110° C. for 2 hours. The reaction mixture is subsequently concentrated under reduced pressure and then poured into 100 ml of water. A solid is recovered by filtration and is dried so as to obtain 0.55 g of the expected product in the form of a yellow solid which will be used as it is in the rest of the synthesis.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][C:10]2[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 46.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (390 mg, 1.83 mmol), 4-chloro-2-nitrobenzene-1-sulfonyl chloride (Intermediate 454) (565 mg, 2.22 mmol), DMAP(cat) and pyridine (0.3 ml, 5.55 mmol) in DCM (7 ml) gave the title compound (370 mg, 46%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: Cl.[CH2:2]([C@@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH2:26])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1)[CH2:3][CH3:4].[CH3:27][C:28]1[NH:32][C:31]2[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:30]=2[N:29]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>CN(C=O)C.O>[CH3:27][C:28]1[NH:32][C:31]2[CH:33]=[CH:34][C:35]([C:37]([NH:26][C@@H:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]3[C:18]([N:17]3[C@@H:13]4[C@@H:14]([C@H:5]([CH2:2][CH2:3][CH3:4])[NH:6][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=54)[CH2:15][CH2:16]3)=[O:19])=[O:38])=[CH:36][C:30]=2[N:29]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: CCC[C@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc2[nH]c(C)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47 %

Procedure:
To a suspension of (1R,2S)-2-{[(3aR,4R,9bR)-4-(propyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (203 mg, 0.490 mmol) in DMF (4 ml) were added 2-methyl-1H-benzimidazole-5-carboxylic acid (86.2 mg, 0.490 mmol), triethylamine (0.206 ml, 1.47 mmol) and DEPC (0.0812 ml, 0.490 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and eluted with ethyl acetate-methanol (1:0-9:1) to give the title compound (115 mg, 47%) as an amorphous form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][C:11]([F:21])=[CH:12][CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:21][C:11]1[N:10]=[C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]2=[CH:13][CH:12]=1)=[CH:3][C:2]([C:28]1[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1nc(F)ccc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)ccc12
Temperature: 110 °C

Procedure:
A mixture of 7-bromo-2-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (26.0 mg, 0.074 mmol), 2-fluoro-3-pyridineboronic acid (16.74 mg, 0.119 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (2.103 mg, 2.97 μmol) and potassium phosphate (47.3 mg, 0.223 mmol) in a 2:1 mixture of dioxane and water (1.5 ml) was heated at 110° C. in the microwave for 20 minutes. The reaction mixture was subjected to purification by silica gel chromatography (SiO2, CH2Cl2 to CH2Cl2/MeOH=100:1 to 100:6) to give 2-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid. MS m/z=367.0 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[N:16]1[CH:15]=[CH:14][C:13]([C:10](=[N:11][OH:12])[CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:3][CH:4]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Reactant: OB(O)c1cncnc1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(-c2cncnc2)cc1

Procedure:
In analogy to example 22, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and pyrimidine-5-boronic acid was prepared the title compound as a mixture of E and Z isomers (2.3:1) as a white foam, MS (ESI+): m/z=395.2 ([M+H]+).