Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:26][N:25]=[N:24][N:15]=3)=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(COc2ccc(C#N)cc2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(COc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of 4-(4-acetyl-3-hydroxy-2-propylbenzyloxy)benzonitrile, 13.0 g. of sodium azide, and 10.9 g. of ammonium chloride in 250 ml. of dimethylformamide was heated to 115° C. for eight hours. An additional 13.0 g. of sodium azide and 10.9 g. of ammonium chloride were added every 2.5 hours during this period. The reaction was stirred overnight at room temperature and then heated an additional six hours with more reagents being added. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in 800 ml. of water. The solution was made acidic with hydrochloric acid and the resulting precipitate was filtered. The precipitate was dissolved in lN sodium hydroxide and the solution was washed once with ethyl acetate. The basic solution was made acidic with hydrochloric acid and the precipitate was recovered by filtration. The precipitate was crystallized first from isopropyl alcohol/ethyl acetate/water and then recrystallized from isopropyl alcohol providing 10.3 g. of the desired title product, m.p. 203°-205° C., IR, NMR.
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[C:23](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:19]1([NH:22][CH2:23][CH:2]2[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC(CNC2CC2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
The product from Example 250, Part 4 (174 mg, 0.644 mmol) and cyclopropylamine (35.6 mg, 0.611 mmol) were dissolved in methanol (6.0 mL). That solution was treated with acetic acid (0.209 mL) and sodium cyanoborohydride (38.4 mg, 0.611 mmol). The reaction mixture was stirred at rt overnight. It was concentrated, diluted with ethyl acetate and washed with a saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was flash chromatographed (silica, 5% to 6% to 10% MeOH/CH2Cl2) to provide the desired product as a colorless oil (131 mg, 68.8% yield). LCMS: m/z 312.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[N:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>CN(C=O)C>[F:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[N:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)nc2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)nc2)CCN1C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 33.3 %

Procedure:
To 1,1-dimethylethyl (2S)-4-({6-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (D106) (0.139 g, 0.303 mmol) in DMF (4 mL) under an argon atmosphere was added potassium carbonate (0.293 g, 0.212 mmol) and 4-fluorophenol (0.169 g, 1.51 mmol). The reaction mixture was stirred and heated at 130° C. for 5 h then concentrated in vacuo. The residue was re-dissolved in DCM/water. The organic layer was washed with 2M NaOH solution and brine then dried (Na2SO4) and concentrated to give the crude product which was purified by column chromatography. Elution with EtOAc/DCM gave the title compound as a colourless oil (0.054 g). MS (ES): MH+ 536.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[S:25]([CH2:32][C:33](Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:33]2[CH2:32][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: O=C(Cl)CSc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(CSc2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) was added thiophenoxyacetyl chloride (102 mg, 0.545 mmol). The mixture was stirred at room temperature for 3 h, then irradiated (uwave) at 90° C. for 15 min. The mixture was quenched with methanol, concentrated, and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenylthio)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (20 mg, 15%); LC/MS: MS (ES+) m/e 499 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 3.52-3.59 (m, 4H), 3.62-3.73 (m, 4H), 4.18 (s, 2H), 5.59 (s, 2H), 6.52 (d, J=7.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.21-7.42 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:5])[OH:4].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][NH:1][CH2:2][CH:3]([CH3:5])[OH:4]
Reactant: CC(O)CN
Reactant: O=Cc1ccccc1Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CNCc1ccccc1Cl
Temperature: 10 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A mixture of 2-amino-1-methylethanol (25.0 g), 2-chlorobenzaldehyde (51.5 g), sodium bicarbonate (33.6 g), and methanol (1000 ml) is refluxed with stirring for 4 hours. After the reaction mixture is cooled to 10° C., sodium borohydride (13.9 g) is added in small portions, and the resulting mixture is stirred at 25° C. for 1 hour. The solvent is removed under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound (55.0 g) as an oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]([OH:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)C1C=CC=CC=1.ClCCl.C(=O)(O)[O-].[Na+].Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>[Pd].CO.O>[OH:21][CH:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:9][NH:8][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]
Reactant: COc1ccc(OCC(O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(OCC(O)CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A mixture of 1-[bisbenzylamino]-3-(4-methoxyphenoxy)propan-2-ol (1.26 g, 3.74 mmol), as prepared in the preceding step, 10% palladium on carbon (125 mg) and methanol (120 mL) was degassed under reduced pressure and refilled with H2 gas several times. After stirring under 1 atm H2 balloon at room temperature overnight, the mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to a white solid (0.78 g, 100%). This solid (0.78 g, 3.96 mmol) was dissolved in methanol (20 mL), dichloromethane (20 mL), and water (10 mL). To this solution were added sodium bicarbonate (0.83 g, 9.88 mmol) and benzyl chloroformate (0.7 mL, 4.66 mmol) at room temperature. After stirring for 4 hours, the solution was concentrated and the residue was partitioned between dichloromethane and water. The organic layer was dried (Na2SO4), concentrated, and flash chromatographed on silica gel to give the title compound as a white solid (1.00 g, 80.8%). 1H NMR (CDCl3) δ 7.37-7.33 (m, 5H), 6.83 (s, 4H), 5.20 (m, 1H), 5.12 (s, 2H), 4.10 (m, 1H), 3.94-3.88 (m, 2H), 3.77 (s, 3H), 3.53-3.47 (m, 1H), 3.38-3.27 (m, 1H), 2.95 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13](B(O)O)=[CH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:18]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[C:33]([N:39]=2)=[N:34][C:35](Cl)=[CH:36][CH:37]=3)=[C:26]([F:40])[CH:25]=1.C(Cl)Cl>O1CCOCC1.O>[O:20]1[CH2:21][CH2:22][CH2:23][O:18][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[C:33]([N:39]=2)=[N:34][C:35]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH2:14])=[CH:36][CH:37]=3)=[C:26]([F:40])[CH:25]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2nc(Cl)ccc2s1
Reactant: C=C(B(O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=C(c1ccccc1)c1ccc2sc(-c3ccc(C4OCCCO4)cc3F)nc2n1
Temperature: 80 °C

Procedure:
A slurry of (amphos)2PdCl2 (0.0333 g, 0.0470 mmol), potassium carbonate (0.442 g, 3.20 mmol), 1-phenylvinylboronic acid (0.306 g, 2.07 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[4,5-b]pyridine (0.330 g, 0.941 mmol) in 4.5 mL dioxane and 1 mL water was flushed with argon and sealed, and heated to 80° C. overnight. The reaction mixture was cooled and treated with water and DCM. The aq. Layer was extracted with DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was suspended in 2 mL MTBE and filtered, rinsing with 1 mL MTBE, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[4,5-b]pyridine as a gray solid. MS (ESI) m/z: calculated: 418.1; Observed: 419.0 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CCOCC>[Si:28]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (5.00 g, 0.0198 mol) was dissolved in anhydrous DMF (30 mL, 0.4 mol) under an atmosphere of nitrogen. To this solution was added 1H-imidazole (3.2 g, 0.046 mol) followed by tert-butyldimethylsilyl chloride (3.92 g, 0.0260 mol). The resulting mixture became translucent. After stirring for 16 h at RT, the reaction mixture was diluted with ether (100 mL) and washed with water (3×20 mL), and brine (2×10 mL), then dried (Na2SO4), filtered, concentrated and purified by CombiFlash chromatography (120 g column, eluting with 0-25% EtOAc/hexanes). LC/MS: 260.2 (M−Boc+2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>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]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 108 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol, 1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 7 h. When HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the desired (5S)—N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 123 (18.8 g, 94%) as brown solids. This product was directly used in subsequent reactions without further purification. C18H24BFN2O5, HPLC/MS (ESI) m/e 379 (M++H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([C:25]([OH:27])=O)[NH:17]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH3:28][S:29]([Cl:32])(=[O:31])=[O:30].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[ClH:32].[NH2:17][C@@H:16]([C:25](=[O:27])[N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:15][S:14][CH2:13][CH2:12][NH:11][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H](CSCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCSC[C@@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-3-(2-{[benzyloxycarbonyl]-amino}-ethylthio)-N-(tert-butyloxy-carbonyl)-alanine, methanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 37.
Reaction SMILES: C1(OP(O)OC2C=CC=CC=2)C=CC=CC=1.[CH:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=1.[NH:27]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:28][C:29](O)=[O:30]>N1C=CC=CC=1>[N+:23]([C:22]1[CH:21]=[CH:20][C:19]([O:26][C:29](=[O:30])[CH2:28][NH:27][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])=[CH:18][CH:17]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: OP(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(CNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Yield: 75 %

Procedure:
A mixture of 2.93 g. (0.0125 mole) of phosphorous diphenyl ester and 3.37 g. (0.0125 mole) of mercuric chloride was refluxed for 1 hour in 20 ml. of pyridine. Thereafter, 1.74 g. (0.0125 mole) of p-nitrophenol and 10 ml. of pyridine were added, and the mixture was further reacted for 1 hour. To the reaction mixture were added 2.61 g. (0.0125 mole) of Z-Gly. OH having an amino group protected with Z and 10 ml. of pyridine, and the mixture was reacted under reflux for 1 hour. After completion of the reaction, pyridine was removed by distillation under reduced pressure, and the residue was extracted with 100 ml. of ethyl acetate. The ethyl acetate layer was washed with 2N--HCl, a saturated aqueous NaHCO3 solution and water in this order and then dried over anhydrous Na2SO4, and thereafter ethyl acetate was removed by distillation under reduced pressure. The resulting residue was allowed to stand to form a solid, which was then recrystallized from ethanol to obtain N-benzyloxycarbonyl glycine p-nitrophenyl ester (hereinafter represented by ##SPC6##
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][CH:11]=C)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[O:15]=[O+][O-].[BH4-].[Na+]>CO.CCOCC.O>[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:15])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1cc(C#N)c(OC)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COc1cc(F)c(CCO)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluoro-2-methoxy-5-(prop-2-en-1-yl)benzonitrile (1.2 g, 6.0 mmol) in methanol (50 mL) was cooled in a dry ice acetone bath and treated with ozone. Since the starting material was contaminated with some tributylstanane residue from the previous reaction, the reaction turned brown at first. The mixture was flushed with nitrogen and quenched with dimethylsulfide (4 mL). The solution was allow to warm to about 0° C. which resulted in a clear yellow solution and then sodium borohydride (0.27 g, 7.2 mmol) was added under nitrogen and the reaction was stirred for 30 minutes at room temperature. TLC of an aliquot in ether/water (30% ethyl acetate in hexanes) indicated a product band without evidence of starting material. After a total of 1 hour, the reaction was quenched with 18% aqueous citric acid and concentrated in vacuo to remove the methanol. The residue was partitioned between ethyl acetate and 18% citric acid, washed with brine, dried over sodium sulfate and evaporated. Purification of the residue with a Biotage 40+M column (10 to 60% ethyl acetate in hexanes) gave the title alcohol as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 1.60 (br s, 1H), 2.842 (t, J=6.5 Hz, 2H), 3.853 (t, J=6.5 Hz, 2H), 3.904 (s, 3H), 6.682 (d, J=11.2 Hz, 1H), 7.487 (d, J=8.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][NH2:11])=O.C([O-])([O-])=O.[K+].[K+]>CO.CCO>[S:6]1[C:5]2[C:3](=[O:2])[NH:11][CH2:10][C:9]=2[CH:8]=[CH:7]1
Reactant: COC(=O)c1sccc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: O=C1NCc2ccsc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 3-aminomethyl-thiophene-2-carboxylic acid methyl ester (0.82 g, 4.79 mmol) in 1:1 MeOH-EtOH (125 mL), is added K2CO3 (0.66 g, 4.79 mmol) and the mixture is stirred at 90° C. for 5 hours. The solvent is removed in vacuo and the residue purified by silica gel column chromatography eluting with 97:3 DCM:MeOH. The title compound is isolated (0.365 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.Cl[CH:12]([CH3:15])[CH:13]=[O:14].C1([N+]([O-])=C)CCCCC1.S(=O)=O>C(Cl)Cl.[Ag]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][C:4]=1[CH:12]([CH3:15])[CH:13]=[O:14]
Reactant: CC(Cl)C=O
Reactant: COc1ccc(OC)cc1
Agent: [Ag]
Agent: C=[N+]([O-])C1CCCCC1
Agent: O=S=O
Solvent: ClCCl
Product: COc1ccc(OC)c(C(C)C=O)c1
Reaction time: 6 h

Procedure:
432 mg of silver tetrafluoborate and 305 mg of hydroquinone dimethyl ether are first introduced into a flask fitted with a cold finger. After fitting a dropping funnel sealed by a serum cap and equipped with a pressure compensating device, the apparatus is evacuated 5 times under a waterpump vacuum and is subsequently filled with dry nitrogen. Sulphur dioxide was then condensed in the apparatus at -20°C until the volume of the solution is 40 ml. A solution of 2-chloropropanal-N-cyclohexylnitrone in 10 ml of absolute methylene chloride is then introduced into the dropping funnel and is added dropwise over the course of 2 hours to the vigorously stirred sulphur dioxide solution. The temperature is kept at -10°C for a further 6 hours and the sulphur dioxide is then pumped off in a waterpump vacuum. Towards the end, fresh methylene chloride is added in portions in order to keep the volume at between 10 and 20 ml. After filtering off the silver chloride (through Celite, with rinsing with 3×15 ml of methylene chloride), the filtrate is vigorously stirred with 60 ml of 5% strength hydrochloric acid for 5 hours and then separated off. After washing with concentrated sodium bicarbonate solution and concentrated sodium chloride solution (each wash solution being extracted with 2×10 ml of methylene chloride), and drying with sodium sulphate, the solution is evaporated and the yellow-brown oil which remains is filtered through 10 g of aluminium oxide IV (column filled with hexane and eluted with 30 ml of hexane and 80 ml of 4:1 hexane-benzene). The concentrated eluate is distilled in a rotating bulb tube at 90°C/2 mm Hg. α-(2,5-Dimethoxy-phenyl)-propionaldehyde is thus obtained.
Reaction SMILES: [F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])C2C=C(O)C=CC=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[C:38](=[O:41])([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:32]1([CH2:31][O:41][C:38]2[CH:11]=[C:12]([CH2:27][C:22]([NH:14][CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:29])([F:1])[CH:3]([F:4])[F:5])[CH:8]=3)([OH:28])[C:23]([F:25])([F:24])[F:26])[CH:7]=[CH:8][CH:9]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(O)(N(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(O)c1)C(F)(F)F
Reactant: BrCC1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OC(Cc1cccc(OCC2CCCCC2)c1)(NCc1cccc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 50 °C

Procedure:
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](1,1,1-trifluoro-2-hydroxypropyl)-amino]phenol (100 mg, 0.23 mmol) and bromomethylcyclohexane (42 μL, 0.30 mmol) were dissolved in 2 mL of acetonitrile. Cesium carbonate (144 mg, 0.44 mmol) was added, and the stirred solution was warmed to 50° C. for 48 hours, at which time HPLC analysis indicated that no phenolic starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 55 mg (35%) of the desired ether product as a brown oil, which was greater than 99% pure by reverse phase HPLC analysis. HRMS calcd. for C25H29F7NO3: 524.2036 [M+H]+, found: 524.2028. 1H NMR (CDCl3) δ0.9-1.4 (m, 5H), 1.7-1.9 (m, 6H), 3.6 (m, 3H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.7 (m, 2H), 5.1 (s, 1H), 5.9 (tt, 1H), 6.5 (m, 3H), 7.0-7.4 (m, 5H).