Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]([F:40])([F:39])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[N:27]2)=[CH:22][CH:21]=1>O1CCCC1.O>[F:40][C:18]([F:17])([F:39])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([C:31]3[CH:38]=[CH:37][C:34](/[CH:35]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:33][CH:32]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To an oven-dried 2 L three-necked round bottomed flask equipped with a stirring bar was added sodium hydride (60% oil immersion, 7.20 g, 180 mmol) as a solid that was pre-weighed into a 25-mL vial. This was diluted with anhydrous tetrahydrofuran (1 L) under nitrogen, and the solution was stirred in an ice bath. Ethyl 2-(diethoxyphosphoryl)acetate (30.0 mL, 151 mmol) was added dropwise in portions over 20 minutes, and the reaction was stirred at 0° C. for an additional 2 hours. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (50.0. g, 150 mmol) was added in solid portions over 20 minutes, and the reaction turned orange. After stirring for 30 minutes, the ice bath was removed and the reaction was warmed to room temperature over 1 hour. The reaction was quenched with slow addition of saturated aqueous ammonium chloride (500 mL) and allowed to stand at room temperature overnight. The biphasic reaction mixture was diluted with water and extracted with 1:1 ethyl acetate/hexanes (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as an orange solid (61.4 g, 100%): mp 135-137° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.85-7.77 (m, 2H), 7.73 (d, J=16.0 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.51 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 404 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O:41][CH3:42])=[O:40])#[CH:31].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:42][O:41][C:39](=[O:40])[CH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]#[C:31][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A78) (500 mg, 1.16 mmol), methyl 2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.39 mmol), Et3N (0.60 mL), PdCl2(PPh3)2 (0.041 g, 0.058 mmol), CuI (0.022 g, 0.117 mmol) and PPh3 (0.031 g, 0.117 mmol) in DMF (4 mL) were heated under microwave irradiation at 120° C. for 15 minutes. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 0-30% EtOAc in cyclohexane) to give the title compound A79 as a yellow foam (0.570 g, 86%); 1H NMR (300 MHz, d6-DMSO) δ 8.65 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.48-7.33 (m, 6H), 4.35 (t, J=8.6 Hz, 2H), 4.01-3.96 (m, 4H), 3.75-3.72 (m, 4H), 1.49 (s, 9H). LCMS-B: rt 9.160 min; m/z 567 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=2[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]([NH:1][CH:2]([CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=3[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:39])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (127 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole-hydrate (102 mg, 0.67 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (290 mg, 80%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[NH2:15].[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[C:5](=[C:4]([O:3][CH3:2])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)[NH2:15]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(N)c1OC
Agent: Cl
Product: COC(=O)c1ccc(OC)c(OC)c1N
Yield: 82 %

Procedure:
Hydrogen chloride was passed into a solution of 3,4-dimethoxyanthranilic acid (100 g., 0.51 mole) in 1.5 liters methanol for 40 minutes. The reaction mixture was refluxed for 4 days while introducing hydrogen chloride gas intermittently. The solvent was removed in vacuo, and the residual white solid was dissolved in 500 ml. water, cooled and basified to pH 10 with sodium hydroxide solution. After cooling for an additional hour, the cream color product (87.0 g., 82% yield) was filtered. Recrystallization from methanol furnished pure product, M.P. 66°-67° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[CH3:16][S-:17].[Na+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]2[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH2:2][S:17][CH3:16]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1c(C)oc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (200 mg) and sodium thiomethoxide (68 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2-methyl-3-methylthiomethyl-7-nitrobenzo[b]furan (144 mg).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>ClCCl>[C:1]([NH:8][C@@H:9]([C:13]([N:47]1[CH2:46][CH2:45][N:44]([CH:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)[CH2:49][CH2:48]1)=[O:15])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C2CCN(C)CC2)CC1
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a stirring solution of Boc-D-valine (5.0 g, 23 mmol) in dichloromethane (230 mL) is added HOBt (3.42 g, 25.3 mmol), followed by EDCI (4.85 g, 25.3 mmol), followed by 4-(1-methylpiperidin-4-yl)piperazine (4.2 g, 23 mmol). After stirring overnight, the solution is washed with saturated aqueous NaHCO3, followed by brine, and then concentrated in vacuo. The residue is chromatographed over silica gel, eluting with a gradient of 0-10% (2 N ammonia/methanol) in chloroform. The product-containing fractions are combined and concentrated in vacuo to give the title product (8.98 g, quantitative) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:17][CH:18]=1)=[O:24])([CH3:61])[CH3:60]
Reactant: CC(C)(N)CO
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (50 mg, 0.15 mmol) and TBTU (54 mg, 0.17 mmol) in DMF (2 mL) was added DIPEA (130 μL, 0.76 mmol). Then 2-amino-2-methyl-1-propanol (16 μL, 0.167 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (56 mg, 92%) as a white foam. MS: m/e=402.4 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:27])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[O:25])=[CH:15][C:14]=2[F:26])[CH2:9][N:8]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:7]1)=[O:5])C>O1CCOCC1.O>[F:26][C:14]1[CH:15]=[C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=[O:25])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]([C@H:10]1[CH2:9][N:8]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:27]
Reactant: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1C[C@H](C(=O)O)[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 28d (3.7 g; 8 mmol) is dissolved in a mixture of 1,4-dioxane/water (1:1; 30 ml). LiOH monohydrate (1.03 g; 25 mmol) is added to the mixture and complete saponification is obtained after stirring for 24 h at 25° C. The mixture is evaporated to dryness and dissolved in ethyl acetate and the product is extracted with saturated aqueous Na2CO3 solution. The aqueous phase is cooled to 10° C. and acidified with 25% aqueous HCl solution until pH=1. The product is extracted several times with ethylacetate (3×100 ml). The combined organic phases are washed with brine and dried over Na2SO4. After filtration the organic phase is evaporated to dryness. Yield: 1.57 g (45.2%), ESI-MS: m/z=422 [M−H]−
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:29])=[O:2])[C:13](=[O:28])[CH:14]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2C(C)(C)C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 137.5 %

Procedure:
To a stirred solution of (S)-2-[4-(2-t-butyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (585 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (184 mg, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(2-t-butyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (530 mg, 94%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[CH:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[O:30][N:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1cc(C(F)(F)F)on1
Agent: Cl
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN 1018782-82-5) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride (example BF) as starting materials; MS: 478.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:9]([Cl:30])[CH:8]=1)C.[OH-].[Na+]>O>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([O:31][CH3:32])[C:4]([OH:33])=[O:3])=[CH:8][C:9]=2[Cl:30])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(Cl)c1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
The title compound was prepared as follows: 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester (0.017 g, 0.037 mmol) was dissolved in 0.25 M ethanolic NaOH solution (0.3 mL, 0.075 mmol). The mixture was stirred 16 hours at room temperature and water was added. The aqueous layer was extracted with Et2O (3×5 mL). The aqueous layer was acidified to pH=1 with 1 N HCl and extracted with Et2O (5×10 mL). The organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow oil (0.006 mg, 38%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.25 (m, 9H), 7.0–6.86 (m, 3H), 4.23 (q, 4H, J=6.18), 3.96 (dd, 1H, J=7.24, 4.28), 3.40 (s, 3H), 3.06 (dd, 1H, J=14.5, 4.28), 2.92 (dd, 1H, J=14.5, 7.24), 2.32 (qn, 2H, J=5.92).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21](=[O:28])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:29][CH2:30][O:31]C)[CH:4]=[CH:5]2.O.[C:34](O)(=O)C>>[C:30]([O:29][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21](=[O:28])[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH:11]=[CH:10][C@@H:9]35)(=[O:31])[CH3:34]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)Cc4cccs4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](OC(=O)Cc4cccs4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 100 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution of 4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-ene (1.00 g, 2.20 mmol) in glacial acetic acid (30 ml) is mixed with (30 ml) of water and stirred for 5 hours at 100° C. under N2. The solution is evaporated down using a Rotavapor. The residue obtained is purified by flash chromatography (silica gel; mobile phase: CH2Cl2 :MeOH=9:1) and lyophilised in order to obtain 4,5α-epoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-en-3-ol acetate (0.444 g, 89.9%) as a colourless foam.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7]1([CH3:25])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:9]=2[O:8]1.C1(C)C=CC=CC=1>CCCCCC>[CH3:1][NH:2][C:3]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[O:8][C:7]([O:6][CH3:5])([CH3:25])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[CH:19][CH:20]=1)=[O:4]
Reactant: COC1(C)CCc2cc(Oc3ccc(N)cc3)ccc2O1
Reactant: CN=C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(C)(OC)O3)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
Methyl isocyanate (0.16 g) was added at room temperature to a solution composed of 0.4 g of 4-(2-methoxy-2-methyl-2,3-dihydro-6-benzopyranyloxy)aniline and 3.0 ml of toluene, and the mixture was stirred for 6 hours. Addition of n-hexane to the mixture yielded crystals which were collected by filtration to give the desired product as white crystals (yield not less than 97%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH:2]=[CH2:3].[F-].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+](C1C=C(S(O[CH2:45][C@@H:46]2[O:48][CH2:47]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:45][C@@H:46]1[O:48][CH2:47]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccccc1OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
o-Allyloxyphenol (1.0 g) was dissolved in THF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Potassium fluoride (1.55 g) and tetrabutyl ammonium fluoride (0.2 g) were added thereto and the mixture was stirred for 1 hour. Then, (R)-glycidyl m-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and the mixture was stirred for 40 hours at the same temperature. After the reaction, water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 3:2) to give 0.96 g of (R)-3-(o-allyloxyphenoxy)-1,2-epoxypropane (yield 70%, optical purity 95.9% e.e.) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([C:13]3[CH:14]=[C:15]([OH:33])[C:16]4[O:25][C:24]5[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C:19]=5[C:17]=4[CH:18]=3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O.ClCCl>[CH2:40]([O:39][C:37]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([C:13]3[CH:14]=[C:15]([OH:33])[C:16]4[O:25][C:24]5[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:20][C:19]=5[C:17]=4[CH:18]=3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:38])[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccc5[nH]ccc5c4)cc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(O)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Reaction time: 2 h
Yield: 29.2 %

Procedure:
A mixture of the product of step B (90 mg, 0.19 mmol), sodium hydroxide (31 mg, 0.76 mmol) tetrabutylammonium hydrogen sulfate (13 mg, 0.04 mmol) and water (2 drops) in dichloromethane (10 mL) was stirred at ambient temperature for 5 min under an argon atmosphere before addition of ethyl chloroformate (24 μL, 0.25 mmol). The reaction mixture was stirred for 2 h before quenching with aqueous ammonium chloride (15 mL) and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 30:70 hexane/ethyl acetate) to give tert-butyl 8-((1-(ethoxycarbonyl)-1H-indol-5-yl)sulfonyl)-6-hydroxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 29%) as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 8.25 (d, J=8.8 Hz, 1H), 8.20 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.78-7.52 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 6.70-6.63 (m, 1H), 4.54 (s, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.89-3.72 (m, 2H), 2.91-2.77 (m, 2H), 1.51 (s, 9H), 1.46 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[N+:5](=[O:6])[C:4]([CH3:11])([CH3:10])[N:3]=1.NN.O.NN>CO>[OH:6][N:5]1[C:7]([CH3:9])([CH3:8])[C:2]([CH3:1])=[N:3][C:4]1([CH3:11])[CH3:10]
Reactant: CC1=NC(C)(C)[N+](=O)C1(C)C
Agent: NN
Solvent: O
Solvent: CO
Product: CC1=NC(C)(C)N(O)C1(C)C
Reaction time: 12 h

Procedure:
1.5 g (0.01 mole) of 2,2,4,5,5-pentamethyl-3-imidazoline-1-oxyl prepared as described in either of Examples 4 and 5 was solved in 10 ml methanol and treated with 1.5 ml (0.03 mole) of hydrazine or hydrazine-hydrate at ambient temperature. This solution was stored for 12 hours and over this period the methanol evaporated and the color of the solution disappeared. The partly crystallized residue was stirred with acetone and the colorless crystals were filtered and rinsed with acetone. 1.32 g of the isolated crystals with a yield of 88% were crystallized from ethyl acetate producing 1-hydroxy-2,2,4,5,5-pentamethyl-3-imidazoline having a melting point of 127°-128° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].C([O:20][C:21]([C:23]1([NH:28][C:29]([CH:31]2[CH2:35][CH:34](O)[CH2:33][CH:32]2[C:37](=[O:46])[N:38]([CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45])[CH3:39])=[O:30])[CH2:25][CH:24]1C=C)=[O:22])C>>[CH2:1]([O:3][C:4]1[N:13]=[C:12]([O:14][CH:34]2[CH2:35][CH:31]3[CH:32]([C:37](=[O:46])[N:38]([CH3:39])[CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH:25]4[C:23]([C:21]([OH:20])=[O:22])([NH:28][C:29]3=[O:30])[CH2:24]4)[CH2:33]2)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc(O)c2ccc(OC)c(C)c2n1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Product: CCOc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1

Procedure:
Reaction of the quinazolinol (148) and the alcohol (143) according to the procedure described in examples 144-146, gave the title compound m/z=567 (M+H)+.