Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][CH:11]2[CH:7]([N:8]=[C:9]([NH:19][CH2:20][CH:21]=[CH2:22])[S:10]2)[C@H:6]1[O:23]C(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:20]([NH:19][C:9]1[S:10][CH:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:23])[CH:7]2[N:8]=1)[CH:21]=[CH2:22]
Reactant: C=CCNC1=NC2C(O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCNC1=NC2C(O[C@H](CO)[C@@H](O)[C@@H]2O)S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.3 %

Procedure:
(5R,6S,7R)-5-(acetoxymethyl)-2-(allylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (0.281 g, 0.73 mmol) was dissolved in anhydrous MeOH. Solid K2CO3 was added to the solution until it was basic, and the reaction was stirred at room temperature (1.5 h). The reaction was filtered and then concentrated in vacuo. The crude material was purified via flash column chromatography (DCM:MeOH, 5:2) providing (5R,6S,7R)-2-(allylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (31) (0.048 g, 18% yield). 1H NMR: (500 MHz, methanol-d4) δ 3.50 (dd, 1H, J=5.5, 8.9 Hz), 3.6-3.7 (m, 2H), 3.81 (d, 1H, J=10.7 Hz), 3.87-3.95 (m, 3H), 4.09 (t, 1H, J=6.2 Hz), 5.15 (d, 1H, J=10.3 Hz), 5.25 (d, 1H, J=17.2 Hz), 5.88-5.96 (m, 1H), 6.36 (d, 1H, J=6.4 Hz). 13C NMR (125 MHz, methanol-d4) δ: 39.23, 61.80, 69.52, 73.52, 74.51, 75.39, 90.67, 161.87, 165.33.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:47]=1[CH2:48][NH:49][CH:50]([CH2:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][C@@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)=[CH:58][CH:57]=1)[CH2:51][NH2:52]>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:47]=1[CH2:48][NH:49][CH:50]([CH2:53][CH2:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][CH2:63][C@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)=[CH:60][CH:61]=1)[CH2:51][NH:52][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12]
Reactant: COc1ccc(CNC(CN)CCCc2ccc(OC[C@@H]3COC(C)(C)O3)cc2)c(OC)c1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(CCCc2ccc(OC[C@H]3COC(C)(C)O3)cc2)CNC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (161 mg, 0.86 mmol) and HATU (325 mg, 0.86 mmol) in DMF (10 mL) is added N-methylmorpholine (0.38 mL, 3.42 mmol) followed by N*2*-(2,4-dimethoxy-benzyl)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentane-1,2-diamine (391 mg, 0.86 mmol) and the mixture is stirred at RT overnight. The solvent is removed in vacuo. To the crude residue is added water (10 mL), which is then decanted off to leave an orange solid that is washed with diethyl ether (10 mL) and dried in vacuo at 50° C. to afford the title compound. [M+H]+ 629.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](=[N:13][OH:14])[NH2:11]
Reactant: NO
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CCO
Product: NC(Cc1c(Cl)cccc1Cl)=NO
Yield: 17.5 %

Procedure:
15.0 g (81 mmol) of (2,6-dichlorophenyl)acetonitrile in 60 ml of ethanol were admixed with 10.3 g (148 mmol) of hydroxylamine hydrochloride and then with 11.1 g (105 mmol) of sodium carbonate dissolved in 40 ml of water. This mixture was refluxed for 4 h, poured into aqueous sodium dihydrogen phosphate buffer (pH 7–8) and extracted with methylene chloride. The resulting white solid precipitate (14.0 g) was filtered off and dried under reduced pressure. More product (3.1 g) was obtained from the extract after removal of the solvent under reduced pressure. The overall yield was 17.1 g, m.p. 172–173° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].Br[CH:10]([CH3:18])[C:11](=O)[CH2:12][C:13](OC)=[O:14]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:10]([CH3:18])=[C:11]([CH2:12][CH2:13][OH:14])[N:8]=1
Reactant: COCCNC(N)=S
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCNc1nc(CCO)c(C)s1
Yield: 66.2 %

Procedure:
The title compound (800 mg) was prepared from 750 mg (5.59 mmol) of 2-methoxyethyl thiourea and 1.17 g (5.59 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 60, followed by the procedure outlined for the preparation of Intermediate 43 nd purification via silica gel flash column chromatography using chloroform/MeOH 9/1 as eluent: 1H NMR (CDCl3, 400 MHz) δ 3.82 (t, 2H, J=5.5), 3.58 (t, 2H, J=6.9), 3.41 (m, 2H), 3.36 (s, 3H), 2.65 (t, 2H, J=6.9), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:8]1=[O:25])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCc2ccc3cccnc3n2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 6-3 (380 mg, 0.8 mmol) and 10% Pd/carbon (200 mg) in EtOH (20 mL) was stirred under a balloon of hydrogen for 6 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 to 70:20:10 chloroform/ethyl acetate/MeOH) to give 6-4 as a yellow oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][NH:13][C:12]1=[O:18])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])([CH3:17])[CH2:14][NH:13][C:12]1=[O:18]
Reactant: CC1(C)CNC(=O)N1CCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CNC(=O)N1CCO

Procedure:
9b (9 g) was dissolved in ethanol (150 ml) and 5% Pd/C (2.0 g) was added. The mixture was treated with 3 atm. of H2 gas for 36 h. Filtration and removal of solvent gave 1-(2-hydoxyethyl)-5,5-dimethylimidazolidin-2-one as an oil. Yield: 5.1 g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)c1ccccc1)C(C)(C)C
Temperature: 5 °C
Yield: 91 %

Procedure:
Diisopropylamine (5.6 ml) was dissolved in tetrahydrofuran (56 ml), butyllithium (1.6M hexane solution, 25 ml) was added dropwise thereto at 5° C. with stirring under a nitrogen atmosphere, and the resulting mixture was stirred for 15 minutes. The reaction mixture was cooled to -70° C., and 3,3-dimethylbutyric acid ethyl ester (6.7 ml) was added dropwise thereto, followed by stirring of the resulting mixture for 10 minutes. Then, benzoyl chloride (2.3 ml) was added dropwise to the reaction mixture and the resulting mixture was stirred at the same temperature for 10 minutes. After the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to obtain the title compound (4.5 g, 91%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 7 g of 7-hydroxyisoflavone in 190 ml of N,N-dimethylformamide, 2 g of sodium hydride (80% in paraffin oil) were added. The mixture was stirred for 10 minutes, then 4.2 g of pivaloyl chloride were dropped in 1 minute, under vigorous stirring. After 20 minutes at r.t. the mixture was poured into water (400 ml), the precipitate was filtered, washed with water (1000 ml) and dissolved in chloroform (800 ml). The organic solution was dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [Cl:1][C@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.[C:15]1([C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:1][C@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([O:12][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@H](Cl)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
The 7α-chloro-3-methyl-3-cephem-4-carboxylic acid (10.0 g, 0.0428 mol) was dissolved in methylene chloride (200 ml), and diphenyldiazomethane (10.8 g, 0.0557 mol) dissolved in methylene chloride (50 ml) was added dropwise over 30 minutes. The mixture was stirred at room temperature for two hours. Solvent was removed under reduced pressure and the product was purified over silica column using hexane-ethyl acetate mixture to yield benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate (7.8 g, 45.6%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:27]=[CH2:28])[CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]([O:10][P:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:1])[F:15])=[CH:8][CH:7]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH:27]=[CH2:28])[CH:18]=1)=[O:13])[CH3:12]
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Reactant: CCO[PH](=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1cc(P(=O)(OCC)c2ccc(C(F)(F)F)cc2)ccc1OC(C)C
Temperature: 70 °C
Yield: 8.6 %

Procedure:
To a degassed solution of ethyl 4-(trifluoromethyl)-phenylphosphinate (1.00 g, 4.20 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (921 mg, 3.81 mmol) in DMF (40 mL) were added the triethylamine (1.1 mL, 7.62 mmol) and tris(dibenzylideneacetone)dipalladium (698 mg, 0.762 mmol). The mixture was heated at 70° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography using 5 to 100% ethyl acetate in petroleum ether to afford compound BA1 (130 mg) as a dark green oil in 8.6% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.37 (d, J=6.0 Hz, 6H), 1.38 (t, J=7.1 Hz, 3H), 4.07-4.17 (m, 2H), 4.63 (sept., J=6.1 Hz, 1H), 5.31 (dd, J=11.2 and 1.1 Hz, 1H), 5.79 (dd, J=17.7 and 1.1 Hz, 1H), 6.92 (dd, J=8.6 and 3.1 Hz, 1H), 6.99 (dd, J=17.3 and 10.8 Hz, 1H), 7.59-7.66 (m, 1H), 7.67-7.72 (m, 2H), 7.87-7.96 (m, 3H); 31P NMR (CDCl3, 161.8 MHz): δ (ppm) 30.7.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:17])(=[S:16])[CH2:14][CH3:15]>C1C=CC=CC=1>[N:10](=[C:4]([C:3]1[N:17]=[C:13]([CH2:14][CH3:15])[S:16][CH:2]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:11]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(CC)n1
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.00 g, 10.3 mmol) and thiopropionamide (0.92 g, 10.3 mmol) in dry benzene (15 mL) was heated to reflux. After 4 hours, the reaction mixture was poured onto NaHCO3 (sat. aq., 50 mL), The resulting mixture was extracted with ethyl acetate (2×50 mL), and the combined extracts dried over MgSO4 and evaporated under reduced pressure. Flash chromatography (ethyl acetate:hexane 1:4) then afforded impure ethyl α-oximino-2-ethylthiazole-4-acetate (0.83 g). The crude oxime was then dissolved in methanol (25 mL) and formic acid (50% aq., 10 mL) was added. The mixture was cooled to 0° C. and zinc dust (1.00 g, 15.3 mmol) was added portionwise over 30 mins. The reaction mixture was allowed to warm to room temperature, and stirred for 6 hours. The solution was then filtered, basified to pH 9 with solid NaHCO3, and extracted with ethyl acetate (3×80 mL). The combined extracts were then dried and evaporated to afford DL-2-ethylthiazol-4-ylglycine ethyl ester (0.56 g, 2.6 mmol). The ester (560 mg, 2.6 mmol) was then dissolved in tetrahydrofuran (50 mL). Triethylamine (0.4 mL, 3.9 mmol) was added, followed by di-t-butyl dicarbonate (0.57 g, 2.6 mmol). After stirring at room temperature overnight the mixture was concentrated, water (20 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined extracts were evaporated to afford N-t-butyloxycarbonyl-D/L-2-ethylthiazol-4-ylglycine ethyl ester (824 mg,) as a golden oil. The oil was dissolved in methanol (25 mL) and aqueous sodium hydroxide (2 M, 5 mL) was added. After stirring at room temperature for 2 hours, the solution was concentrated, water (30 mL) was added, and the solution extracted with ethyl acetate (30 ml). The aqueous layer was then acidified to pH 4 with 2 N HCl, and extracted with ethyl acetate (2×20 mL), The latter extracts were combined and evaporated to afford N-t-butyloxycarbonyl-D/L-2-ethylthiazol-4-ylglycine (450 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.N1C=CC=CC=1.CN(C)C=O>O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]3[NH:34][N:33]=[N:32][N:2]=3)[O:4][C:5]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: c1cc(COc2ccc3nc(-c4nnn[nH]4)oc3c2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
2-cyano-6-(3-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazole (2.97 mmoles), sodium azide (965 mg), pyridine hydrochloride (1.72 g) and dimethylformamide (7 ml) are combined and heated at 100° C. for 48 hours. The reaction mixture is poured into cold water and the resulting precipitate is collected. The precipitate is dissolved in hot ethanol and reprecipitated by addition of water to give 5-(6-(3-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazol-2-yl)tetrazole.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[C:14]([O:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.50 g, 1.18 mmol) in THF (8 mL) was added tetrabutylammonium fluoride (1.78 mL, 1.0 M in THF, 1.78 mmol). The resulting mixture was stirred at room temperature for 1 hour, concentrated and purified by flash chromatography using a gradient run from 5-100% EtOAc in toluene. The selected fractions were concentrated in vacuo to give the product as a clear oil. Yield: 0.34 g (93%). 1H NMR (400 MHz, CDCl3) δ 7.54 (t, 1H, J=7.66 Hz), 6.78 (d, 1H, J=7.26 Hz), 6.59 (d, 1H, J=8.16 Hz), 5.15-5.26 (m, 1H), 4.62 (s, 2H), 3.66-3.77 (m, 2H), 3.25-3.37 (m, 3H), 1.89-1.99 (m, 2H), 1.59-1.82 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:90][CH2:89][CH2:88][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:84]([O:86]C)=[O:85])[CH2:79][CH2:80][CH2:81][CH2:82][NH2:83])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].N>O>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:90][CH2:89][CH2:88][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:84]([OH:86])=[O:85])[CH2:79][CH2:80][CH2:81][CH2:82][NH2:83])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Agent: N
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
80 mg of H-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys-OMe (Example 7) are dissolved in 1.5 ml of H2O and the pH value is adjusted to 5.5 by the addition of 0.1N NH3. 8 μl of a 1% aqueous trypsin solution are added and the pH value is maintained at 5.5 by the addition of 0.1N NH3 by means of a pH stat. After approximately 20 minutes the absorption of base is complete, whereupon 350 μl of glacial acetic acid are added and the whole is heated for 2 minutes in a boiling water bath. The solution is concentrated to dryness, the residue is dissolved in 2 ml of 0.05N AcOH and, in order to separate off the inactivated enzyme, pumped through a column (φ=1.2 cm, length=25 cm) of Biogel P-10 polyacrylamide gel, exclusion limit at a molecular weight of 20 000; manufacturer: Bio-Rad, Richmond, Calif., USA). The fraction having a molecular weight matching the peptide mentioned below, which is ascertained by UV detection, is concentrated to a small volume and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys-OH; Rf (D)=0.12; Rf (M)=0.07; Rf (N)=0.05.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:43]=[CH:42][CH:41]=[CH:40][C:29]=1[NH:30][C:31]([CH2:38][CH3:39])=[CH:32][C:33]([O:35]CC)=O>CCCCCC>[CH2:38]([C:31]1[CH:32]=[C:33]([OH:35])[C:40]2[C:29](=[C:28]([O:27][CH3:26])[CH:43]=[CH:42][CH:41]=2)[N:30]=1)[CH3:39]
Reactant: CCOC(=O)C=C(CC)Nc1ccccc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCc1cc(O)c2cccc(OC)c2n1
Temperature: 235 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a mixture of diphenyl ether (30 ml) and biphenyl (30 g) was added ethyl 3-(2-methoxyanilino)-2-pentenoate (15.1 g) during which time the internal temperature was maintained 230°-235° C. The mixture was stirred at 235° C. for 1 hour. To the reaction mixture was added hexane (150 ml). The precipitate was collected by vacuum filtration and washed with hexane to give 2-ethyl-4-hydroxy-8-methoxyquinoline (10.37 g) as crystals.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[O-]CC.[Na+].[Na].[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[N+:22]=[N-:23])=[CH:18][CH:17]=1.Cl>C(O)C.O>[NH2:2][C:1]1[N:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:22]=[N:23][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1N
Reaction time: 0.5 h

Procedure:
Ethyl cyanoacetate (1.96 mL) was added to a solution of sodium ethoxide, prepared from sodium (0.423 g) and ethanol (45 mL), and the solution was stirred for 30 min. A solution of 4-methoxybenzylazide (3.0 g) in ethanol (5 mL) was added dropwise and the mixture was heated under reflux for 5 h. The cooled mixture was poured into water and acidified with dilute hydrochloric acid then extracted with ethyl acetate. The extracts were washed with water, brine and evaporated. Purification by flash chromatography (ethyl acetate/dichloromethane 1:9 then 15:85) gave the product as a pale yellow solid (0.85 g).