Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: CC(C)(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)(C)C)[nH]n1
Yield: 22 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using tert-butylamine instead of 2,2,2-trifluoroethylamine, to the title compound (25 mg, 22%) which was obtained as a white solid. MS: m/e=374.1 [M+H]+.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[C:13]([O:15]C)=O.[Cl-].[NH2:18][C:19]([NH2:21])=[NH:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:21][C:19]1[N:18]=[C:13]([OH:15])[C:3]2[CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=2[N:20]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCCc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)-c1ccccc1CCC2
Yield: 68.4 %

Procedure:
A solution of the product from Example 4A (4.2 g, est. 18 mmol), guanidine chloride (7.1 g, 72.8 mmol), and K2CO3 (10.8 g, 78 mmol) in DMF (30 mL) was heated to 125° C. for 3 hours. The mixture was cooled and the solids were removed by filtration. The solids were washed with EtOAc. The combined filtrates were concentrated under reduced pressure and the residue was passed through silica gel pad eluting with EtOAc:hexanes (8:2) and then with MeOH:EtOAc:CH2Cl2 (10:45:45) to provide the title compound as a white solid (2.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:26])[C@H:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:26])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:14]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(O)CCc1ccc(O)cc1
Product: CCOC(=O)CCC(NC(=O)CCc1ccc(O)cc1)C(=O)OCC
Yield: 90.1 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and glutamic acid diethyl ester (1.34 g, 6.6 mmol) were used, 1.9 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[N:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=3)=[CH:14][CH:15]=2)=[C:7]([CH3:32])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:17]1[C:16]([C:13]2[S:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=3[CH3:32])=[CH:15][CH:14]=2)=[CH:20][C:19]([C:21]([F:24])([F:22])[F:23])=[N:18]1
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
(4-{5-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl}-3-methylphenyl)-acetic acid methyl ester (122 mg, 025 mmol) was dissolved in 6 mL mixture of THF and water (3:1, V/V). Lithium hydroxide monohydrate (23 mg, 0.55 mmol) was then added. After stirring at room temperature for 2 hrs, the mixture was neutralized to pH 7 by 1N HCl, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by reverse HPLC to give a white solid (66 mg, 55% yield). 1H-NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.65 (s, 2H), 6.88-6.84 (m, 3H), 7.17-7.11 (m, 1H), 7.17 (m, 1H), 7.27 (m, 1H), 7.56-7.42 (m, 4H). MS (ES) 477.2, [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:38][C:39]1[CH:53]=[CH:52][C:42]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][C@H:46]([CH2:50][OH:51])[CH2:45]2)=[CH:41][CH:40]=1>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:13]/[C:14]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:53][CH:52]=3)[CH2:45][C@H:46]2[CH2:50][OH:51])=[O:16])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: OC[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.3 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (2.2 g, 9.36 mmol), EDCI (3.6 g, 18.7 mmol); HOBT (2.5 g, 18.7 mmol) and 2.1 g (9.36 mmol) [(S)-4-(4-Fluorobenzyl)-piperazin-2-yl]-methanol were dissolved in 200 ml THF and stirred for 20 hours at room temperature. This mixture was then extracted 3 times with water and once with saturated sodium chloride solution. The title compound was purified by chromatography (SiO2, ethyl acetate/MeOH/NH3conc. 90/10/1) and was isolated as a pale solid (1.6 g, 39%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)(=[O:27])=[O:28])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: NC(=O)c1cc(-c2ccc(CO)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of 5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (14.4 mg, 0.027 mmol) in THF (5 mL) was added MnO2(71.7 mg, 0.81 mmol). The reaction mixture was stirred at room temperature overnight and filtered through a pad of celite after that. The filtrate was collected and concentrated at reduced pressure to give the crude product (8.3 mg, 58%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[CH:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: COc1cc(CN)on1
Reactant: Cc1cc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)ccc1Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)c(C)c3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BN) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 456.0938 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>C(O)C>[N:7]1([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=Cc1cccc(CBr)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1cccc(CN2CCCC2)c1
Temperature: 65 °C
Yield: 88.5 %

Procedure:
A suspension of K2CO3 (2.09 g, 15.2 mmol, 3.00 equiv) in absolute ethanol (20 mL) was treated with pyrroldine (439 μL, 5.05 mmol, 1.00 equiv). 3-(bromomethyl)-benzaldehyde (1.00 g, 5.05 mmol, 1.00 equiv) was introduced, and the reaction was heated to 65° C. for 1 h. The reaction was cooled and filtered. The cake was washed with more ethanol. The filtrate was concentrated to a cloudy oil and partitioned between DCM (50 mL) and 2% w/v aq NaHCO3 (50 mL). The organic phase was collected, and the aq layer was extracted with DCM (2×50 mL). All organic layers were combined, dried (Na2SO4), filtered, and concentrated, giving 3-(pyrrolidin-1-ylmethyl)-benzaldehyde (846 mg, 88% yield) as a pale yellow oil, which was used without further purification. 1H-NMR: 300 MHz, (CDCl3) δ: 10.00 (s, 1H), 7.84 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.47 (dd, J=7.6 Hz, 7.6 Hz, 1H), 3.69 (s, 2H), 2.52 (m, 4H), 1.79 (m, 4H). LCMS-ESI+: calc'd for C12H16NO: 190.1 (M+H+). Found: 190.1 (M+H+).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>C1COCC1>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:50][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of 4-(4-biphenylylmethoxy)phenylacetic acid (0.6 g) in THF (30 ml) were added WSC (0.4 g) and HOBt (0.3 g). N,N-Dimethylethylenediamine (0.2 g) was added to the reaction mixture. After stirring at room temperature for 18 hr, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/ethanol to obtain the titled compound (0.3 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[S:11])=[N:6][CH:7]=1.[CH3:25][C:26]([O-])=[O:27].[Na+].BrCC(OCC)=O>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:9]2[C:26](=[O:27])[CH2:25][S:11][C:10]2=[N:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[N:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cnc(CNC(=S)Nc2ccc(N3CCOCC3)cc2)cn1
Agent: CCOC(=O)CBr
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(CN2C(=O)CSC2=Nc2ccc(N3CCOCC3)cc2)cn1
Temperature: 80 °C
Yield: 73 %

Procedure:
A suspension of 1-(5-Methylpyrazin-2-ylmethyl)-3-(4-morpholin-4-ylphenyl)-thiourea (1.7 g, 5.0 mmol, 1.0 equiv) and NaOAc (0.82 g, 10.0 mmol, 2.0 equiv) in 30 mL ethanol was treated with ethyl bromoacetate (0.55 ml, 5.0 mmol, 1.0 equiv) as a neat liquid via syringe. The heterogeneous mixture was heated to 80° C. overnight. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated NaHCO3. After drying the organic layer with brine and Na2SO4, the product was purified by flash chromatography (40 to 90% EtOAc in hexanes) to afford 1.4 g (73%) of the title compound as a yellow-orange foam: 1H NMR (500 MHz, CDCl3) δ 8.53 (d, 1H, J=1.5 Hz), 8.39 (d, 1H, J=1.5 Hz), 6.85 (s, 4H), 5.15 (s, 2H), 3.90 (s, 2H), 3.85 (m, 4H), 3.12 (m, 4H), 2.54 (s, 3H); MS (ESI) m/z=384.2 (MH+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.O[C@@H]1CCN(C(OC(C)(C)C)=O)C1.NN>CO>[NH2:3][O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](ON)C1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
(S)-tert-Butyl 3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate (2.91 g, 8.77 mmol) prepared from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate following a procedure analogous to Reference Example 7 was gradually added to methanol (43 mL) and hydrazine.monohydrate (1.54 g), followed by stirring for 3 hours. The reaction solution was filtered and the residue resulting from distilling off the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1) to afford 1.75 g of the title compound (yield 98.7%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:23]=[CH:22][C:11]2[N:12]([CH:19]([CH3:21])[CH3:20])[C:13]3[C:18]([C:10]=2[CH:9]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])C>CO.O>[C:6]([C:8]1[N:23]=[CH:22][C:11]2[N:12]([CH:19]([CH3:20])[CH3:21])[C:13]3[C:18]([C:10]=2[CH:9]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)([OH:7])=[O:5]
Reactant: CCOC(=O)c1cc2c3ccccc3n(C(C)C)c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)n1c2ccccc2c2cc(C(=O)O)ncc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.1 %

Procedure:
A solution (1 mol dm−3) of sodium hydroxide (21 ml, 21 mmol) was added over 10 minutes to a stirred solution of 3-ethoxycarbonyl-9-isopropyl-9H-pyrido[3,4-b]indole (Method 1; 2.9 g, 10.3 mmol) in a MeOH/water mix (100 ml 2:1 v/v), and the mixture was allowed to stir for 20 hours at room temperature. MeOH was removed in vacuo and the mixture acidified by the addition of HCl (1 mol dm−3). The precipitate was filtered, washed with water and dried under vacuum at 65° C. for 2 hours to give a light yellow solid (2.15 g). NMR (300 MHz) 9.19 (s, 1H), 8.91 (s, 1H), 8.41 (d, 1H), 7.85 (d, 1H), 7.62 (t, 1H), 7.31 (t, 1H), 5.26 (m, 1H), 1.66 (d 6H); m/z 255.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[S:10])[NH2:9].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=O>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:10][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:9]=1
Reactant: COC(=O)CCCCC(N)=S
Reactant: COc1ccccc1C(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)cs1
Temperature: 80 °C
Yield: 142.4 %

Procedure:
Add THF (125 mL, anhydrous) to a sealed vessel containing 5-thiocarbamoyl-pentanoic acid methyl ester (7.25 g, 41.4 mmol) and 2-bromo-2′-methoxyacetophenone (9.48 g, 41.4 mmol). Flush vessel with N2, seal, and heat at 80° C. overnight. Cool to room temperature, add EtOAc, wash with saturated aqueous NaHCO3 solution, brine, and backextract from each aqueous layer with EtOAc. Dry combined organic layers over MgSO4 and concentrate to get 18 grams of purple residue. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford the title compound (9.7 g, 77%). TLC (30% EtOAc/hexanes) Rf=0.38. MS (IS) 306 (M+1)+.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:23]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:24]
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CCN1c2ccccc2Oc2ccccc21
Yield: 78.5 %

Procedure:
Into a reaction flask were introduced 3.0 g (16.4 mmol) of phenoxazine, 6.5 g (98.5 mmol) of 85% KOH, 3.7 g (26.8 mmol) of potassium carbonate, 577 mg (1.7 mmol) of tetra-n-butylammonium hydrogensulfate, and 100 ml of toluene. Thereto was gradually added 5.1 g (32.7 mmol) of ethyl iodide with a dropping funnel (slight heat generation occurred). Subsequently, the mixture was reacted at 60 to 80° C. for 7 hours. After the disappearance of the phenoxazine was ascertained by TLC and gas chromatography, the resultant toluene solution was cooled, washed with water three times, dried (with MgSO4), and then concentrated. The residue was distilled under vacuum to obtain 2.72 g of 10-ethylphenoxazine. Yield, 78.7%; b.p., 120-122° C./1 mmHg.
Reaction SMILES: [Na].C1(C2C=CC(O)=CC=2)CCCCCCC=1.[CH2:17]([O:19][C:20](=[O:29])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:18]
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: Oc1ccc(C2=CCCCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCC(=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 2.1 g of sodium in 150 ml of absolute ethanol are added with stirring 15 g of p-(1-cyclooctenyl)-phenol. After stirring has continued for a further 30 minutes, 30 g of 2-bromo-octanoic acid ethyl ester are slowly added dropwise to this solution and the mixture is maintained at 50° C for 24 hours. After the solvent has been removed in vacuo the residue is partitioned at 0° C between ether and 2N sodium hydroxide solutuion. The organic phase is washed until neutral, dried over sodium sulphate and evaporated in vacuo, to thus yield the oily α-[p-cyclooctenyl)-phenoxy]-octanoic acid ethyl ester of the formula ##STR9##
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+]>CO>[OH:22][C:7]1[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])=[N:11][C:10]([CH3:12])=[C:9]2[O:13][N:14]=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=12
Reactant: CCOC(=O)c1nc(C)c2onc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccccc3)noc12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of 4-hydroxy-7-methyl-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (93 mg, 0.31 mmol), glycine (470 mg, 6.27 mmol), and a 0.5 M solution sodium methoxide in methanol (11.9 ml) was refluxed for 42 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 ml) and the solution was extracted with methyl t-butyl ether (2×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a gray solid (89 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.25 (t, 1H), 8.03 (m, 2H), 7.57 (m, 3H), 4.01 (d, J=6.2 Hz, 2H), 2.71 (s, 3H); MS: (+) m/z 327.98 (M+1), (−) m/z 325.99 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[C:31]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:24][C:23]=2[O:22]1>CCOCC.C1COCC1>[OH:39][C:32]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)=[C:31]1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [OH-].[K+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:14]1[C@H:18]([CH2:19][CH2:20][CH3:21])[C@H:15]1[CH2:16][OH:17].O>C(OCC)C>[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([O:17][CH2:16][C@H:15]2[O:14][C@@H:18]2[CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCC[C@H]1O[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCC[C@H]1O[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 71 %

Procedure:
26 g of powdered potassium hydroxide (0.45 mol) and 14.3 g (75 mmol) of p-toluenesulfonyl chloride were added in succession at −10° C. to a stirred solution of (2R,3R)-2,3-epoxy-1-hexanol (8 g, 69 mmol) in diethyl ether. After 5 hours at 0° C., the reaction mixture was poured into 200 ml of water. The organic layer was separated off and the aqueous phase was extracted twice with 100 ml of diethyl ether in each case. The combined organic phases were washed with concentrated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent, (2-R,3R)-2,3-epoxyhexyl p-toluenesulfonate remained in the form of light yellow crystals which crystallized from diethyl ether/n-hexane as colorless needles (yield: 71%; [α]D20=+36.3°(c=2.0 in trichloromethane)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@@H:8]([CH2:11][O:12][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:7][C:6]=2[CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC[C@@H]1COc2ccc(Br)cc2O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)O[C@H](COc1ccccc1)CO2
Temperature: 0 °C
Yield: 37.2 %

Procedure:
A mixture of [(2R)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.648 g, 2.64 mmol), phenol (0.248 g, 2.64 mmol), triphenylphosphine (0.692 g, 2.64 mmol) and THF (26 mL) is cooled in a 0° C. bath under N2. Diethylazodicarboxylate (0.42 ml, 2.7 mmol) is added and the mixture allowed to warm to rt overnight. The mixture is concentrated, partitioned between EtOAc and H2O, the organic layer dried (MgSO4), adsorbed onto SiO2, and chromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane). The product fractions are pooled and concentrated to afford 0.315 g (37%) of (2R)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine as an oil. A solution of this oil (0.280 g, 0.87 mmol) and THF (30 ml) is cooled in a CO2 (s)/acetone bath under N2. To this is added a solution of tert-butyl lithium in pentane (1.7 M, 1.10 ml, 1.9 mmol). After stirring for 5 min, CO2 (g) is bubbled through the solution for an additional 10 min. The mixture is treated with MeOH/HCl and allowed to warn to rt. The mixture is concentrated, and the residue is chromatographed (Biotage 40S, (1:499) MeOH:CH2Cl2). The product fractions are pooled and concentrated to afford 0.103 g (41%) of (3R)-3-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid as a solid. Example 12 is obtained in 45% yield as a monohydrate solid following the procedures outlined in Example 1, making non-critical changes: 1H NMR (400 MHz, CD3OD) δ 7.40-7.55, 7.25-7.35, 6.90-7.05, 4.35-4.65, 4.20-4.35, 3.75-3.90, 3.25-3.55, 2.30-2.40, 2.15-2.30, 2.05-2.15, 1.85-2.00; MS (EI) m/z 394 (M+).