Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.[ClH:75]>>[ClH:75].[ClH:75].[F:1][C:2]1[CH:3]=[C:4]([NH:23][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Nc1ccc(Oc2ccncc2C#Cc2ccccn2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Cl
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2C#Cc2ccccn2)c(F)c1
Yield: 60 %

Procedure:
The title compound was prepared from 3-fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)benzenamine (19 mg, 0.062 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) in a manner similar to that of Step D of Example 33. Purification of the reaction mixture by flash chromatography on SiO2 eluting with 0-100% EtOAc/CH2Cl2 gave a white solid which was converted to the hydrochloride in a manner similar to Step D of Example 33 to give the title compound (19 mg, 60%) as a white solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.61 (s, 1H), 8.79 (s, 1H), 8.63 (d, 1H, J=5.6 Hz), 8.47 (d, 1H, J=5.6 Hz), 7.89-7.86 (m, 1H), 7.83 (dd, 1H, J=1.5, 12.7 Hz), 7.67 (d, 1H, J=7.6 Hz), 7.47-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.27 (m, 1H), 7.20-7.16 (m, 2H), 7.14-7.10 (m, 1H), 6.77 (d, 1H, J=5.6 Hz), 3.75 (s, 2H); MS (ESI+): m/z 485.17 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[O:16])=[CH:10][CH:9]=1)C>O.C(O)C>[C:22]1([C:19]2[O:18][C:17]([C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:28])=[O:5])=[CH:13][CH:12]=3)=[O:16])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccc(-c3ccccc3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of sodium hydroxide (100 mg) in water (5 ml) was added to a stirred solution of {4-[(5-phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (1) (75 mg, 0.214 mmoles) in ethanol (10 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH=2 with 1 M aqueous hydrochloric acid. The precipitate was collected, washed with water and the residue was triturated with cyclohexane to afford (2) (61.5 mg) as a white solid. LC/MS System D; Rt=3.01 mins, m/z (ES−)=320 (M−H for C19H15NO4).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[CH2:25][CH2:26][NH2:27]>>[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[CH2:25][CH2:26][NH:27][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCC1OCCO1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCC3OCCO3)s2)c(C)[nH]c1=O
Yield: 50.5 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(1,3-dioxolan-2-yl)ethylamine as described in Step 5, Example 24 to give the title compound as a solid (50.5% yield). LC/MS: RT 2.58 min; m/e 399 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.8 (1H, br s); 7.56 (1H, d); 7.35 (1H, s), 7.18 (1H, d), 4.8 (1H, t), 3.8 (2H, m), 3.75 (2H, m), 2.95 (2H, m), 2.4 (2H, q), 2.36 (3H, s), 1.75 (2H, m), 1.08 (3H, t).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:16]>C1(C)C=CC=CC=1.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:16])=[O:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)on1
Reaction time: 0.5 h

Procedure:
A solution of 5-phenylisoxazole-3-carboxylic acid (0.86 g, 4.55 mmol) in toluene (15.0 mL) and methanol (3 mL) was added a 2M solution of TMS-diazomethane in hexanes (3.1 mL, 6.14 mmol) dropwise at room temperature. The reaction mixture was stirred for 30 minutes and concentrated. The residue was dispersed in methanol (3 mL), stirred for 5 minutes, and filtered to give methyl 5-phenylisoxazole-3-carboxylate (897 mg). The compound had an HPLC ret. time=2.67 min.: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=204+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:18]([CH:20]=[CH2:21])=[O:19].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:14](/[CH:21]=[CH:20]/[CH:18]=[O:19])=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C=CC=O
Reactant: CC(C)(C)OC(=O)COc1cc(I)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc(/C=C/C=O)ccc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
t-Butyl (2-chloro-5-iodophenoxy)acetate (851 mg, 2.00 mmol) was dissolved in dimethylformamide under an atmosphere of nitrogen, and thereto were acrolein (0.400 ml, 6.00 mmol), sodium carbonate (0.510 g, 6.00 mmol), benzyltriethylammonium chloride (683 mg, 3.00 mmol) and palladium acetate (14.0 mg, 60.0 μmol). The mixture was stirred for 3 hours at 60° C. The reaction mixture was cooled and thereto was added sodium thiosulfate. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium thiosulfate, 10% aqueous citric acid solution, water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in the order, and dried over magnesium sulfate. The solvent was removed to give the subject compound as yellow crystals (631 mg, quantitatively).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][CH2:35][NH:36][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][N:11]=2)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Reactant: NCCN1CCOCC1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 44 %

Procedure:
Following the procedure described above in Example 34, 6-Fluoro-4-(4-phenoxy-phenylamino)-[1,7]naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2% methanol in methylene chloride) to give a yellow solid (0.12 g, 44%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 4 H) 2.6 (t, J=6.8 Hz, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.6 (t, J=5.6 Hz, 1 H) 7.0 (m, 2 H) 7.1 (m, 4 H) 7.4 (m, 3 H) 8.2 (s, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H) 9.6 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH:4]([OH:9])[C:5](OC)=[O:6].[NH3:12].CO>>[F:1][C:2]([F:11])([F:10])[CH2:3][CH:4]([OH:9])[C:5]([NH2:12])=[O:6]
Reactant: N
Reactant: COC(=O)C(O)CC(F)(F)F
Solvent: CO
Product: NC(=O)C(O)CC(F)(F)F

Procedure:
A solution of 12-3 (200 mg, 1.16 mmol) in 7N NH3/MeOH (10 mL) was heated at 70° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in 1,2-dimethoxyethane (10 mL) and filtered to remove insolubles. The filtrate was concentrated to dryness to afford Intermediate 12. 1H NMR (500 MHz, DMSO-d6) δ 7.40 (br s, 1H), 7.34 (br s, 1H), 5.93 (m, 1H), 4.10 (m, 1H), 2.64-2.65 (m, 1H), 2.40-2.41 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16](NCCOCC)[CH3:17])=[CH:6][CH:5]=1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOCCNC(C)c1ccccc1-c1ccc(OCC)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(-c2ccccc2CC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 13.5 mg [1-(4′-ethoxy-biphenyl-2-yl)-ethyl]-(2-ethoxy-ethyl)-amine (43.1 μmol, 1.00 equiv), 10.5 mg 4′-(trifluoromethyl)phenylacetic acid (51.7 μmol, 1.20 equiv), 9.9 mg EDC (51.7 μmol, 1.20 equiv), and 1.0 mg HOBT (7.4 μmol, 0.18 equiv) dissolved in 2.0 mL dichloromethane was stirred at room temperature for 2 h. To the reaction solution was added 5 mL aqueous saturated sodium bicarbonate solution. The aqueous layer was diluted with water to 15 mL and extracted with dichloromethane (2×20 mL). The combined organic separations were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a yellow oil. The crude product was adsorbed onto a column of silica gel (3.5 cm o.d.×10 cm h) and eluted with 17% to 25% ethyl acetate gradient in hexane. Fractions containing product were combined and concentrated in vacuo to afford 12.8 mg purified product as a colorless oil. 1H NMR (d6-DMSO; T=140° C.) δ 1.04 (t, 3H, J=6.8 Hz), 1.34 (t, 3H, J=6.8 Hz), 1.44 (d, 3H, J=7.2 Hz), 3.00–3.06 (m, 1H), 3.17–3.36 (m, 6H), 3.49 (d, 1H, J=16.0 Hz), 4.07 (q, 2H, J=6.8 Hz), 5.43 (q, 1H, J=7.2 Hz), 6.92–6.96 (m, 2H), 7.13–7.18 (m, 3H), 7.22–7.26 (m, 2H), 7.34 (ddd, 1H, J1=1.2 Hz, J2=7.6 Hz, J3=8.4 Hz), 7.39 (ddd, 1H, J1=2.0 Hz, J2=7.6 Hz, J3=9.2 Hz), 7.53–7.59 (m, 3H) ppm. At room temperature, compound exists as a mixture of cis/trans amide rotamers in ca. 2:1 ratio as determined by integration of characteristic 1H NMR signals (CDCl3; T=25° C.), δmajor 5.19 (q, 2.1H, J=7.2 Hz) and δminor 5.89 (q, 1.0H, J=7.6 Hz) ppm. MS (ESI, positive mode) 500.1 [MH]+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:31]=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:17][CH:16]=1.C(O)C>[Pt]=O.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C=Cc1c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc2ccccc12
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]-2-propenoate (1.51 g), platinum oxide (0.18 g), ethanol (5 mL) and tetrahydrofuran (10 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated to give crystals (1.36 g, 90%) of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionate. Recrystallization from acetone-hexane gave colorless needle crystals. melting point: 86-87° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1N
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Nc1ccccc1C(=O)O
Temperature: 120 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 40 g (0.25 mole) of 2-chlorobenzoic acid, 21 ml (0.26 mole) of 2-methoxyaniline, 3.84 g cupric acetate, 35.4 g of potassium carbonate and 155 ml of dimethylformamide was heated at 120° C. for 12 hours. The reaction mixture was poured into ice-water, neutralized with concentrated hydrochloric acid to pH 2, and stirred for one hour. The solid product was collected by filtration, air dried and recrystallized from toluene to give 28.61 g of 2-(2-methoxyphenylamino)benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[O:24][CH3:25]>>[CH3:21][O:22][CH:23]([C:26]1[CH:27]=[C:28]([NH:29][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH:30]=[CH:31][CH:32]=1)[O:24][CH3:25]
Reactant: COC(OC)c1cccc(N)c1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Nc1cccc(C(OC)OC)c1
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted with 3-(1,1-dimethoxymethyl)aniline to give N-[3-(1,1-dimethoxymethyl)phenyl]-2-(4-benzyloxy-2-methoxyphenyl)acetamide in 51% yield. The compound was obtained as a mixture of the dimethoxyacetal and the corresponding aldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:44][OH:45]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([NH:44][OH:45])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC
Yield: 87.3 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-dimethylaminophthalimido)-propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-dimethylaminophthalimido)propanoic acid (0.31 g, 0.75 mmol), carbonyldiimidazole (140 mg, 0.86 mmol) and hydroxylamine hydrochloride (66 mg, 0.95 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-dimethylaminophthalimido)propionamide as a yellow solid (280 mg, 87% yield): mp, 187.0-188.6° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=7.0 Hz, 3H, CH3), 3.01 (s, 6H, CH3), 3.08 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.63 (t, J=7.9 Hz, 1H, NCH), 6.88 (br s, 2H, Ar), 7.00 (br s, 1H, Ar), 7.19 (m, 2H, Ar), 7.57 (dd, J=7.1, 8.3 Hz, 1H, Ar), 8.78 (br s, 1H, OH), 10.57 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.66, 34.42, 42.96, 49.88, 55.45, 63.72, 111.75, 112.41, 112.71, 113.74, 119.63, 122.32, 131.61, 133.94, 134.92, 147.60, 148.43, 149.75, 166.11, 166.76, 167.56; Anal Calcd for C22H25N3O6: C, 61.82; H, 5.89; N, 9.83. Found: C, 61.79; H, 5.90; N, 9.58.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].C(=O)([O-])OC1C([C@@H](C)CCCCCCC)=CC=CN=1.[CH3:33][C@H:34]([O:42][C:43](N1C=CC=CC1=O)=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:43]([O:42][C@@H:34]([CH3:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:44])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCCCCCC[C@H](C)OC(=O)n1ccccc1=O
Agent: CCCCCCC[C@H](C)c1cccnc1OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC[C@H](C)OC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 60.8 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in water (3 mL), the crude mixture containing [(1S)-1-methyloctyl]-2-pyridyl carbonate and [(1S)-1-methyloctyl]-2-oxopyridine 1-carboxylate (0.501 g, 1.88 mmol) in THF (3 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.220 g, 62%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 290 [M−H]+; (ESI) m/z: 288 [M−H]−. 1H NMR (DMSO-d6): δ 0.87 (t, J=6.8 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.2 Hz, 3H), 1.21-1.34 (m, 10H), 1.40-1.57 (m, 2H), 3.92 (dd, J=3.4, 9.0 Hz, 1H), 4.01-4.11 (m, 1H), 4.60-4.70 (m, 1H), 6.55 (d, J=9.0 Hz, 1H), 12.49 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+].[I-].[K+].C([O-])(O)=O.[Na+]>C(O)C>[CH3:18][C:12]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
A mixture of 3-nitrophenol (0.50 g, 3.6 mmole), ethyl bromodimethylacetate (0.64 g, 3.3 mmole), K2CO3 (1.3 g, 9.4 mmole), potassium iodide (catalytic) in absolute ethanol (8 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled, poured into a saturated solution of NaHCO3, and extracted with dichloromethane. The product, ethyl 2-methyl-2-(3-nitrophenoxy)propanate, was obtained after purification by column chromatography over silica gel. 1H NMR (CDCl3): δ 7.85 (dt, 1H, J=1.2 and 8.1 Hz), 7.68 (t, 1H, J=2.4 Hz), 7.40 (t, 1H, J=8.4 Hz), 7.19-7.13 (m, 1H), 4.26 (q, 2H, J=7.2 Hz), 1.64 (s, 6H), 1.26 (t, 3H, J=7.21),
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH:12]=O.[C:19]([O:27]C)(=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C(OC(C)C)(C)C>C(O)(C)(C)C.O1CCCC1.O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:20]([C:19]([OH:27])=[O:26])=[CH:12][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)CC(=Cc1cc(OC)cc(OC)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.5 %

Procedure:
Potassium tert-butoxide (14.2 g) is dissolved in tert-butyl alcohol (120 ml), and thereto is added dropwise a solution of 3,5-dimethoxybenzaldehyde (20 g) and dimethyl succinate (21.1 g) in tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes, and water and isopropyl ether are added to the mixture. The aqueous layer is separated, and the remaining organic layer is further extracted with water. The aqueous layers are combined, and the pH value thereof is adjusted to pH 2-3 with conc. hydrochloric acid. The resulting oily product is extracted with ethyl acetate, and the extract is dried, concentrated under reduced pressure to give 4-(3,5-dimethoxyphenyl)-3-carboxy-3-butenoic acid methyl ester (42 g) as an oily product.
Reaction SMILES: O.[OH-].[Li+].[C:4]([NH:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([NH2:39])=[NH:38])[CH:31]=2)(=[O:29])=[O:28])[CH:21]=1)[CH2:14][C:15]([O:17]CC)=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C1COCC1>[C:4]([NH:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([NH2:39])=[NH:38])[CH:31]=2)(=[O:29])=[O:28])[CH:21]=1)[CH2:14][C:15]([OH:17])=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(NC(=N)N)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)Nc1cccc(S(=O)(=O)Nc2cccc(C(CC(=O)O)NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
94 mg of lithium hydroxide monohydrate were added to a solution of 298.5 mg of (4f) in 30 ml of water and 30 ml of THF. The reaction mixture was stirred at room temperature for 20 h and then concentrated. Chromatographic purification on silica gel (acetonitrile/water=7:1) afforded a white solid (yield: 155 mg).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 10.0 g (91 mmol) of thiophenol in 170 mL of DMF is added 6.2 g (95 mmol) of KOH. When the KOH has dissolved, 17 g (91 mmol) of 2,5-dichloronitrobenzene is added. After stirring for 3 hours at 70° C., the solvent is removed in vacuo. The residue is partitioned between CHCl3 and N NaOH. The organic layer is washed with N NaOH, H2O, N HCl, H2O and is dried over NaSO4 anhydrous, filtered, and stripped. The product is crystallized from cyclohexane.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1]
Reactant: Cn1ccc2c(C#N)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2c(CN)cccc21
Temperature: 50 °C
Yield: 90.9 %

Procedure:
Dissolve 1-methylindole-4-carbonitrile (1.0 g, 6.18 mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in THF (12.4 mL, 12.37 mmol) at ambient temperature. Heat the reaction mixture at 50° C. for 17 h and cool to ambient temperature. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.9 g, 91%). GC-MS m/z: 160 (M+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])[CH3:3].[CH:18]([S:26](Cl)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:26]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])=[CH:14][CH:15]=1)=[O:17])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1ccc(NS(=O)(=O)C=Cc2ccccc2)cc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Boc amine from Example 4 and β-styrenesulfonyl chloride: 1H NMR (400 MHz, CDCl3) δ7.47 (d, 1H, J =15.4 Hz), 7.42-7.33 (m, 5H), 7.11 (s, 4H), 6.77 (d, 1H, J=15.4 Hz), 6.56 (br s, 1H), 4.48 (br s, 1H), 4.10 (br m, 2H), 2.72 (t, 2H, J=7.1 Hz), 1.39 (s, 9H).