Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-:15].[Na+].[Na+].CN1CCCC1=O>O>[CH3:1][O:2][CH:3]([OH:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(Cl)C(=O)Nc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(O)C(=O)Nc1ccccc1
Yield: 70 %

Procedure:
In a 250 ml flask, 10 g (0.05 mol) of 2-methoxy-chloroacetanilide (prepared from chloroacetyl chloride and 2-methoxyaniline) and 6 g (0.55 mol) of sodium carbonate are heated at 100° C. in a solvent mixture of 100 ml of N-methylpyrrolidone and 70 ml of water. A GC check after a reaction time of 6 hours reveals a yield of 70% of 2-methoxy-hydroxyacetanilide and 5.5% of 2-methoxydiglycolanilide.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1.C1(N=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:20][N:3]([CH3:2])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:6][C:7](=[CH:10][C:11]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:29][CH:28]=2)=[O:13])[CH2:8][CH2:9]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
(4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (592 mg, 2.0 mmol) in dry dimethylformamide (10 ml) under argon. The clear solution was cooled to 0° C. and dicyclohexylcarbodiimide (834 mg, 4.0 mmol) was added. The reaction mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. 5 M sodium hydroxide solution (5 ml, 25 mmol) was added to the aqueous phase and the mixture was diluted with water (300 ml) and stored at 5° C. for 16 h. The product thereby precipitated out as a colourless solid in a yield of 45% (387 mg) with an m.p. of 77-88° C.
Reaction SMILES: Cl.C([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])C.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([NH:8][CH2:7][CH2:6][C:5]([OH:4])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCN
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)CCNCc1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Ten grams of β-alanine ethyl ester hydrochloride and 9 g of benzaldehyde were added to 100 mL of toluene and heated and refluxed using a Dean-Stark trap. After heating and stirring for three hours, the product was cooled in air, and the reaction system was concentrated under reduced pressure. 200 mL of ethanol were added to the resulting residue, and 5 g of sodium borohydride were added while stirring under freezing conditions. After stirring over a period of one night, hydrochloric acid was added and the pH was brought to 2 or less. After filtering, the product was concentrated under reduced pressure, the resulting residue was dissolved in 200 mL THF-water, and 2 g of sodium hydroxide were added. After stirring for six hours at room temperature, the product was neutralized with Amberlite IR120B[H] and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized to obtain 8.2 g f the desired product (yield of 70%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[CH3:10].Cl[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1>CN(C=O)C>[N:30]1([CH2:29][N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:15]2[CH2:16][CH2:17][CH2:18][N:14]2[S:11]([C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([Cl:3])[CH:5]=2)(=[O:13])=[O:12])=[O:20])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)Nc2ccccc2)cc1Cl
Reactant: ClCn1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)N(Cn2nnc3ccccc32)c2ccccc2)cc1Cl
Reaction time: 1 h
Yield: 42.8 %

Procedure:
Under inert atmosphere, to a stirred solution of NaH (12 mg, 0.31 mmol) in 0.20 ml anhydrous DMF at 0° C., was added a solution of parent compound 1-((3-chloro-4-methylphenyl)sulfonyl)-N-phenylpyrrolidine-2-carboxamide (0.040 g, 0.11 mmol) in 0.60 ml anhydrous DMF. After 1 h at 0° C., a solution of 1-(chloromethyl)-1H-benzotriazole (0.052 g, 0.31 mmol) in 0.50 ml anhydrous DMF was added to the reaction mixture. This mixture was stirred for 16 h, and then solvent was completely removed. The crude was chromatographically purified over SiO2 using Hexane/AcOEt as the eluant, yielding 0.024 g (46%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:42][CH2:43][CH2:44][CH3:45]>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][CH:13]([C:14]([N:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCNCCCCC
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CCCCCN(CCCCC)C(=O)C(Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 53.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and dipentylamine (46 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (64 mg). 1H-NMR (400 MHz, CD3OD) δ 0.90 (m, 6H) 1.14-1.53 (m, 21H) 2.65-2.82 (m, 1H) 2.86-3.38 (m, 7H) 4.30 (m, 1H) 4.80 (d, 2H) 4.94 (m, 1H) 7.02 (m, 1H) 7.21 (m, 5H) 7.35-7.35 (dd, 1H) 7.76 (dd, 1H); HRMS m/z 669.3634 (calc. of monoisotopic mass for C36H51N3O9 gives 669.3625); mp 87-90° C.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH2:23])[CH3:22]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:23][CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNC(CC)C(=O)Nc1ncc(Cc2ccccc2Cl)s1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing ethylamine (2 M in tetrahydrofuran, 1.00 mL, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (19 mg, 0.056, 56%). ESI-MS m/z calc. 337.1. found 338.0 (M+1)+ Retention time 2.08 minutes.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)[NH2:3].C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:35])[C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=O)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=2)[N:2]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[N:3]=1)=[O:35])[CH3:20]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C)c1
Reactant: COc1ccc(NN)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(C)c2)n(-c2ccc(OC)nc2)n1

Procedure:
5-Hydrazino-2-methoxypyridine hydrochloride (0.380 g) obtained from Referential Example 1 and triethylamine (0.30 mL) were added to a solution of the above-obtained 4-(3-methylphenyl)-2,4-dioxobutanoic acid ethyl ester (1.014 g) dissolved in ethanol (20 mL) at room temperature. The resultant mixture was refluxed under heat for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure, and the residue was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate: 20%), to thereby give the title compound as an oily substance (0.451 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]([CH3:37])[C@@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.[NH3:47]>>[NH2:47][C:34](=[O:35])[C@H:32]([N:31]([CH3:37])[C:29](=[O:30])[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:45][CH3:46])([CH3:44])[CH3:43])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH3:33]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@H](C)C(=O)O)c1)C(F)(F)F
Reactant: N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@H](C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 14 from N-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-N-methyl-D-alanine and ammonia.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O)#[N:2].C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][N:27]=[N+:28]=[N-:29])#[N:2]
Reactant: COc1ccc(C#N)c(CO)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C#N)c(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-cyano-5-methoxybenzyl alcohol (1.8 g, 11 mmol) in THF (50 mL) was cooled to 0° C. and then treated sequentially with diphenylphosphoryl azide (2.8 mL, 13 mmol) and DBU 1.9 mL, 13 mmol), the former added in one portion and the latter dropwise. The reaction mixture was allowed to warm gradually to room temperature and to then stir there overnight. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with dilute citric acid, then brine and dried (Na2SO4). The solvent was removed in vacuo and the residue purified by column chromatography eluting with 4:1:1 hexane/chloroform/ethyl acetate to give the product as a yellow oil: 1H NMR (CDCl3) δ7.62 (d, J=8.6 Hz, 1H), 7.02 (d, J=2.6 Hz, 1H), 6.92 (dd, J=2.6, 8.6 Hz, 1H), 4.59 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH2:4][CH2:3][OH:2])[CH3:6])=[CH:15][CH:14]=2)=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: COCCC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 0.85 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmol) and triethylamine (258 mg, 2.55 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (130 mg, 0.85 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (47 mg, 17%). LRMS (M+H+) m/z: calcd 324.19 found 324. 1H. NMR (300 MHz, CD3OD): δ 12.96 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.95 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.20-3.14 (m, 5H), 2.93 (q, J=7.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7][C:8]#[N:9])C.[CH2:17](N)[CH2:18][NH2:19]>>[C:10]1([C:6]2[CH:7]=[C:8]3[NH:9][CH2:17][CH2:18][N:19]3[C:4](=[O:16])[CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=CC#N)c1ccccc1
Reactant: NCCN
Product: O=c1cc(-c2ccccc2)cc2n1CCN2
Temperature: 160 °C

Procedure:
4-Cyano-3-phenyl-but-3-enoic acid ethyl ester (crude, 9.37 g, 0.043 mol), ethylenediamine (3 mL, 0.043 mol) were mixed in dichlorobenze (20 mL) and heated at 160° C. overnight. The resulting suspension was cooled to room temperature, filtered, and the filtrated cake was washed with EtOAc and finally dried to provide the title compound as a brownish yellow solid. MS m/e 213 (M+H)+.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[N:10]1.C(N(C(C)C)C(C)C)C>C(O)C>[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)=[N:10]1
Reactant: O=C1NC(=S)CS1
Reactant: NCc1ccon1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccon2)CS1
Yield: 49.5 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (700 mg) in ethanol (20 mL) were added (isoxazol-3-ylmethyl)amine hydrochloride (707 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.42 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (513 mg).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[F:40]C1C=CC=C(OC)C=1B(O)O>CCCCCCC.CCOC(C)=O>[F:40][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([O:38][CH3:39])[C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16]
Reactant: COc1cccc(F)c1B(O)O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to Example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-fluoro-6-methoxyphenylboronic acid (CAS RN 78495-63-3) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (65%). MS (ESI): m/z=233.109 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=O.[NH2:33][OH:34]>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4](=[N:33][OH:34])[C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1
Reactant: NO
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccccc3F)cc2)cc1)C(=O)O
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccccc3F)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 10, (0.01 mmol, 1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with ethyl acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H22FNO5 [M+H]+: 448.2, [M−H]−: 446.2.
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH2:18])=[CH:13][CH:12]=1.C(O)(=O)C>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([NH:18][CH:2]=[C:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Reactant: N#CCC(C#N)C=O
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Product: N#CCC(C#N)=CNC(c1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of formyl succinonitrile potassium salt (7.26 g, 49.7 mmol) and 1-(4-fluorophenyl)-1-phenylmethaneamine (11.0 g, 54.7 mmol) in water-(20 ml) was added acetic acid (20 ml) at room temperature, the mixture was stirred at 100° C. for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was poured into iced water, made basic by adding potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.Cl.[CH3:10][NH:11][O:12][CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of thiophene-2-carboxylic acid (2 g, 15.6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.6 mmol), EDCI (3.1 g, 15.6 mmol), HOBT (2.4 g, 15.6 mmol), Et3N (6.5 mL, 46.8 mmol) in DCM (30 mL) was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and purified by column to give N-methoxy-N-methylthiophene-2-carboxamide (1.8 g, yield 67%) as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][C:7]=1[CH3:26])([OH:5])[CH3:4].C1C(=O)N([Cl:34])C(=O)C1>CN(C)C=O.CO>[Cl:34][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[C:7]([CH3:26])[CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-methylbenzamide (40 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.57 mL) to give a light yellow solution. NCS (14 mg, 0.10 mmol) was then added at room temperature. The mixture was heated mixture at 60° C.; after 3 hr, another 15 mg of NCS was added, and the reaction completed after 1 hr. The mixture was diluted with MeOH (1 ml) and then purified by preparatory HPLC (basic mode, 20-70% ACN in water). Product-containing fractions were combined, concentrated and freeze-dried to obtain the title compound as a tan colored solid (10 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.20 Hz, 3H) 1.48 (s, 3H) 2.58 (s, 3H) 3.58-3.64 (m, 2H) 4.19 (q, J=7.24 Hz, 2H) 4.77 (br. s., 1H) 4.92 (br. s., 1H) 7.55 (d, J=8.34 Hz, 1H) 7.68 (s, 1H) 7.76-7.88 (m, 2H) 8.36 (d, J=0.76 Hz, 1H) 8.59 (d, J=1.01 Hz, 1H) 10.58 (s, 1H); ESI-MS: m/z 388 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:20][NH:19][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:22][CH:21]=1
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NNC(=O)c2ccc(Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from a mixture 2,4-dimethylphenylisocyanate (50 mg, 34 mmol) and 4-chlorobenzoic acid hydrazide (63 mg, 37 mmol) in methylenedichloride (10 ml). The mixture was stirred at room temperature for 2 h and the resultant precipitate was collected by filtration and isolated as pale white solid (90 mg, 89%). 1H NMR (DMSO-d6): 10.39 (s, 1H), 8.34 (s, 1H), 8.05 (s, 1H), 7.94 (d, J=6.6 Hz, 1H), 7.57 (d, J=6.6 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J=7.5 Hz, 1H), 2.72 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][C:23]([CH3:24])=[O:25])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1

Procedure:
A solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (1 mmol) and acetic anhydride (10 mmol) in anhydrous pyridine (1 ml) is kept at 0°-5° C. for 3 days. The solution is concentrated under vacuum, diluted with ethyl acetate, washed with water, pH 2 buffer, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to give benzyl 6-azido-3-acetoxyl-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.