Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])C.[ClH:23].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[OH:34])[CH2:28][CH2:29][NH2:30].C(O)CCC>O>[ClH:23].[CH2:13]([O:12][C:10]([N:6]([CH2:5][CH:4]1[C:26]2[C:27](=[CH:31][CH:32]=[C:33]([OH:34])[C:25]=2[OH:24])[CH2:28][CH2:29][NH:30]1)[CH:7]([CH3:8])[CH3:9])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)C(C)C)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(C)N(CC1NCCc2ccc(O)c(O)c21)C(=O)OCc1ccccc1
Yield: 16.6 %

Procedure:
N-benzyloxycarbonyl-N-isopropylaminoacetaldehyde diethyl acetal (9 g) and 3,4-dihydroxyphenethylamine hydrochloride (4.5 g) were added to a mixture of n-butyl alcohol (100 ml) and water (15 ml) and then the mixture was refluxed for 6 hours. The above-mentioned acetal (2 g) was added thereto and the resultant mixture was refluxed for 1.5 hours. The solvent was distilled off from the reaction mixture. To the residue was added a mixed solvent of isopropyl alcohol, methanol and ether. The crystals obtained were recrystallized from the same mixed solvent to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.6 g), mp 200° to 205° C. (dec). The mother liquor was concentrated and allowed to stand to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.4 g), colorless crystals, mp 207° to 210° C. (dec).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:8]([C:7]1[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1-n1cccn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and powdered potassium carbonate (2 g) in DMF (10 mL) was stirred vigorously at room temperature for 4 days. The mixture was diluted with water, causing precipitation of a solid, which was filtered and dried, affording 670 mg (63%) of 3-nitro-2-(pyrazol-1-yl)pyridine. 1 H NMR (CDCl3) δ 6.51 (m, 1), 7.37 (dd, 1 J=5, 8), 7.76 (m, 1) 8.03 (dd, 1, J=2, 8), 8.40 (m, 1), 8.60 (dd, 1, J=2, 5).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNCc2ccccc2)cc1

Procedure:
According to scheme 6, tyramine (1) is reacted with benzaldehyde under reductive amination conditions to yield 4-(2-benzylamino-ethyl)-phenol (28). The amine 28 is protected as the t-butyl carbamate (29). The carbamate 29 is reacted with 4-fluoronitrobenzene under basic reaction conditions (as shown or known modifications thereof) to afford the coupled product 30. The coupled product 30 is then reduced at the nitro group utilizing catalytic hydrogenation (palladium on carbon) to afford {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (31). The resulting amine 31 may be acylated with one of various acid chlorides to form the desired reverse amide compound 32. The Boc protecting group is removed with TFA in dichloromethane to afford compound 33, a compound of the invention.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[OH-:31].[K+].Cl>C(O)(C)(C)C.O>[OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:14])=[O:31])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(N)=O)ccc32)cc1

Procedure:
0.18 g (0.44 mmol) 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile (Example 15A) is dissolved in 15 ml tert-butanol, mixed with 0.23 g (3.6 mmol) pulverized, 88% potassium hydroxide and heated under reflux for 11 h. Having cooled down, the mixture is hydrolyzed in water and acidified with 1N hydrochloric acid. Three extractions with diethyl ether, concentration to half the volume on the rotary evaporator, washing with water and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 1:1) and yields the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][F:15])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:14][CH2:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FCCNc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
In a round bottom flask 4-fluoroaniline (1.3 g, 11.6 mmol, 1.6 mL) 2,6-lutidine (1.24 g, 11.6 mmol) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (2.5 g, 11.6 mmol) were combined in DMF (5 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (100 mL). This was washed with water (3×40 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10% B, 100 g, 12 CV, 60 mL/min) to afford 383 mg (20%) of (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.30-3.35 (1H, m, NCH2CH2F), 3.40-3.45 (1H, m, NCH2CH2F), 3.90 (1H, s, br, NH), 4.53 (1H, t, J=3 Hz, NCH2CH2F), 4.69 (1H, t, J=3 Hz, NCH2CH2F), 6.51-6.72 (2H, m, 2×NCCH), 6.85-7.05 (2H, m, 2×NCCHCH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:24][C:22]1[CH:21]=[CH:20][C:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=3[NH:13][C:14]=2[CH:23]=1
Reactant: COC(=O)Cc1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of Example 695C (0.3 g, 0.91 mmol) and TsOH.H2O (0.35 g, 1.82 mmol) in toluene (50 mL) was heated to reflux for 20 hours using a Dean-Stark trap to remove water. The reaction was cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.21 g (81%) of the desired product. MS (DCI) m/e 317 (M+H)+, 334 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.03 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.91-6.93 (m, 2H), 6.86-6.87 (m, 2H), 3.60 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: Br.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH2:10]([O:9][N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][S:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[CH:34]=[CH:35][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)(=[O:31])=[O:32])[C:4]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1CCCN(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br
Solvent: O
Solvent: ClCCl
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of (R)-3-amino-1-benzyloxy-piperidin-2-one hydrogen bromide salt (0.086 g, 0.29 mmol) (synthesized according to Miller's procedure J. Org. Chem. 2002, 67, 4759) and 4-(4-chloro-phenoxy)-benzenesulfonyl chloride (0.095 g, 0.31 mmol) in dry CH2Cl2 (3 mL) was treated with TEA (0.12 mL, 0.86 mmol) under N2. The reaction mixture was stirred at room temperature for 6 h and diluted with CH2Cl2 and water. After the usual work-up, the crude material was purified by chromatography (silica gel, 35% EtOAc/hexanes) to give the desired product, (R)—N-(1-Benzyloxy-2-oxo-piperidin-3-yl)-4-(4-chloro-phenoxy)-benzene-sulfonamide. MS (EI) 487 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][OH:43].N1C=CC=CC=1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19](=[N:42][OH:43])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=NO)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
Compound 13 (10 mg, 0.018 mmol) and hydroxylamine hydrochloride (50 eqv., 0.92 mmol, 64 mg) were dissolved in 2 mL of EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45° C. for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to yield 6 mg of a white solid (58% yield; mixture of isomers). Expected mass=555. Observed mass=556.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[OH:39].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:49][CH2:48][O:47]1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:9]=2)=[CH:4][C:3]=1[O:39][CH2:49][CH2:48][OH:47]
Reactant: O=C1OCCO1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(O)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(OCCO)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-fluoro-3-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 7AU (1.25 g, 2.42 mmol), K2CO3 (402 mg, 2.91 mmol) and ethylene carbonate (2.6 mL, 24.00 mmol) in DMF (10 mL) was stirred in a sealed tube at 160° C. for 4 h and cooled to rt. H2O was added to quench the reaction. The resulting mixture was extracted with EtOAc, which was washed with H2O, brine, dried (MgSO4) and concentrated to give a yellow oil. Chromatograph on silica gel (4:1, hexanes/EtOAc) gave 3-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 14AX (1.4 g) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=S)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12].[OH2:35]>CO.[Hg]=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:35])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12]
Reactant: O=C(NCCc1ccc(S(=O)(=O)NC(=S)NC2CCCCC2)cc1)N1Cc2ccccc2C1=O
Reactant: O
Agent: O=[Hg]
Solvent: CO
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reaction time: 3 h

Procedure:
0.3 g of mercury oxide is added to 0.3 g of N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-thiourea (melting point 194°-196° C., prepared from 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonamide and cyclohexyl mustard oil) in a mixture of 50 ml of water and 50 ml of methanol and the whole is stirred for 3 hours at 40°-45° C. The precipitated mercury sulfide is filtered off with suction, the filtrate is concentrated under reduced pressure, the residue is treated with very dilute ammonia, filtered and the filtrate is acidified with dilute hydrochloric acid. The precipitated N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-2,5-cyclohexyl-urea is recrystallized from dilute acetone and melts at 211°-213° C. The mixed melting point with the compound obtained according to Example 1 is without depression.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C>[N:14]([C:3]1[C:4](=[O:13])[N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:8])[NH:7][C:2]=1[NH2:1])=[O:15]
Reactant: CCCCn1c(=O)cc(N)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 70 °C

Procedure:
A mixture of 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (4.0 g, 21.8 mmol) and aqueous acetic acid (120 ml) was heated at 70° C. until complete solution as attained, and the solution was cooled to 30° C. Sodium nitrite (3 g) was added in small portions while stirring, forming an orange precipitate. The reaction mixture was cooled to 0° C., and the precipitate filtered off, washed with water, and dried under reduced pressure, to provide 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, which was used in the next reaction with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([CH2:36][C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=3)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A suspension of 6.9 g (30 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 12.6 ml (90 mmol) of triethylamine, and 300 ml of dichloromethane is stirred at 0°-5° and 12 ml (94.5 mmol) of chlorotrimethylsilane is added. The reaction mixture is stirred at room for 1 hr and is cooled with a dry ice-acetone bath and 4.6 ml (35 mmol) of phenylacetyl chloride is added. The solution is stirred overnight while warming to room temperature. The dichloromethane is evaporated and water is added. The solid is filtered, washed with water and ether, and dried to give 7.0 g of 6-[4-(phenylacetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>280° after crystallization from 100 ml of N,N-dimethylacetamide.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=O)([CH3:6])[C:3]#[C:4][CH3:5].[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:19]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][CH2:12][C:11]2[CH:14]=[C:7]([C:2]([CH3:6])([CH3:1])[C:3]#[C:4][CH3:5])[CH:8]=[CH:9][C:10]=2[O:15][CH3:16])[C@@H:19]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC#CC(C)(C)c1ccc(OC)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 55 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:26])=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:26])=[CH:22]/[C:23]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: C/C(=C\C(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C/C(=C\C(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To (E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoic acid (C28) (1.14 g, 2.93 mmol) in isopropanol (9.8 mL) was added triethylamine (0.53 mL, 3.81 mmol) and diphenyl phosphorazidate (0.68 mL, 3.23 mmol). The reaction was stirred at room temperature overnight. The white precipitate was vacuum-filtered and dried in a vacuum oven to afford the title compound as a white solid (0.978 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.19 (m, 2H), 7.85-7.78 (m, 2H), 7.65-7.58 (m, 2H), 7.44-7.37 (m, 2H), 6.16 (d, J=1.3 Hz, 1H), 2.68 (d, J=1.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 387 ([M+H]+) (isocyanate).
Reaction SMILES: FC1C=CC(C=NO)=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:14][CH:13]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I>C1COCC1.O>[Cl:36][CH2:37][CH2:38][CH2:39][CH:24]1[C:23](=[O:27])[C:22]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)=[N:19][O:20][C:21]=2[CH2:26][CH2:25]1
Reactant: O=C1CCCc2onc(-c3ccc(F)cc3)c21
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: ON=Cc1ccc(F)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(-c3ccc(F)cc3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 4-fluorobenzaldehyde oxime, the starting ketone is prepared. In 170 ml anhydrous THF was dissolved 4.0 g 6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 17.3 ml lithium diisopropylamide (1.50 molar in cyclohexane) was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 2.2 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and the layers were then separated. The aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 4.2 g of 5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:43].[Na+].C(=O)C>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCN(CC)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Example 290 and sodium triacetoxyborohydride in 9/1 dichloromethane/methanol was added excess acetaldehyde. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by reverse phase preparative HPLC with the AA method to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.35 Hz, 3 H) 1.09 (t, J=6.99 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.55 (m, 2 H) 3.24 (m, 3 H) 3.38 (q, J=6.99 Hz, 2 H) 6.71 (d, J=8.82 Hz, 2 H) 6.87 (d, J=8.82 Hz, 1 H) 7.26 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.88 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=1.84 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 656/658 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl>O>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:16]1
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Product: O=C(O)c1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
A mixture of 2-chloro-5-nitroisonicotinic acid (28.5 g, 141 mmol), morpholine (36.8 g, 423 mmol) and k2CO3 (58.4 g, 423 mmol) was stirred at 100° C. for 4 h. The mixture was cooled to room temperature and poured into water (1.5 L). It was acidified with 4N HCl to pH=1 and extracted with EA (1 L×3). The combined organic layers were washed with brine (1 L×5), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product as a yellow solid (27 g, 76%); LC/MS: MS (ES+) m/e 254 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.68 (t, J=4.8 Hz, 1H), 3.77 (t, J=4.8 Hz, 4H), 6.99 (s, 1H), 8.91 (s, 1H).
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 30 g (133 mmol) of benzyl 3-pyrroline-1-carboxylate in 700 mL of methylene chloride was added 57.2 g (200 mmol) of mCPBA. The reaction mixture was stirred at room temperature overnight and quenched with 250 mL of 20% NaHSO3 aqueous solution. The organic phase was separated, and the aqueous layer was extracted with methylene chloride twice (100 mL×2). The combined extracts were washed with saturated NaHCO3 aqueous solution twice (250 mL×2), brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel column with 40% EtOAc-Hexane provided the title compound (24 g, 83%). MS (M+H)+220.