Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27](Br)[N:28]=1)[CH2:18]2.C(O)C>C1(C)C=CC=CC=1>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:28]=1)[CH2:18]2
Reactant: Brc1csc(CN2CC3CC3C2)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2csc(CN3CC4CC4C3)n2)cc1
Temperature: 97.5 °C
Yield: 79.8 %

Procedure:
(4-chlorophenyl) boronic acid (0.34 g, 2.17 mmol) and potassium carbonate (0.63 g, 4.53 mmol) were added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4-bromothiazole (Step-1 of compound 102, 0.47 g, 1.81 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.10 g, 0.09 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.42 g, 79.0%). MS: m/z 291 (M+1).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]2[C:9]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[O:10][CH2:11][C:5]=2[CH:4]=1)=O.CO.CC([O-])=O.[Na+].[NH2:29][OH:30].Cl>O>[OH:30][N:29]=[CH:1][C:3]1[N:8]=[CH:7][C:6]2[C:9]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:12]3)[O:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ncc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a stirred solution of tert-butyl 6′-formyl-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-carboxylate (0.15 g, 0.52 mmol, 1 eq.) in mixture of methanol (4.0 mL):water (4.0 mL) was added NaOAc (85 mg, 1.03 mmol, 2 eq.) followed by addition of NH2OH.HCl (72 mg, 1.03 mmol, 2 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption starting material, reaction mixture was concentrated under reduced pressure; resulting residue was diluted with water (5.0 mL) and extracted by ethyl acetate (3×20 mL). Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford title compound as brown solid (0.15 g, 95%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.16 (d, J=9.64 Hz, 2H), 4.34 (d, J=9.6 Hz, 2H), 5.10 (s, 2H), 7.67 (s, 1H), 8.27 (s, 1H), 8.72 (s, 1H). LC-MS (m/z): 306.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(Cl)ccc3c2C1
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccc(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 7-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.2 g, 5.0 mmol) in DMF (10 mL) and stirred for 5 min. NaH (60% in hexane) (654 mg, 16 mmol) was added and the mixture stirred at RT for 10 min. Then 4-(2-methyloxiran-2-yl)pyridine (1.35 g, 10 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1HNMR (DMSO, HCl salt) d (ppm): 8.70 (d, 2H), 7.95 (d, 2H), 7.50 (m, 1H), 7.40 (m, 1H), 7.0 (t, 1H), 6.10 (m, 1H), 4.60 (m, 1H), 4.42-4.20 (m, 3H), 3.30 (m, 3H), 2.90 (s, 3H), 1.60 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C:11]3[N:15]=[CH:16][C:17](I)=[CH:18][C:10]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:17]2[CH:16]=[N:15][C:11]3[NH:12][CH2:13][CH2:14][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[C:10]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ncccc1CN1CCNc2ncc(I)cc21
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cccnc2Cl)CCN3)cc1

Procedure:
1-(2-Chloropyridin-3-ylmethyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (389 mg) was reacted with (4-ethoxycarbonylphenyl) boronic acid as in General Procedure 4B to give the title compound as a yellow solid. LCMS: m/z=409.34 (M+H+).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH2:13][C:14]1[C:15]([Cl:29])=[N:16][C:17]([Cl:28])=[CH:18][C:19]=1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH3:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](=O)[CH3:38])[CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[Cl:29][C:15]1[C:14]([N:13]=[C:37]([C@H:34]2[CH2:35][CH2:36][C@H:31]([CH3:30])[CH2:32][CH2:33]2)[CH3:38])=[C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:18]=[C:17]([Cl:28])[N:16]=1
Reactant: CC(=O)[C@H]1CC[C@H](C)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=Nc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
p-TsOH.H2O (3.4 g, 0.018 mol) was added to a mixture of tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate (85 g, 0.306 mol) and 1-(trans-4-methylcyclohexyl)ethanone (64 g, 0.46 mol) in toluene (1.3 L). The mixture was heated to reflux with a Dean-Stark trap for 14 h. TLC (petroleum/ethyl acetate=5:1) showed about ⅔ of tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate was consumed. The solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether) to give crude tert-butyl (2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethylidene)amino)pyridin-4-yl)carbamate.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23]N[CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CC[O:30]CC1>>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:20][CH2:21][O:30][CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCOCC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using morpholine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.01 (4H, brm), 3.78 (4H, brm), 7.12 (1H, dt, J=7.56, 7.33 Hz), 7.23 (1H, d, J=9.28 Hz), 7.45 (2H, dd, J=8.54, 7.32 Hz), 7.88 (1H, d, J=9.53 Hz), 8.21 (2H, dd, J=8.55, 1.22 Hz), 8.57 (1H, s). m/z 348.4 (MH+).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>C(O)C.O.[Fe]>[OH:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(SCCCO)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(SCCCO)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Iron powder (330 mg) and conc. hydrochloric acid (0.3 ml) were added to a solution of 1-(3-hydroxypropylthio)-4-nitrobenzene (Method 82; 1 g, 4.69 mmol) in ethanol (6 ml) and water (3 ml). The mixture was stirred and heated at 90° C. for 3 hours, further iron powder (300 mg) and conc. HCl (0.2 ml) were added and heating continued for a further 2 hours. The volatiles were removed by evaporation and water (20 ml) added to the residue. The mixture was acidified to pH 1 with 2M hydrochloric acid, filtered through diatomaceous earth, and the filtrate washed with EtOAc (2×25 ml). The aqueous layer was basified to pH11 with conc. aqueous sodium hydroxide solution and extracted with EtOAc (2×25 ml). The extracts were combined, washed with brine (15 ml), dried and evaporated under reduced pressure to give the title compound (900 mg, 100%). m/z 184.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[Br:10][CH:11](Br)[CH3:12]>CN(C=O)C>[Br:10][CH2:11][CH2:12][N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9]
Reactant: CC(Br)Br
Reactant: O=C1CSC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 392.2 %

Procedure:
To a 50 ml 3-neck flask, NaH (60% in mineral oil) (0.614 g, 25.6 mmole) was taken in DMF (20 mL) under N2 atmosphere and cooled to 0° C. To this, thiazolidine-2,4-dione (2.0 g, 1.707 mmole) followed by dibromoethane (1.61 mL, 18.78 mmole) were added at 0° C. and the reaction mixture was stirred at room temperature for 2 hrs. After completion of the reaction, ice was added to the reaction mixture and product was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4 and evaporated to get the crude product which was subjected for the column purification. The crude compound was purified using column purification using 60-120 mesh size neutral silica by eluting the compound with 20-25% EtOAc in hexanes to yield 1.5 g of 3-(2-bromoethyl)thiazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)[C:20](=[O:21])[NH:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1CO
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(-c2cc3ccc(Cl)cc3[nH]c2=O)cc1

Procedure:
2-Amino-4-chlorobenzyl alcohol (4 g, 25.3 mol) and 4-methoxyphenyl acetic acid (14.0 g, 76.4 mmol) were reacted in a similar manner to that described in Example 19 to give 7-chloro-3-(4-methoxyphenyl)-2(1H)-quinolone; mp 256°-257° C. (ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:15])[CH3:3].C(N(CC)CC)C.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH3:1]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)CCn1c(N)nc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nc3ccccc3n2CCN(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(N,N-Dimethylaminoethyl)-2-aminobenzimidazole (0.40 g, 1.96 mmol) was dissolved in CH2Cl2 (50 mL) and cooled to 0° C., triethylamine (2 mL) was added followed by 4-methybenzoyl chloride (0.26 g, 1.96 mmol). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for an additional 1 h. The volatiles were evaporated and then the residue was purified by column chromatography using CH2Cl2-MeOH (9.8-0.2). The oily material collected (0.2 g) was dissolved in anhydrous ethyl ether and transformed to the hydrochloride salt. MS 322 (M+1). 1H NMR (DMSO): δ 2.48 (s, 3H), 2.81 and 2.86 (2s, 6H), 3.54 (m, 2H), 4.73 (m, 2H), 35 7.34 (m, 4H), 7.52 (2m, 2H), 8.14 (d, 2H), 10.79 (broad s, NH).
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](OC)=[O:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1COCC1>ClCCl>[CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:27])([F:28])[F:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A 25-mL round bottom flask was charged with methyl 2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.069 g, 0.17 mmol) and dichloromethane (6 mL) at 0° C. A 1M solution of DIBAL-H in THF (0.70 mL, 0.70 mmol) was added and the resulting solution was stirred at 0° C. for 1 h until the starting material was consumed (monitored by LCMS analysis). The reaction was quenched with methanol then absorbed onto silica (2 g) and concentrated under reduced pressure. Purification by column chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as the eluent afforded the title compound (0.055 g, 87%) as a white solid. MW=366.38. M.p. 48-50° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.51 (s, 1H), 7.23 (d, J=7.5 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 5.38-5.32 (m, 1H), 4.58 (t, J=5.5 Hz, 1H), 4.09 (s, 2H), 3.56 (q, J=6.0 Hz, 2H), 2.68 (t, J=7.0 Hz, 2H), 2.00-1.89 (m, 2H), 1.77-1.66 (m, 4H), 1.66-1.55 (m, 2H); APCI MS m/z 367 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]2[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:35]=2[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][C:36]5[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:35]=5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nn(C)c2c1CN(CCCCl)CC2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCc2c(c(C)nn2C)C1
Temperature: 80 °C
Yield: 244.6 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.50 g, 0.16 mmol, 1.0 eq) and K2CO3 (0.05 g, 0.32 mmol, 2.0 eq) in 20 mL of DMF was added 5-(3-chloropropyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.05 g, 0.19 mmol, 1.2 eq) at room temperature. The reaction mixture was heated at 80° C. for 8.0 h and concentrated in vacuo. The residue was poured into a mixture of water (100 mL) and CH2Cl2 (150 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a yellow solid (0.20 g, 24.98%), HPLC: 95.21%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 513.02 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.91-2.08 (m, J=4.0 Hz 2H), 2.51 (s, 3H), 2.78 (s, 3H), 2.79-2.89 (m, 6H), 2.90-2.96 (m, 2H), 3.95 (s, 3H), 4.19 (m, 2H), 7.25 (s, 1H), 7.47 (t, J=8.12 Hz, 1H), 7.54 (s, 2H), 8.11 (t, J=5.16 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: N([O-])=[O:2].[Na+].[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21](N)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>S(=O)(=O)(O)O.C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21]([OH:2])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1

Procedure:
Sodium nitrite (1.84 g, 26.7 mmol) was dissolved in 32 ml of concentrated sulfuric acid at 0° C. Then, 6-(4-benzyloxyphenoxy)pyridin-3-ylamine (7.1 g, 24.29 mmol) in 75 ml of acetic acid were slowly added dropwise. After 1 h the ice bath was removed and stirring was continued for an hour. The reaction mixture was added dropwise to 250 ml of boiling water, and the mixture was stirred for 1 hour and after cooling extracted with ethyl acetate. The precipitated solid was filtered off and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 269 mg (4%), M+H+: 294.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:38][CH2:37][CH2:35][OH:36])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.36 (t, J=5.7 Hz, 1 H), 8.53 (s, 1 H), 7.41 (s, 1 H), 7.18 (dd, J=8.3, 5.5 Hz, 2 H), 7.03 (t, J=8.6 Hz, 2 H), 4.16-4.11 (m, 4 H), 3.85 (t, J=5.0 Hz, 2 H), 3.63 (m, 2 H), 3.38-3.33 (m, 4 H), 2.40 (t, J=8.0 Hz, 2 H), 2.03 (m, 2 H), 1.82 (m, 2 H); HRMS C25H27FN4O5 (M+H)+ calcd 483.2044, found 483.2046.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][C:14]([O-])(C)C.[K+].C(Br)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:13][CH3:14])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCN1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of ethyl bromide (724 mg, 6.64 mmol) in 10 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 1/1, Rf=0.52) gave 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (583 mg, 2.29 mmol, 59%) as a colorless solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C>O1CCCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc(OC2C=CCCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: OCc1ccc(OC2C=CCCC2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
4-(Cyclohex-2-enyloxy)benzoic acid (25 g, 115 mmol) was dissolved in 250 mL dry tetrahydrofuran and cooled to -10° C. under an atmosphere of dry nitrogen. N-Methylmorpholine (12.6 mL, 115 mmol) and isobutylchloroformate (15.9 mL, 115 mmol) were added. After 10 minutes at -10° C., the mixture was warmed to room temperature and filtered. The volume was reduced to 50 mL under reduced pressure before cooling to 0° C. and adding diisobutylaluminum hydride (1.5M in toluene, 160 mL) over 10 minutes. After 30 minutes, the reaction was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was cooled in an ice bath, diluted with ether, quenched with methanol, and poured into cold Rochelle's salt solution. The crude product was extracted with ether, dried over Na2SO4, and concentrated in vacuo. The residue obtained was chromatographed eluting with 20% ethyl acetate in hexane to give 4.24 g (18%) of the title alcohol.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[F:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1C1C=CC(O)=C(C(O)=O)C=1>>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][C:37]([C:48]2[CH:47]=[CH:46][C:45]([F:44])=[CH:50][C:49]=2[F:51])=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCC

Procedure:
Ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C43H53F2NO5=701.88. found: [M+H]+=702.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:37][CH:38]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(Oc3ccccc3)nc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(Oc3ccccc3)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 48.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42 g) and (4-isopropylphenyl)[(6-phenoxypyridin-3-yl)methyl]amine (0.47 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.
Reaction SMILES: C(O[C:10]1[C:18]2[CH:17]=[C:16]([C:19](=[O:21])[CH3:20])[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-:23].[K+].[K+].[OH-].[Na+]>O1CCCC1>[OH:23][C:11]1[CH:12]=[CH:13][C:14]2[S:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][C:18]=2[CH:10]=1
Reactant: CC(=O)c1cc2c(OC(=O)c3ccccc3)cccc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1cc2cc(O)ccc2s1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 2-acetylbenzo[b]thiophen-4-yl benzoate (0.13 g), potassium carbonate (0.18 g), tetrahydrofuran (25 ml) and 5M aqueous sodium hydroxide solution (10 ml) was heated under reflux for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The aqueous residue was acidified by the addition of 5M hydrochloric acid (20 ml), then the product was extracted into dichloromethane (2×25 ml). The combined extracts were washed with water (20 ml), 10% aqueous sodium hydrogencarbonate solution (3×20 ml) and water (2×20 ml), then dried (MgSO4) and the solvent was removed in vacuo to give 1-(5-hydroxybenzo[b]thiophen-2-yl]ethan-1-one (0.07 g) as a yellow solid which was used without further purification.