Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=2[O:18][CH3:19])=[C:4]([CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[O:23][C:22]2=[O:41])[CH:3]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:50]>>[F:39][C:37]([F:38])([F:40])[C:29]1[CH:28]=[C:27]([C@H:24]2[O:23][C:22](=[O:41])[N:21]([CH2:20][C:4]3[CH:3]=[C:2]([Br:50])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=3[O:18][CH3:19])[C@H:25]2[CH3:26])[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=1
Reactant: BrC(Br)Br
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(C)(C)ON=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution (4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (526 mg, 0.90 mmol) in bromoform (2.5 mL) was added tert-butyl nitrite (186 mg, 1.80 mmol). The resulting mixture was stirred at 80° C. for 20 min. An aliquot indicated completion of the reaction. The reaction crude was purified silica gel to afford the title compound as a yellow glass. LC-MS: 650.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.85 (s, 1H), 7.69 (s, 2H), 7.60 (s, 0.5H), 7.48-7.53 (m, 1.5H), 7.07-7.11 (m, 1H), 6.93-6.99 (m, 1H), 6.62-6.67 (m, 1H), 5.59 (d, J=8.0 Hz, 0.5H), 5.39 (d, J=7.0 Hz, 0.5H), 4.82 (d, J=6.5 Hz, 0.5H), 4.75 (d, J=6.5 Hz, 0.5H), 3.98 (d, J=16.0 Hz, 0.5H), 3.76-3.85 (m, 1.5H), 3.75 (s, 1.5H), 3.74 (s, 1.5H), 3.13-3.23 (m, 1H), 1.13-1.29 (m, 6H), 0.52 (d, J=6.5 Hz, 1.5H), 0.34 (d, J=7.0 Hz, 1.5H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:19]=2)[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][N:37]=1)[N:34]([CH2:38][C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)[CH:33]=[C:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:31]2=[O:50].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][N:37]=2)[N:34]([CH2:38][C:39]2[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=2)[CH:33]=[C:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:31]3=[O:50])=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:19]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2cn(C)cn2)c2cnc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn(Cc4cn(C)cn4)c3cn2)cn1
Temperature: 90 °C
Yield: 26.1 %

Procedure:
In a microwave vessel, 6-(3-ethylureido)-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 98, 0.2 g, 0.54 mmol), ethyl 6-bromo-1-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 102, 0.21 g, 0.54 mmol) and cesium carbonate (0.229 g, 0.70 mmol) were combined and suspended in a mixture of dioxane and water (5:1; 2.5 mL/0.5 mL). The suspension was degassed and purged with nitrogen. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the mixture was degassed and purged a second time. The reaction mixture was heated in the microwave at 90° C. for 90 minutes. The reaction was partitioned between water and ethyl acetate, the layers were separated, and the organic phase was washed with saturated NaHCO3, water and brine, then dried over magnesium sulfate, and concentrated. The resulting solids were filtered, washed with acetonitrile followed by chloroform. Isolation gave 90 mg of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)[CH3:2].[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: CCc1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Yield: 17 %

Procedure:
The title compound was prepared from 4-ethyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellowish solid, 53 mg (17% yield): HRMS Calcd (found) for C12H13ClN2O2S2 m/z 316.0107 (316.0120).
Reaction SMILES: Cl.[CH3:2][NH2:3].O=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)[CH:15]=2)=[O:12])[CH2:7][CH2:6]1>C1COCC1.CO>[CH3:2][NH:3][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:31][CH2:32]4)[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]3)[CH:15]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CC1CCC(c2cccc(NC(=O)N3CCC(=O)CC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CCN(C(=O)Nc2cccc(C3(N4CCN(c5ccccc5)CC4)CCC(C)CC3)c2)CC1
Temperature: 25 °C

Procedure:
Methylamine hydrochloride (37 mg, 0.546 mmol) was added to a solution of 4-(oxo)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) (43 mg, 0.091 mmol) in THF/MeOH (1:1) and stirred at room temperature. When all the methylamine hydrochloride had dissolved, NaCNBH4 (6 mg, 0.091 mmol) was added and the reaction allowed to stir overnight at room temperature. The reaction mixture was concentrated, dissolved in an excess of 3N HCl, and the aqueous solution washed with ether (3×). The aqueous solution was made basic with 10N NaOH, extracted with EtOAc (4×), dried (Na2SO4), and concentrated to give 4-(methylamino)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)-cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) as a clear oil. The HCl salt was prepared by adding excess saturated EtOAc/HCl solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a white solid which was washed with EtOAc. mp=154-155° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[OH:23].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:16][C@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[OH:23])=[O:14])[CH:3]=1
Reactant: O=C(O)c1cc(Br)c2ccccc2n1
Reactant: N[C@H]1CCOC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-bromoquinoline-2-carboxylic acid (A3) (0.5 g, 2.0 mmol) in 10 mL CH2Cl2 was added (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrogen chloride (0.37 g, 2.4 mmol), BOP reagent (1.1 g, 2.6 mmol), and triethylamine (0.83 mL, 6.0 mmol). The reaction was stirred at room temperature for 4.5 h, diluted with CH2Cl2, washed twice with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 30-100% ethyl acetate in hexanes to afford 4-bromo-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide (O1) that gave a mass ion (ES+) of 353.2 (81Br) for M+H+.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])=[O:13]>>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18]([C:17]2[CH:16]=[C:15]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)c1ccc(NC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1

Procedure:
The entitled compound was produced according to the method of Reference Example 1 but using 4-isopropylaniline and 3-(chlorosulfonyl)benzoyl chloride as the starting materials.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[O:15]1[C:11]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:4]([O:3][CH2:2][CH3:1])=[O:5])[O:12][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCCC12OCCO2
Yield: 99.4 %

Procedure:
To ethyl 2-cyclohexanonecarboxylate (Aldrich, 169.5 g, 1.0 mol) and ethylene glycol (Sigma, 166.7 g, 2,7 mol) in benzene (1.5 L) was added pyridinium tosylate (50.2 g, 0.2 mol). The reaction was refluxed under a nitrogen atmosphere and the water generated was removed using a Dean-Stark trap. After cooling the reaction to room temperature, half of the benzene was removed under reduced pressure and the residue was washed with 25% aqueous NaHCO3, stripped of all solvent, dissolved in CH2Cl2, dried (Na2SO4), filtered, and again stripped of all solvent under reduced pressure to provide 213 g of the title material.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]3=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH2:7][CH2:6]1
Reactant: O=c1ccccn1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(n2ccccc2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(1,4-dioxaspiro[4.5]decan-8-yl)pyridin-2(1H)-one (150 mg, 0.64 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (x4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][CH:20]([S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23])[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:27][CH2:26][N:25]([S:22]([CH:20]([CH3:21])[CH3:19])(=[O:23])=[O:24])[CH2:30][CH2:29]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-(propane-2-sulfonyl)-piperazine using procedure C yielded 2-chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc2[nH]cc(-c3cc4nccnc4[nH]3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A stirred solution of 6-(5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [70 mg, Example 11] in dry dimethylformamide (10 mL) was treated with sodium hydride (21.6 mg, 60% dispersion in mineral oil). After stirring for 30 minutes this mixture was treated with a solution of 4-(2-chloroacetyl)morpholine (44.1 mg) in dimethylformamide (1 mL) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (20 mL) and then extracted three times with ethyl acetate (30 mL). The combined extracts were dried over sodium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (55 mg) as a yellow solid, m.p. 263-267° C. MS: 392.21 (MH+).
Reaction SMILES: CCOCC.[CH:6]1([Mg]Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([OH:29])=[C:19]([CH:28]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([OH:29])=[C:19]([C:20]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:21])[CH:28]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Solvent: c1ccccc1
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1C(O)(c1ccccc1)C1CCCCC1

Procedure:
295 ml of an ether solution titrating 1.23 M/liter of cyclohexyl magnesium bromide were added over 2 hours at 40°-45° C. to a solution of 5-chloro-2-hydroxy-benzophenone in 150 ml of anhydrous benzene and the ether was distilled while being replaced with benzene. The mixture was refluxed for 4 hours, was cooled and poured into a liter of ice and ammonium chloride. The mixture was extracted 3 times with 400 ml of ether and the combined ether phases were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was taken up in 250 ml of cyclohexane to obtain 15.9 g of 5-chloro-2-hydroxy-α-cyclohexyl-α-phenyl-benzene-methanol melting at 170° C.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>CC(C)=O>[CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[C:13]([C:14]=1[O:15][CH2:30][CH2:31][OH:32])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1c(OCCO)c2cccnc2n(-c2ccccc2)c1=O
Yield: 58.5 %

Procedure:
Reflux a stirred solution of 16.2 gm of 3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one and 11.4 gm of anhydrous potassium carbonate powder in 600 ml of dry acetone for 30 minutes. 95% 2-bromoethanol (10.3 gm) is added dropwise to the solution. The reaction is refluxed for 26 hours, cooled and the solvent removed by stripping. The resulting solid is dissolved in 500 ml chloroform and the chloroform solution is washed with 300 ml water, twice with 100 ml of 0.5N sodium hydroxide solution and finally with 100 ml of water. The chloroform solution is dried over magnesium sulfate, filtered and the solvent is removed to give the crude product. The crude product is triturated with warm isopropyl ether to give 10.9 gm of the 3-(n-butyl)-4-(2-hydroxyethoxy)-1-phenyl-1,8-naphthyridin-2(1H)one; which after recrystallization from acetone melts at 138°-140° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])[CH3:4].[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.O>CN(C)C=O>[NH2:30][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:7]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCCCCCCCc1ccc(CCC(C(=O)OCC)C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1ccc(CCC(N)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.8 %

Procedure:
60% Sodium hydride (0.38 g) was suspended in dry dimethylformamide (30 ml) and ethyl 2-ethoxycarbonyl-4-(4-octylphenyl)butyrate (3.0 g) was added thereto. The mixture was stirred at room temperature for 2 hours. O-(2,4-Dinitrophenyl)hydroxylamine (1.14 g) was added thereto and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into cool water and extracted with toluene. The extract was washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled away under reduced pressure to give 3 g of the subject compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([N:23]=[C:24]=[S:25])(=O)[C:16]1C=CC=CC=1>C1COCC1>[S:25]1[CH:16]=[CH:15][N:23]=[C:24]1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Yield: 94 %

Procedure:
To a solution of N-Boc-4-aminopiperidine (6.0 g) in THF (100 ml) was added benzoyl isothiocyanate (4.1 ml), and mixed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol, potassium carbonate was added thereto, and mixed at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The mixture was washed with 1 N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow solid (7.3 g, 94%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>CCO>[N+:20]([C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)([O-:22])=[O:21]
Reactant: NCC1CCOCC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
4-Aminomethyl tetrahydropyran (13.7 g, 0.119 mol) was added to a solution of N-(4-Fluoro-3-nitrophenyl)acetamide (20.2 g, 0.102 mol) and TEA (20.9 mL, 15.2 g, 0.15 mol) in EtOH (350 mL). The reaction mixture was stirred overnight at reflux. The orange-red solid was collected by filtration, washed with water and dried in vacuo. The filtrate was concentrated. The residue was dissolved in EtOAc, washed with H2O, brine and dried over anhydrous Na2SO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Total yield: 28.9 g (97%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.4 (m, 2 H), 1.7 (m, 2 H), 1.89-2.00 (m, 1 H), 2.18 (s, 3 H), 3.22 (dd, J=6.44, 5.66 Hz, 2 H), 3.42 (dt, J=11.86, 2.05 Hz, 2 H), 4.02 (dd, J=10.94, 3.71 Hz, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10-8.12 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(OCCO)C.CCOC(C)=O>[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: CN(C)CCN
Solvent: CCOCCO
Solvent: CCOC(C)=O
Product: CN(C)CCNc1ccc(I)cn1
Yield: 34.7 %

Procedure:
A stirred solution of 2-chloro-5-iodopyridine (0.50 g, 2.18 mmol) and N,N-dimethylethylenediamine (0.81 g, 1.00 mL, 9.20 mmol) in 2-ethoxyethanol (5 mL) was heated in a sealed tube under microwave irradiation at 125° C. for 1 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual oil was purified by column chromatography (SiO2, 3:1 EtOAc/MeOH) to give the title compound (0.22 g, 36%) as a viscous oil which solidified on standing. δH (CDCl3) 8.19 (1H, br. s), 7.53 (1H, m), 6.23 (1H, m), 3.29 (2H, m), 2.52 (2H, m), 2.24 (6H, s). Exchangeable proton not observed. LCMS (ES+) 292.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CC#N>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: OCCCc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cccc(CCCO)c1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-(3-hydroxypropyl)phenol (100 g) in MeCN (750 mL) was added K2CO3 (109 g) at ambient temperature. Ethyl bromoacetate (87.4 mL) was added dropwise to the mixture at 0° C. over 30 minutes, and then the mixture was stirred at ambient temperature for 20 hours and at 60° C. for 7 hours. Water (800 mL) was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc(1 L) two times. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford ethyl [3-(3-hydroxypropyl)phenoxy]acetate (121 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 78.2 %

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (5.00 g), 3-benzyloxyphenylboronic acid (4.38 g), sodium carbonate (3.70 g), water (14 mL) and N,N-dimethylformamide (70 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.01 g), and the resulting mixture was stirred at 80° C. for 14 hours. The reaction mixture was cooled to room temperature and the insoluble material was filtered out. The filtrate was partitioned between ethyl acetate (110 mL) and water (50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=6/1) to give the title compound (5.32 g).