Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-4-methyl-1-nitrobenzene (1.0 g, 6.45 mmol) in DMSO (3 mL) was purged with a stream of nitrogen prior to addition of phenylamine (1.18 mL, 12.9 mmol) and then stirred in a sealed tube at 100° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (125 mL) and water (150 mL). The organic layer was then washed with water (150 mL×3), followed by brine, then dried (Na2SO4) and concentrated in vacuo affording (5-Methyl-2-nitrophenyl)phenylamine as a red solid (1.5 g, quantitative). 1H NMR (DMSO, 400 MHz): δ 9.40 (1H, s), 8.03 (1H, d, J=8.70 Hz), 7.45-7.39 (2H, m), 7.35-7.30 (2H, m), 7.21 (1H, t, J=7.33 Hz), 6.98 (1H, s), 6.72-6.68 (1H, m), 2.24 (3H, s).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[N:24]1[N+:28]([O-])=[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=[N:25]1.S(=O)(=O)(O)O>C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[N:24]1[N:28]=[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=[N:25]1
Reactant: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reaction time: 6 h

Procedure:
Example 7 of U.S. Pat. No. 4,835,284 is duplicated. 97% sodium hydroxide (14.4 g) is added to a mixture of methanol (72 ml) and water (36 ml). 2-nitro-2'-hydroxy-5'-t-butylazobenzene (15.0 g) is then added to the resultant mixture and the mixture is heated to 45°-5020 C. Hydroquinone (0.4 g) and then glucose (5.0 g) are added to the heated mixture over 30 minutes while stirring. The mixture is further stirred for one hour. As this result, the azobenzene disappears to produce 2-(2'-hydroxy-5'-t-butylphenyl)benzotriazole-N-oxide. 9-fluorenone (0.7 g) is then added to the reaction liquor thus obtained, and the liquor is heated to 55°-60° C. Thereafter, glucose (6.0 g) is added to the reaction liquor over 30 minutes, and the reaction is conducted at 75° C. (boiling point) for 6 hours. As a result, the N-oxide disappears. Thereafter, the pH of the reaction liquor is brought to 8 with 62% sulfuric acid (19.0 g) to precipitate a crystal. The precipitated crystal is separated by filtration, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus obtaining 11.6 g of 2-(2'-hydroxy-5'-t-butylphenyl)benzotriazole. One can see that the reaction using an aromatic ketone takes over 8 hours to complete. Two catalysts are also required.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:33])[C:16]=2[CH:34]=1)=[O:11]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCN(C)CC3)cc(Cl)c1O2

Procedure:
N-Methyl piperazine (0.140 g, 0.675 mmol) was added to a solution of Example 133 (0.3 g, 1 mmol) in DMF (1 mL) and refluxed for 1.5 h. The reaction mixture was concentrated, treated with water and filtered to obtain the crude title compound, which was purified using flash chromatography (silica gel). Yield: 0.237 g, (70%); 1H NMR (DMSO-d6): δ 2.2 (s, 3H, CH3), 2.4 (s, 4H, 2CH2), 2.8 (s, 4H, 2CH2), 3.2 (s, 2H, CH2), 3.9 (s, 3H, CH3), 5.2 (s, 2H, CH2), 7.8 (s 1H, Ar), 7.9 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (ES+) 508 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]#[N:16])=[CH:7][N:8]2[CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([N:1]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:10]=3)[C:6]([C:15]#[N:16])=[CH:7]2)[CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cn(C2CCC2)c2cc(N)ccc12
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cn(C2CCC2)c2cc(N3CCOCC3)ccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 6-amino-1-cyclobutyl-3-cyanoindole (4.60 g, 21.8 mmol), bromoethylether (6.07 g, 26.16 mmol), DIEA (10.79 mL, 65.4 mmol) in DMF (100 mL) was stirred at 90° C. overnight and then poured into ice-water (1.0 L). The precipitate was filtered, washed with water, and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (5.24 g, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of p-hydroxybenzoic acid (3 g) and triethylamine (2.4 g) in dichloromethane (30 ml) were added undecanoyl chloride (4.5 g) and dimethylaminopyridine (0.2 g). The mixture was stirred at room temperature for about 20 hours. After dilute aqueous hydrochloric acid solution was added, an organic layer was separated by a funnel. After the solution was distilled to remove the solvent, the residue was washed with n-hexane and dried to obtain the titled compound (about 5 g).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(C1C=C(CCl)C2C3C(=CC(C(C)(C)C)=CC=3)CC=2C=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C=O)=CC=1)([O-])=[O:57].[OH-].[K+]>O.N1C=CC=CC=1>[C:1]1(=[O:57])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)cc(CCl)c1-2
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 33 %

Procedure:
Into a 200 ml round-bottom flask, 5.0 g of a fluorene compound (m.p. 205.5°-207.5° C.) having the following structural formula ##STR8## which had been obtained by reacting 2,7-di-t-butyl-4-chloromethylfluorene with triphenylphosphine and then condensing the reaction product with 4-nitrobenzaldehyde, was introduced together with 0.3 g of potassium hydroxide and 100 ml of pyridine. The resulting mixture was stirred at room temperature for 20 hours in an air atmosphere. After completion of the reaction, 200 ml of water was added to the reaction mixture, and the reaction product was extracted with methylene chloride. The resulting organic layer was dried with Na2SO4 and the solvent was then removed by evaporation under reduced pressure. The residue was purified with a silica gel short column (methylene chloride/hexane = 2/1). Thereafter, the solvent was removed by evaporation under reduced pressure and the residue was recrystallized from a mixture of ethyl acetate and ethanol, thereby obtaining 1.7 g (yield 33%) of a fluorenone compound having the following structural formula as a yellow powder. The melting point of this compound was 223°-224° C. ##STR9##
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]2=[O:30])[CH2:9]1)C1C=CC=CC=1.Cl.CN1C2C=CC=CC=2N(CC2OCCNC2)C1=O.[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]\[C:53]([OH:55])=[O:54]>C(O)(C)C>[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]\[C:53]([OH:55])=[O:54].[C:24]1([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]([CH2:14][CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:16]2=[O:30])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ccccc2n1-c1ccccc1
Agent: Cl
Agent: Cn1c(=O)n(CC2CNCCO2)c2ccccc21
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Product: O=c1n(CC2CNCCO2)c2ccccc2n1-c1ccccc1

Procedure:
18 g of 4-benzyl-2-(1-phenyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine are treated as in part (a) of Example 2. After evaporation of the solvent under reduced pressure, 15 g of an oily product are obtained and are dissolved in hot isopropyl alcohol. A hot solution of maleic acid in isopropanol is added. The salt precipitates slowly. 16.5 g of 2-(1-phenyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine maleate are obtained, m.p. 200° C.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]([CH3:41])[C@H:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[F:40])[NH:13][C:14]([N:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[N:21][C:20]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:19][C:18]=3[CH2:17]2)=[O:15])=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].O>CO>[F:40][C:31]1[C:32]([C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=[CH:35][C:30]=1[C@H:12]([NH:13][C:14]([N:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[N:21][C:20]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:19][C:18]=2[CH2:17]1)=[O:15])[C@H:11]([OH:10])[CH3:41]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1cccc(C(F)(F)F)c1F)[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1cccc(C(F)(F)F)c1F)[C@@H](C)O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,2R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)propan-2-yl 4-nitrobenzoate (40 mg, 0.040 mmol) in MeOH (1 mL) was added 2M K2CO3 (40 μL, 0.079 mmol) at RT. The solution was stirred at RT for 30 min. Water was added and reaction was extracted with DCM. The organic layer was concentrated and the resulting residue was purified by reverse phase column chromatography (SP4) eluting with a MeCH/H2O gradient (5 to 95% MeCN). The recovered product was further purified by SiO2 chromatography eluting with a MeOH/EtOAc (1 to 3% MeOH) to afford 0.6 mg (3.3%) of I-19: LCMS (ACPI-pos) m/z 420.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([O-:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:12]1([NH:15][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[OH:2])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COc1ccccc1C(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)c1ccccc1O
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of methylsalicylate (4.36 g, 28.69 mmol) and cyclopropylamine (1.64 g, 28.69 mmol) was heated at 80–100° C. for 3 h. An additional 0.5 equivalent of cyclopropylamine was added and the reaction mixture was kept at 70° C. for overnight. The reaction mixture was co-evaporated with toluene and the residue was purified by silica gel flash chromatography to give the subtitle compound (2.71 g).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:44]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 3 h

Procedure:
A solution of 10.99 g of isoamyl nitrite in 10 ml of acetonitrile was added to a mixture of 15.46 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(ethoxycarbonyl)methoxypyridine, 6.19 g of copper(I) chloride, 12.61 g of copper(II) chloride and 120 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 3 hours. This reaction solution was poured into a mixture of ice and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 13.16 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy)-2-(ethoxycarbonyl)methoxypyridine [present compound 7-8].
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[CH2:12]([NH:19][C:5]1[N:4]([CH3:11])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 80.6 %

Procedure:
2 g (7.02 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 11 g (0.1 mole) of benzylamine in 50 ml ethanol for 10 hours at boiling temperature. After cooling, the reaction mixture is poured on 100 ml water, the separated product is filtered and washed with water (20 ml). After vacuum drying, 1.76 g (81 percent of theory) of 5-benzylamino-3-bromo-1-methyl-4-nitropyrazole are obtained in the form of yellow needles with a melting point of 133° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS(OO[CH2:29][CH2:30][CH:31]([F:40])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:29][CH2:30][C@H:31]([F:40])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(F)CCOOS(C)(=O)=O
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCC[C@H](F)CCCCCCCC)cc2)nc1
Yield: 19.5 %

Procedure:
The titled compound was synthesized from 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine and 3-fluoroundecyloxy methanesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]2[NH:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(C(NCCOC3C=CC=CC=3)=C([N+]([O-])=O)C=N2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Agent: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Product: CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Yield: 77.2 %

Procedure:
The general method described in Part B of Example 46 was followed using N-(6-benzyloxy-3-nitroquinolin-4-yl)-N-methylamine (11.36 g, 36.7 mmol) in lieu of (7-benzyloxy-3-nitroquinolin-4-yl)-(2-phenoxyethyl)amine. 6-Benzyloxy-N4-methylquinoline-3,4-diamine (7.91 g) was obtained as a dark yellow oil and used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:18].[Na+].OO>C1COCC1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]2[OH:18])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Reactant: [OH-]
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(c2ccc(Cl)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4-chlorophenyl)-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine (654 mg, 2.407 mmol) was dissolved in THF (4.81 mL). Borane-THF complex (2.407 mL, 2.407 mmol) was added dropwise via syringe and the reaction was stirred 72 h at rt. Then sodium hydroxide (1.5 mL, 4.50 mmol) and hydrogen peroxide (1.2 mL, 11.75 mmol, 30% solution) were added. The reaction was stirred 2 h at rt, then diluted with saturated Na2S2O3 and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 25 g column by eluting with 20% to 100% EtOAc:Hexane to provide the desired product. LC-MS: calculated for C12H16ClNO3S 289.05 observed m/e: 289.92 (M+H)+ (Rt 1.35/4 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of 2-tert-Butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd/C in 100 ml of methanol under hydrogen at 1 atmosphere was stirred for 4 hrs. The solution was filtered through Celite 545 and the filtrate evaporated in vacuo to afford 11.95 g of the title compound in quantitative yield as a dark brown solid that was used without purification. 1H NMR (CD3OD) δ6.75-6.70 (3H,m), 6.65-6.58 (1H, m), 4.35-4.3 1H, m), 3.6-3.38 (2H, m), 1.45 (9H, s).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[CH3:24][CH:25]([CH3:30])[CH2:26]B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:24][CH:25]([CH3:30])[CH3:26])[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)CB(O)O
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)Cc1cc(C(C)(C)NC(=O)OC2CN3CCC2CC3)ccc1F
Yield: 23 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (125 mg, 0.324 mmol), 2-methylpropylboronic acid (66 mg, 0.65 mmol) and palladium (II) acetate gave the title compound as a white solid (27 mg, 23%). 1H NMR (400 MHz, CDCl3) δ 7.23-7.11 (m, 2H), 7.04-6.82 (m, 1H), 5.11 (s, 1H), 4.59 (s, 1H), 3.32-2.12 (m, 6H), 2.48 (d, J=7.2 Hz, 2H), 1.86 (d, J=6.7, Hz, 1H), 2.05-0.96 (m, 5H), 1.62 (d, J=5.8 Hz, 6H), 0.90 (d, J=6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) 161.4, 159.0, 154.7, 142.5, 128.3, 124.0, 115.1, 114.9, 71.2, 66.1, 55.8, 55.0, 47.6, 46.7, 38.7, 29.9, 29.6, 25.6, 24.8, 22.6, 19.7, ppm. Purity: 85% UPLCMS (210 nm); retention time 1.0 min; (M+1) 362.9.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=3)[S:27][C:26]=2[CH:38]=1.[Cl-].[Al+3].[Cl-].[Cl-].[I-].[Li+].C(S)C.Cl>O.O1CCCC1.ClCCl>[ClH:1].[OH:21][C:22]1[CH:23]=[CH:24][C:25]2[C:29]([C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[CH:19][CH:18]=3)=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[S:27][C:26]=2[CH:38]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The acid chloride was made from 1.5 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 1. To the acid chloride were added 30 ml. of dichloromethane, 1.35 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 5 g. of aluminum chloride. The mixture was stirred at ambient temperature for 2.5 hours, and then 0.74 g. of lithium iodide was added. The mixture was stirred for 1 hour, and then 0.68 g. of ethanethiol was added and the mixture was stirred for 30 minutes more at a temperature between 25° and 35°. The reaction was then worked up by the addition of 25 ml. of tetrahydrofuran, 5 ml. of 20% hydrochloric acid and 50 ml. of water. The mixture was stirred overnight and was filtered. The solids were washed with 45 ml. of water and then with 40 ml. of diethyl ether, and the product was vacuum dried. The yield was 2.18 g. of product, which was found by 90 mHz nmr analysis to be substantially identical to the product of Example 1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].OC1C=CC(C=O)=CC=1.C([O:26][C:27]1[CH:43]=[CH:42][C:30]([C:31]([O:33]C2C=CC(C=O)=CC=2)=[O:32])=[CH:29][CH:28]=1)(=O)C.[Mn]([O-])([O-])(=O)=O.[K+].[K+].Cl>C(O)(=O)C.C(OCC)(=O)C.C(C(C)=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:26][C:27]2[CH:43]=[CH:42][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: O=[Mn](=O)([O-])[O-]
Agent: Cl
Agent: O=Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: CC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Yield: 89 %

Procedure:
4-Acetoxybenzoyl chloride and 4-hydroxybenzaldehyde were used to prepare (4-formyl)phenyl 4-acetoxybenzoate, m.p. 98-100° C., in 45% yield. 18 g (0.063 mol) of this aldehyde were dissolved in 180 ml of glacial acetic acid, 9.5 g of potassium manganate and 180 ml of methyl ethyl ketone were added, and the mixture was heated to 50° C. with stirring. After 8 hours of stirring it was acidified with hydrochloric acid, 250 ml of ethyl acetate were added, and the phases were worked up. The concentrated ethyl acetate solution gave 16.8 g (89%) of 4-(4-acetoxybenzoyloxy)benzoic acid, C6H12O6 (300.3). The acid chloride was obtained in 95% yield from this acid by customary reaction with thionyl chloride.