Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.[CH3:28][N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)N.C([O-])([O-])=O.[K+].[K+]>O.[Cl-].[Cl-].[Zn+2]>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:29]([CH3:28])[CH:2]=3)[CH2:11][CH2:12]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: CN(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3cn(C)c4ccccc34)CC2)c1
Temperature: 80 °C
Yield: 18.4 %

Procedure:
A mixture of N-(3-{-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide (100 mg, 0.270 mmol), 1-methyl-1-phenylhydrazine (106 mg, 0.870 mmol), ZnCl2 (119 mg, 0.870 mmol), and HOAC (1.00 mL) was heated for 12 h at 80° C. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was neutralized with saturated K2CO3 solution (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 3% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 2-methyl-N-(3-{1-[3-(1-methyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)propanamide (20.7 mg, 18.7 g): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, 1H, J=8.1 Hz), 7.45 (s, 1H), 7.35 (d, 1H, J=7.4 Hz), 7.26-7.24 (m, 4H), 7.09 (t, 1H, J=7.3 Hz), 6.97 (d, 1H, J=7.3 Hz), 6.86 (s, 1H), 3.75 (s, 3H), 3.11 (d, 2H, J=11.6 Hz), 2.79 (t, 2H, J=7.3 Hz), 2.51-2.50 (m, 4H), 2.12-1.81 (m, 8H), 1.25 (d, 6H, J=7.1 Hz); Anal. Calcd for C27H35N3O+0.225CHCl3: C, 73.57; H, 7.99; N, 9.45. Found: C, 73.93; H, 7.90; N, 9.23; ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[N:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:30]1([CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([N:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:19]=[C:11]3[CH2:10][CH2:9][OH:8])=[CH:25][CH:24]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole (0.4 mmol) was dissolved in tetrahydrofuran (2 mL) under N2, and tetrabutylammonium fluoride (0.44 mL, 1 M in tetrahydrofuran, 0.44 mmol) was added. The reaction was stirred at room temperature for 3 hours, then quenched with saturated ammonium chloride. The mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The residue was purified by semi-prep LC-MS to give the desired product, 15.8 mg. LC-MS (C23H28N2O2 calc'd 364) m/z 365 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.61-7.59 (m, 1H), 7.24-7.20 (m, 2H), 7.13-7.07 (m, 2H), 7.03-7.00 (m, 3H), 6.48 (s, 1H), 4.09 (t, J=6.3 Hz, 2H), 3.75 (t, J=6.6 Hz, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 2.60-2.49 (m, 4H), 2.10-2.01 (m, 2H), 1.85-1.76 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Cl[CH2:15][CH2:16][O:17][CH2:18][CH3:19]>>[CH2:16]([O:17][CH2:18][CH2:19][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:15]
Reactant: CCOCCCl
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Product: CCOCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
1-(2-Ethoxy-ethoxy)-2,3-dinitro-benzene was prepared by a procedure according to example 108 (i) starting from 500 mg (2.72 mmol) 2,3-dinitro-phenol and 0.72 mL (6.52 mmol) 1-chloro-2-ethoxy-ethane. Yield: 450 mg MS (ES+): m/e=257.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:9]=2)=[S:7])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1cc2c(c(C(=S)c3ccc(C)cc3)c1)OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3c2OCC3)cc1

Procedure:
A solution of ethyl 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetate (10.0 g), 50 ml of methanol, 200 ml of water, and 4 g of sodium hydroxide was heated at reflux for approximately 2 hours. The reaction mixture was cooled and washed with ether. The ether washed aqueous residue was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The combined organic extracts were washed with water and evaporated to give a residue which was crystallized from acetone/hexane to give 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid, m.p.--150°-152° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Yield: 93.5 %

Procedure:
tert-Butyl 3-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]propylcarbamate (60.0 g, 132.6 mmol) was dissolved in ethyl acetate (400 mL) and transferred to a Parr hydrogenation vessel charged with 5% platinum on carbon (15.6 g, 80 mmol, 0.03 eq). The vessel was purged with nitrogen gas and placed under hydrogen pressure (50 psi, 3.45×105 Pa) overnight. The catalyst was removed by filtration through a layer of CELITE filter aid, and the filter cake was rinsed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to provide 52.4 g of tert-butyl 3-[(3-amino-7-benzyloxy-quinolin-4-yl)amino]propylcarbamate.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11](OCCF)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@H:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.[CH3:41][O:42]C(=O)N=C(SC)C(C1C=C(OC)C=C(O[C@@H](C)CO[Si](C(C)(C)C)(C)C)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([O:4][C@@H:1]([CH3:2])[CH2:41][OH:42])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[NH:37])=[CH:39][CH:40]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[N:20]=1
Reactant: COc1cc(OCCF)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1F
Solvent: CC(=O)O
Product: COc1cc(O[C@@H](C)CO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (3e) to (3h), except that {2-{3-[(S)-2-(t-butyldimethylsilanyloxy)-1-methylethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester was used instead of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (3e), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[OH:16])[C:9]([O:11][CH3:12])=[O:10])(=O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1/[C:1](=[N:24]/[OH:25])/[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(=O)OC)ccc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC/C(=N\O)c1cc(C(=O)OC)ccc1O

Procedure:
A stirred solution of methyl 3-butyryl-4-hydroxybenzoate, pyridine (3.7 mL, 46 mmol), and hydroxylamine hydrochloride (3.55 g, 51 mmol) in ethanol (30 mL) was heated reflux for 2 h. The mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 10:1 hexanes/ethyl acetate) provided methyl 4-hydroxy-3-[(1E)-N-hydroxybutanimidoyl]benzoate (170 mg): 1H NMR (500 MHz, CD3OD): δ 8.30–8.28 (m, 1H), 7.85–7.82 (m, 1H), 6.92–6.89 (m, 1H), 3.88 (s, 3H), 2.87–2.84 (m, 2H), 1.67–1.60 (m, 2H), 1.05–1.00 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].C(OC)(OC)OC.C(C(C)=O)=C.[CH3:24][O:25][C:26]([CH:28]=[CH2:29])=[CH2:27].O=C(C)CCO.COC(OC)(C)C=C.COCCC(=O)C>CO>[OH:11][C:3]1[C:2]([CH3:1])=[C:8]2[C:6](=[C:5]([CH3:9])[C:4]=1[CH3:10])[O:7][C:26]([O:25][CH3:24])([CH3:27])[CH2:28][CH2:29]2
Reactant: C=CC(=C)OC
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: C=CC(C)(OC)OC
Agent: C=CC(C)=O
Agent: CC(=O)CCO
Solvent: CO
Solvent: COC(OC)OC
Product: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
In the manner described in Example 1, 3.80 g (25 mmol) samples of trimethylhydroquinone were treated in 25 ml of methanol, 5.0 ml of trimethyl orthoformate, and 0.10 ml of 36 N aqueous H 2 SO 4 with 50 mmole portions of the following methyl vinyl ketone substitutes: (a), 2-methoxybutadiene; (b), 3-ketobutanol, (c), 3,3-dimethoxybutene (contaminated with about 20 percent 2-methoxybutadiene); and (d), 4-methoxy-2 -butanone. The reactions were monitored by tlc. Reactions (a),(c) and (d) were complete after 24 hr and were worked up and dried in the manner of Example 1 to give (±)-6-hydroxy-2-methoxy-2,5,7,8 -tetramethylchroman. In reaction (b), a>50 percent conversion to (±)-6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman was indicated by tlc.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([O:7][C:8]([C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[CH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.[K+].[Br-]>P(Cl)(Cl)Cl>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[O:18][C:10]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)=[CH:9][C:8]=2[O:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(OC(=CC(=O)c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClP(Cl)Cl
Product: Cc1ccc(Oc2cc(-c3ccc(Br)cc3)oc2-c2ccc(Br)cc2)cc1

Procedure:
A solution of 5.0 g (0.01 mole) 1-(4-tolyloxy)-1,2-bis-(4-bromobenzoyl) ethylene in 10 ml phosphorus trichloride was heated under reflux for 3-4 hr (TLC followed). The excess PCl3 was removed by distillation and the residue was triturated with ice/water (exothermic reaction). The solution was extracted with dichloromethane (75 ml) and the dichloromethane layer was washed with saturated sodium bicarbonate solution, water, and dried (Na2SO4). The solvent was removed under reduced pressure. The residual solid was chromatographed over silica gel using ether:hexane (2:8 to 1:1) as eluant. An off white crystalline solid was obtained, 2.78 g (56%), mp 92°-3° C. IR (KBr) 2923, 2851, 1560, 1506, 1467, 1390, 1209, 1072, 1066, 945, 825, 707, 486. 1H NMR (CDCl3 /35° C.) 7.69 (d, 2H, J=8.8), 7.46-7.43 (m, 6H), 7.12 (d, 2H, J=8.3), 7.0 (d, 2H, J=8.3), 6.47 (s, 1H), 2.31 (s, 3H). 13C NMR (CDCl3 /135° C.) 150.8, 150.1, 142.8, 139.3, 133.0, 131.9, 131.7, 130.3, 129.1, 128.6, 125.1, 125.0, 121.8, 120.5, 117.1, 102.7, 20.6. MS m/e 484 (M+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13](/[CH:14]=[CH:15]/[C:16]([CH3:18])=[O:17])[C:12]([CH3:20])([CH3:19])[CH2:11][CH2:10][CH:9]=1.[H][H]>CC(O)C>[CH3:7][C:8]1[CH:13](/[CH:14]=[CH:15]/[CH:16]([OH:17])[CH3:18])[C:12]([CH3:19])([CH3:20])[CH2:11][CH2:10][CH:9]=1
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1=CCCC(C)(C)C1/C=C/C(C)O
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, 64 mg of RuCl2 [(S)-DM-BINAP][(S)-DAIPEN], 720 mg of K2CO3, 100 mL of IPA, and g of α-ionone as a racemic form were mixed. After deaeration, the obtained mixture was subjected to an asymmetric hydrogenation at 30° C. and a hydrogen pressure of 3 MPa for 21 hours. The reaction pressure was returned to the constant pressure. It was confirmed by GC that the raw material disappeared, and a post-treatment was then carried out by a conventional method, to give 20.2 g of desired optically active α-ionol (100% yield; 90% e.e.; 0% d.e.).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[S:15]([OH:18])(=[O:17])=[O:16]>C(O)C>[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[S:15]([OH:18])(=[O:17])=[O:16].[CH2:7]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH3:8]
Reactant: C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)c(C)c1
Solvent: CCO
Product: CCOC(=O)[C@H](C)N
Temperature: 25 °C

Procedure:
L-alanine (1.50 g, 16.84 mmol) and 2,4-dimethylbenzenesulfonic acid (2,4-DMBS) (3.76 g, 20.20 mmol) were added to ethanol (15 ml), and the mixture was heated overnight at 70 EC to perform esterification. To complete the esterification reaction, the mixture was heated to 90 EC, and ethanol (200 ml) was added over 3.5 hours, while distilling away almost the same amount of ethanol. Thereafter, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure. The obtained oily residue was cooled in a refrigerator to allow partial crystallization. Diethyl ether (2.5 ml) and ethyl acetate (17.5 ml) were added, and the residue was dissolved almost entirely at 50° C. The mixture was stirred at room temperature to give a slurry. This slurry was cooled overnight in a refrigerator, and the crystals were separated and dried to give 3.00 g of L-alanine ethyl ester 2,4-dimethylbenzenesulfonate (L-Ala-OEt 2,4-DMBS salt) dry crystals (L-Ala-OEt 2,4-DMBS salt content 99.6%, 9.84 mmol, yield 58.4%).
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Br:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(O)(=O)C>C(OCC)C.C(O)C.O>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:22][C:20]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=[C:16]([Br:15])[CH:21]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Cc1cc(Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of potassium ethoxide (2.05 g, 24.3 mmol) in diethyl ether (70 mL) and ethanol (10 mL) under an argon atmosphere was added diethyl oxalate (3.3 mL, 24.3 mmol) and the reaction stirred at rt for 15 min. A solution of 2-bromo-4-methyl-5-nitropyridine (Preparation 24, 4.8 g, 22.1 mmol) in diethyl ether (20 mL) was added to the reaction mixture giving an immediate black precipitate. The reaction was allowed to stir at rt for 6 h, then cooled to 0° C. and filtered to give a black solid. The solid was dissolved in water (250 mL) and acidified to pH 4 with acetic acid resulting in formation of a red precipitate. The solid was collected and dried to give the title compound as a red solid. δH (d6 DMSO): 1.16 (3H, t), 4.01 (2H, q), 6.55 (1H, s), 7.92 (1H, s), 8.96 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C([O:12][C:13](=O)[CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[C:20]=1[F:26])[C:15](=O)[CH3:16])C>>[F:26][C:20]1[C:21]([NH2:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:14]1[C:13](=[O:12])[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[C:15]=1[CH3:16]
Reactant: CCOC(=O)C(Cc1cccc(N)c1F)C(C)=O
Reactant: COc1cccc(S)c1
Product: COc1ccc2c(C)c(Cc3cccc(N)c3F)c(=O)sc2c1

Procedure:
The title compound was synthesized using 3-methyloxy-benzenethiol and 2-(2-fluoro-3-aminobenzyl)-3-oxobutanoic acid ethyl ester under the same conditions as in the manufacturing example for compound 5d-0-4S1.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1)=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CCCCN(CCCC)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(CCCC)C(=O)n1ccc2c(C(=O)O)cccc21
Reaction time: 0.5 h

Procedure:
To 1H-Indole-4-carboxylic acid (611, 251 mg, 1.56 mmol) in tetrahydrofuran (3 mL), was added 2.5M n-butyllithium in hexane (1.28 mL, 3.19 mmol) at −78° C. After 30 minutes, dibutyl carbamyl chloride (657 mg, 3.43 mmol) was added and stirred for two hours. The reaction solution was quenched with 1M HCl (aq.) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography using 10% ethyl acetate in hexane to give a white solid (612, 88 mg, 18%). MS (ESI) [M−H+]−=315.1.
Reaction SMILES: [Br-].[C:2]([N:5]1[CH2:9][CH2:8][CH:7]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]1=[O:29])(=[O:4])[CH3:3].[CH:30]([C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([CH:42]([CH3:44])[CH3:43])[C:40]=1[OH:41])[CH:36]=O)([CH3:32])[CH3:31].C(N(CC)CC)C.C(OCC)(=O)C>C(O)C.O>[C:2]([N:5]1[CH2:9][CH2:8][C:7](=[CH:36][C:35]2[CH:34]=[C:33]([CH:30]([CH3:32])[CH3:31])[C:40]([OH:41])=[C:39]([CH:42]([CH3:44])[CH3:43])[CH:38]=2)[C:6]1=[O:29])(=[O:4])[CH3:3]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: CC(=O)N1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCC(=Cc2cc(C(C)C)c(O)c(C(C)C)c2)C1=O
Temperature: 60 °C
Yield: 45.3 %

Procedure:
To a solution of 5.90 g (6 mmol) of (1-acetyl-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide in ethanol (12 ml) were added 1.24 g (6 mmol) of 3,5-di-isopropyl-4-hydroxybenzaldehyde and 1.67 ml (12 mmol) of triethylamine, and the mixture was stirred with heating at 60° C. for 2 hours. The reaction mixture was evaporated to give a residue, which was added with ethyl acetate and water. The ethyl acetate layer was washed with water, dried over magnesium sulfate and evaporated to give a residue, which was chromatographed on silica gel (toluene/ethyl acetate=4/1) to give 857 mg of the objective compound in 45% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:12].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(F)c2C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(F)ccc(I)c21
Yield: 74 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-fluoro-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (1.17 g, 2.86 mmol) was dissolved in nitromethane (46 mL), and the solution was treated with trifluoroacetic acid (2.20 mL, 28.6 mmol) and triethylsilane (0.914 mL, 5.72 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0, 85/15) to obtain 4-fluoro-7-iodoisoindolinone (586 mg, yield 74%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH:2]=[CH2:3].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:40]1[CH:49]=[CH:48][C:47]2[N:46]=[C:45]([NH2:50])[C:44]3[N:51]=[CH:52][N:53]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:43]=3[C:42]=2[CH:41]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:50][C:45]1[C:44]2[N:51]=[CH:52][N:53]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:43]=2[C:42]2[CH:41]=[C:40](/[CH:3]=[CH:2]/[CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][C:5]3=[O:9])[CH:49]=[CH:48][C:47]=2[N:46]=1
Reactant: C=CCN1CCCC1=O
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Cn1cnc2c(N)nc3ccc(/C=C/CN4CCCC4=O)cc3c21
Temperature: 120 °C

Procedure:
A thick walled glass tube, equipped with stir bar, was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (15 mL), N-allyl-2-pyrrolidone (650 mg, 5.17 mmol), triethylamine (2.1 ml, 15.65 mmol), tri-o-tolylphosphine (275 mg, 0.9 mmol) and 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 11, 1.5 g, 4.7 mmol). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. for 24 hours. The reaction mixture was concentrated to dryness. The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL). The layers were separated. The aqueous layer was extracted with chloroform (2×25 mL). The combined organic fractions were concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane) to provide 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].O>C(O)C>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)OCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid diethyl ester (934 mg, 2.3 mmol) in a 2:1 mixture of ethanol and water (12 ml) LiOH.H2O (193.3 mg, 4.61 mmol) was added and heated at 40° C. for 19 hrs. Ethanol was evaporated under reduced pressure, the residual aqueous mixture was acidified to pH 1 and extracted with methylene chloride (2×40 ml). The organic extract was dried with MgSO4 and evaporated under reduced pressure to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid monoethyl ester as a thick, yellow oil (831 mg); 1H NMR (CDCl3) 7.4–7.1 (m, 6H), 4.25 (q, J=7.1 Hz, 2H), 3.8–3.4 (m, 8H), 3.20 (d, J=16.4 Hz, 1H), 2.9 (d, J=16.4 Hz, 1H), 2.6 (m, 2H), 2.1–1.8 (m, 4H), 1.25 (t, J=7.1 Hz, 3H). MS: 378 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[OH:16])=[O:8].[OH-].[Na+]>O>[C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:2][C:3]([OH:5])=[O:4])(=[O:8])[CH3:6]
Reactant: O=C(O)CCl
Reactant: CC(=O)c1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(F)ccc1OCC(=O)O
Temperature: 25 °C

Procedure:
Chloroacetic acid (99.3 mmol, 9.4 g) was added to a suspension of 5-fluoro-2-hydroxy acetophenone (33.1 mmol, 5.1 g) in water (60 mL) containing sodium hydroxide (165.4 mmol, 6.6 g) and the reaction mixture was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature, poured into a separatory funnel and the oily liquid at the bottom of the funnel was discarded. The aqueous top layer was collected, cooled to 0° C. and acidified with conc. HCl. The white precipitate was collected, and air died. The dry solid was crystallized from toluene to obtain (2-acetyl-4-fluoro-phenoxy)-acetic acid, (57%, 4.39).