Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C(OOC(C)(C)C)(C)(C)C.[C:26]1([CH:32]([CH3:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:32]([O:13][N:8]1[C:9]([CH3:12])([CH3:11])[CH2:10][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1([CH3:15])[CH3:14])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1ccccc1
Reactant: CC(=O)OC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC(=O)OC1CC(C)(C)N(OC(C)(C)c2ccccc2)C(C)(C)C1
Reaction time: 0.5 h

Procedure:
4.3 g (20 mmol) of 4-acetyloxy-2,2,6,6-tetramethylpiperidine-N-oxide synthesized by the method described in Synthesis Example 1 was dissolved in 20 mL of cumene and 11.7 g (80 mmol) of t-butyl peroxide was added slowly. After a nitrogen bubbling for 30 minutes, it was transferred to a UV laboratory reaction apparatus (System1) made by Heraeus K. K. Light irradiation was performed using a TQ150 type lamp for 10 minutes to carry out a reaction. The reaction mixture was concentrated by a rotary evaporator, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=5/1, volume ratio) to obtain 5.5 g of 1-cumyloxy-2,2,6,6-tetramethyl-4-acetyloxypiperidine was obtained (82.3% of yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:56])=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccccn4)c(C)c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccn4)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.45 g) in methylene chloride (13.5 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.16 g) in methylene chloride (9.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 224) (185 mg).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:37]([O:39][C:40](=[O:49])[C@:41]([C:44](=[O:48])[N:45]([CH3:47])[NH2:46])([CH3:43])[OH:42])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:49])[C@:41]([C:44](=[O:48])[N:45]([CH3:47])[NH:46][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])([CH3:43])[OH:42])[CH3:38]
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)[C@](C)(O)C(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@](C)(O)C(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of acetylalanylalanylproline (0.66 mole) and N-methylmorpholine (0.66 mole) in dry tetrahydrofuran (25 ml) at -20° to -25° is added isobutylchloroformate (0.66 mmole). After 10 minutes a solution of 2-azaalanyl-l-lactic acid ethyl ester (0.66 mmole, example 3, step B) in tetrahydrofuran (2 ml) is added dropwise and the mixture is allowed to warm to room temperature over a period of 1 hour and stirred for a further 3 hours. The precipitate is removed by filtration, and the filtrate is concentrated to dryness. Chromatography of the residue on a silica gel (30 gm) and elution with 8% methanol in chloroform yields acetylalanylalanylprolyl-2-azaalanyl-l-lactic acid ethyl ester.
Reaction SMILES: [OH:1][OH:2].[C:3]([O:6][O-:7])([O-:5])=[O:4].[Na+:8].[Cl-].[Na+]>>[C:3]([O-:6])([O-:5])=[O:4].[C:3]([O-:6])([O-:5])=[O:4].[OH:1][OH:2].[OH:6][OH:7].[OH:6][OH:7].[Na+:8].[Na+:8].[Na+:8].[Na+:8]
Reactant: O=C([O-])O[O-]
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Product: O=C([O-])[O-]

Procedure:
According to British Pat. No. 549,841, sodium percarbonate is produced by reacting sodium silicate or a magnesium salt in the presence of an alkali metaphosphate or an alkali pyrophosphate to obtain soda decahydrate crystals or a suspension of the decahydrate in a saturated soda solution in a reaction with a hydrogen peroxide solution. The solubility of the percarbonate is reduced by the subsequent addition of sodium chloride. This product, however, also has an unsatisfactory grain size distribution curve, i.e. it contains too large an amount of fines which must be removed or agglomerated in a subsequent step to obtain sodium percarbonate of practical usefulness.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[C:43]4=[CH:44][CH:45]=[CH:46][CH2:47][CH:42]4[NH:41][CH2:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[C:43]4=[CH:44][CH:45]=[CH:46][CH2:47][CH:42]4[NH:41][CH2:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C:20]1[CH:33]=[CH:32][C:23]2[C@@H:24]3[C@H:29]([CH2:30][CH2:31][C:22]=2[CH:21]=1)[NH:28][CH2:27][CH2:26][CH2:25]3)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(CC2C=CC3[C@@H]4[C@H](CCC=3C=2)NCCC4)CCCCC1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:28]3[C@@H:29]4[C@@H:24]([C:23]5[CH:32]=[CH:33][C:20]([CH2:13][CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]6)=[CH:21][C:22]=5[CH2:31][CH2:30]4)[CH2:25][CH2:26][CH2:27]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc(Cc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: c1cc2c(cc1CC1CCCCC1)CC[C@@H]1NCCC[C@H]21
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(CC4CCCCC4)cc3CC[C@@H]21
Yield: 50 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and a mixture of cis-8-benzyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and cis-8-cyclohexylmethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (ca. 30:70) following a procedure analogous to that described in Example 1 and separated from the also formed Example 82 by HPLC on reversed phase (MeOH/H2O/NH4OH). Yield: 50% of theory; LC (method 1): tR=4.06 min; Mass spectrum (ESI+): m/z=428 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[C:13]2=[O:16])=[CH:8][C:7]=1[O:24]C.CO>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[C:13]2=[O:16])=[CH:8][C:7]=1[OH:24]
Reactant: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C)CC2
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCc2cc(O)c(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.2 %

Procedure:
BBr3 (4.4 mL) was added to a stirred solution of 7-chloro-6-methoxy-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (86A: 450 mg, 1.480 mmol) in DCM (10 mL) at 0° C. The resulting mixture was stirred for 14 hours at room temperature. The reaction was monitored by TLC (5% methanol in CHCl3). The mixture was slowly quenched with ice water extracted with chloroform (2×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), afforded 300 mg of the product (70.4% yield).
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:7]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([NH2:33])=[C:28]([Cl:34])[CH:27]=1)[OH:25]>C(OCC)(=O)C.C(N(CC)CC)C>[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:22][CH2:23][CH:24]([C:26]2[CH:27]=[C:28]([Cl:34])[C:29]([NH2:33])=[C:30]([Cl:32])[CH:31]=2)[OH:25])=[CH:7]1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=C(CCCCCBr)OCCc1ccsc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCC(=O)OCCc2ccsc2)cc1Cl

Procedure:
According to method I (tetrahydrofuran, reflux 4 days) from {2-(3-thienyl)ethyl}6-bromohexanoate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/triethylamine 8:1). Recrystallized as the base from diethyl ether. Melting point: 71°-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:3]=1[C:4]([O:6][CH2:7][C:8]([CH2:10][O:11][C:12](=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])=[O:9])=[O:5].C([NH:39][C@H:40]([C:48]([NH:50][C@H:51]([C:53]([OH:55])=[O:54])[CH3:52])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(OCC1C=CC=CC=1)=O.C(O)C.[ClH:59]>[Pd]>[ClH:59].[CH3:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[C:14]([CH3:21])[C:13]=1[C:12]([O:11][CH2:10][C:8]([CH2:7][O:6][C:4](=[O:5])[C:3]1[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:2]=1[CH3:1])=[O:9])=[O:22].[NH2:39][C@H:40]([C:48]([NH:50][C@H:51]([C:53]([OH:55])=[O:54])[CH3:52])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cc1cc(C)c(C(=O)OCC(=O)COC(=O)c2c(C)cc(C)cc2C)c(C)c1
Agent: Cl
Solvent: CCO
Product: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
To a mixture of N-CBZ-L-phenylalanyl-L-alanine 2,4,6-trimethylbenzoyloxymethyl ketone (0.38 mmol, 200 mg) in 100 mL of ethanol containing 150 μL (0.75 mmol) of 5N HCl was added 10% palladium on charcoal (20 mg). This mixture was vigorously stirred under an atmosphere of hydrogen gas for 3 hours, the catalyst was removed by filtration through a bed of Celite, and the filtrate was rotary evaporated under reduced pressure. The residue was then precipitated from ethanol-ethyl ether, washed with ethyl ether, and dried at high vacuum to quantitatively afford the product as a powder, m.p. 123°-126° C.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([Mg]Br)=[CH2:12].[NH4+].[Cl-]>C1COCC1>[C:4]1([CH2:3][CH2:2][CH:1]([OH:10])[CH:11]=[CH2:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C[Mg]Br
Reactant: O=CCCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A modified procedure of Molander was used (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297). A stirred solution of hydrocinnamaldehyde 65 (2.50 g, 2.45 ml, 18.6 mmol) in THF (25 ml) was cooled to −78° C. Vinyl magnesium bromide solution (1 M in THF) (22.4 ml, 22.4 mmol) was added dropwise over ˜5 min. The reaction mixture was stirred at −78° C. for 1.5 h, then 0° C. for 3 h. The reaction mixture was poured into saturated NH4Cl solution (50 ml) and extracted with Et2O (3×50 ml). The combined organic phases were washed with saturated NaCl solution (50 ml) before being dried (MgSO4), filtered and concentrated to give a pale yellow liquid. This material was purified by column chromatography, eluting with petrol/EtOAc (9:1), to give the vinyl alcohol 64 (1.89 g, 63%) as a clear colourless liquid. The 1H, 13C, and IR data were consistent with the literature (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297; Kim, J. W. et al., Chemistry—A European Journal 2008, 14, 4104).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OC)=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=1.[OH-].[Na+].Cl.C([N:24](CC)CC)C.[Cl-].[NH4+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:24])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1sc(Br)cc1NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1sc(Br)cc1NCc1cccnc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.5 %

Procedure:
To a solution of methyl 5-bromo-3-[(pyridin-3-ylmethyl)amino]thiophene-2-carboxylate (260 mg, 0.795 mmol) in MeOH (3 mL) was added a solution of sodium hydroxide (96 mg, 2.39 mmol) in water (1.5 mL). After stirring at 80° C. for 5 h, 6 M aqueous HCl (0.25 mL) was added to the mixture to adjust the pH to 10. After removal of the solvent at reduced pressure, the residue was suspended with DMF (5 mL). Then, triethylamine (2.2 mL, 16 mmol) and ammonium chloride (850 mg, 16 mmol) were added. After stirring at room temperature for 5 min, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (914 mg, 4.8 mmol) and 1-hydroxybenzotriazole (645 mg, 4.8 mmol) were added to the mixture, and the stirring was continued for 18 h. Then, water and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc) to give the title compound (175 mg, 71%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][N:3](C)[C:4](=O)C1C=CC(CCC2C=CC3C(=CC=CC=3)N=2)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[C:29]([OH:31])=O>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[C:29]([N:3]([O:2][CH3:1])[CH3:4])=[O:31]
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reactant: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide but substituting 3-Chloro4-(quinolin-2-ylmethoxy)-benzoic acid provided the title compound. (M+H m/z=356.9).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=1.[CH:17](OC)=[O:18].C([O-])(O)=O.[Na+]>C1COCC1>[F:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[C:15]=1[CH:17]=[O:18]
Reactant: Fc1cncc(F)c1
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)cncc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 295.2 %

Procedure:
At 0° C. A solution of LDA 2M in THF (47.792 mL, 95.58 mmol) was diluted with 50 mL THF. It was cooled down to −78° C., then a solution of 3,5-Difluoropyridine (7.886 mL, 86.89 mmol) in 100 mL THF was added dropwise while maintaining the temperature below −70° C., (complete addition in 20 min). It gave a yellow suspension. The reaction mixture was stirred 3 h at −78° C. A solution of Methyl formate (10.8 mL, 173.79 mmol) in 25 mL THF was added dropwise in 15 min. The reaction mixture became a pale yellow solution. It was stirred 45 min at −75° C. and then transferred via cannula to a stirred solution of 100 mL sat aq NaHCO3 held at about 0° C. It was extracted twice with EtOAc and the combined organic phases were washed with brine and dried with Na2SO4. The solvent was evaporated (165 mbar, 30° C.), 36.7 g of residue were obtained as a yellow liquid. The crude product was purified by flash chromatography (Solvent: CH2Cl2). The product was isolated as a pale yellow oil (7.85 g), which crystallized upon standing.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:44]>>[ClH:44].[CH3:6][NH:8][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1
Reactant: CN(Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-methylamino)methyl-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: [F:1][C:2]1[C:3](NC(=O)C)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.N([O-])=O.[Na+].N.[ClH:22]>O>[F:1][C:2]1[C:3]([Cl:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: CC(=O)Nc1c(F)ccc2c1CCC(C)N2
Reactant: Cl
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1CCc2c(ccc(F)c2Cl)N1
Reaction time: 1 h

Procedure:
6-Fluoro-5-acetylamino-1,2,3,4-tetrahydroquinaldine (8 g) was dissolved in a mixture of 35 ml of concentrated hydrochloric acid and 20 ml of water. After refluxing the solution for 1 hour 10 ml of an aqueous solution having dissolved therein 5 g of sodium nitrite was added dropwise to the solution under ice-cooling taking care that the reaction temperature should not exceed 5° C. After completion of the addition the reaction mixture was stirred at the same temperature as above for 1 hour and poured into a solution of 12 ml of concentrated hydrochloric acid and 10 g of cuprous hydrochloride. The mixture was allowed to react at 80° C. for 1 hour and ice-cooled. After rendering it alkaline with an aqueous 28% ammonia solution the reaction mixture was extracted with 300 ml chloroform and Celite (diatomaceous earth, produced by Johns Manville Sales Corp.). The chloroform fraction obtained was dried over anhydrous sodium sulfate and concentrated. The residue was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-ethanol (9:1 by volume) to obtain 3.2 g of 6-fluoro-5-chloro-1,2,3,4-tetrahydroquinaldine as light orange oily product. Production of this compound was confirmed by NMR spectral analysis and mass spectral analysis.
Reaction SMILES: C([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.C(Cl)Cl>CN(C)C=O>[NH2:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, 3 fold molar excess of Boc-L-Tyrosine (Vega, supra.) dissolved in dimethylformamide and adjusted to 15 ml. with the addition of methylene chloride is added to the product of Step (F) above and the resulting mixture shaken. After about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide is added and the resulting mixture is shaken for 4.5 to 5 hours at room temperature. At the end of this period, the reaction mixture is filtered and the residue washed with dimethylformamide. The washed residue is dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:25])[C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:22]2[CH2:23][CH2:24][CH:20]([N:19]([CH3:25])[CH3:18])[CH2:21]2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1cccc(N2CCC(N(C)C)C2)c1
Temperature: 25 °C
Yield: 27 %

Procedure:
A mixture of (S )[1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (6 g), (3R)-3-(dimethylamino)-pyrrolidine (4.56 g), Pd2(dba)3 (1.83 g), di-t-butyl-biphenylphosphine (600 mg), K3PO4 (8.48 g) in DME (40 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down to room temperature, diluted with methylene chloride, and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by Flash Chromatography using Biotage eluting with 20% MeOH in ethyl acetate to give the title compound (1.8 g) as an oil.
Reaction SMILES: [CH2:1]([O:5]C1C=C2C(=CC=1)C=C([Mg]Br)C=C2)[CH2:2][CH2:3][CH3:4].[Mg].[CH2:19]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([SH:34])[CH:28]=[CH:27]2)[CH2:20][CH2:21][CH3:22].ClCCCCO>CC(C)=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[OH:5][CH2:1][CH2:2][CH2:3][CH2:4][S:34][C:29]1[CH:28]=[CH:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])[CH:25]=2)[CH:30]=1
Reactant: CCCCOc1ccc2cc(S)ccc2c1
Reactant: CCCCOc1ccc2cc([Mg]Br)ccc2c1
Agent: OCCCCCl
Agent: [Mg]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1ccc2cc(SCCCCO)ccc2c1

Procedure:
30 g 6-n-butoxy-2-naphthalene thiol was obtained by the method of non-patent document 5 from 72 g of 2-bromo-6-n-butoxy naphthalene prepared according to the method described in J. Am. Chem. Soc., Vol. 118, P. 6841-6852 (1996) and 6-n-butoxy-2-naphthyl magnesium bromide prepared from 7.5 g of magnesium. Next, 30 g of 6-n-butoxy-2-naphthalene thiol was dissolved in 150 ml of acetone and 14.0 g of 4-chloro-1-butanol was added to the solution. After the addition of 26.1 g of triethylamine dropwise over 15 minutes, the mixture was reacted for 15 hours at room temperature while stirring. Next, 150 ml of ethyl acetate and 150 ml of water were added to the reaction mixture. After removing the water layer using a separating funnel, the organic layer was washed three times with 75 ml of a 10 wt % sodium carbonate aqueous solution, then repeatedly washed with 5 wt % oxalic acid aqueous solution until the water layer becomes pH 2. Then, the organic layer was washed with purified water until the water layer becomes pH 7 and dried using magnesium sulfate. After drying, magnesium sulfate was removed by filtration and the solvent was evaporated using a rotary evaporator at 40° C. under reduced pressure by a stream aspirator to obtain 29.4 g of 4-hydroxybutyl-(6-n-butoxynaphthalen-2-yl)sulfide, of which the purity determined by high performance liquid chromatography (HPLC) was 95 wt % or more.