Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85° C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C[Mg]I.Br[C:15]1[C:20](=[O:21])[NH:19][C:17](=[O:18])[C:16]=1Br>C1C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:16]1[C:17](=[O:18])[NH:19][C:20](=[O:21])[C:15]=1[C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=1[CH3:1])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1NC(=O)C(Br)=C1Br
Reactant: Cc1cc2ccccc2[nH]1
Agent: C[Mg]I
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1[nH]c2ccccc2c1C1=C(c2c(C)[nH]c3ccccc23)C(=O)NC1=O
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
A solution of 4.12 g of 2-methylindole in 75 ml of benzene was treated with 9.2 ml of a 3M solution of methylmagnesium iodide in diethyl ether and the resulting solution was stirred under nitrogen for 0.5 hour. 2.0 g of dibromomaleimide were added and the mixture was heated to reflux for 14 hours. The cooled mixture was evaporated, dissolved in 200 ml of dichloromethane and acidified with 100 ml of 2M hydrochloric acid. The organic layer was separated, washed with 100 ml of water, dried and evaporated. The residue was triturated with dichloromethane and the obtained solid was recrystallized from acetone/water to give 1.1 g of 3,4-bis(2-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 311°-313° C.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:21][O:22][C:23]([CH2:24][N:25]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:26]
Reactant: COC(=O)CN
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
11.4 g (0.044 mol) of 6-phthalimido-2,5-hexanedione, 27.6 g ((0.22 mol) of glycine methyl ester hydrochloride and 9.1 g (0.11 mol) of sodium acetate are heated under reflux in ethanol for 16 hours and the mixture is worked up as in Example 1.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[NH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[NH2:14]>C(O)(=O)C>[N:18]1[CH:19]=[CH:20][C:15]([NH:13][N:14]2[CH2:4][C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:1]2)=[CH:16][CH:17]=1
Reactant: NNc1ccncc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2c(c1)CN(Nc1ccncc1)C2
Yield: 110.3 %

Procedure:
Phthalic anhydride (5.1 g) and 4-hydrazinopyridine hydrochloride (5.0 g) were suspended in glacial acetic acid (300 ml), and the mixture was heated under reflux for 8 hrs. The reaction mixture was evaporated, and the residue was triturated with 2-propanol. The solid was collected and dried to give 8.0 g of N-(4-pyridinylamino)-1H-isoindole. 1M lithium aluminum hydride in tetrahydrofuran (72.5 ml) was added dropwise to a portion (4.0 g) of the above solid suspended in tetrahydrofuran (200 ml) at 0° C., under nitrogen. The reaction mixture was warmed to ambient temperature, stirred overnight, under nitrogen, and was added to ice water, with stirring. The mixture was extracted with 2-propanol/chloroform (1/4). The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 5% methanol/chloroform. The appropriate fractions were collected and evaporated to yield 1.3 g (36%) of product free base. The free base was dissolved in methanol, and methanolic hydrogen chloride was added. The precipitate was collected to give 0.25 g (5.8%) of product, mp 253-255° C.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[C:5]([N+:24]([O-])=O)[CH:4]=1>CO>[NH2:24][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: COc1ccc(CNC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Solvent: CO
Product: COc1ccc(CNC2CCN(Cc3ccccc3)CC2)c(N)c1

Procedure:
A solution of 3.2 g (9.003 mmol) of 4-methoxy-2-nitro-N-(1-phenylmethyl-4-piperidinyl)-benzylamine in 30 mL methanol was hydrogenated in the presence of 1 g of 10% rhodium charcoal for 5 hours at ambient temperature. The catalyst was filtered off and the filtrate was evaporated down in vacuo. 2.5 g (85% of theoretical) of a colorless, highly viscous oil was obtained, which was further processed without purification. Rf=0.34 (MP F). IR (KBr): no C═O; MS: M+=325.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:6][N:7](C)C)[CH3:2].C(OC(=O)C(C(=O)C1C=CC=CC=1Cl)=CN(C)C)C>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:18][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1C
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Product: CCOC(=O)c1cnoc1-c1ccccc1C
Yield: 82.6 %

Procedure:
The procedure of Example 22 was employed utilizing ethyl-2-(2'-methylbenzoyl)-3-dimethylaminopropenoate in lieu of ethyl-2-(2'-chlorobenzoyl)-3-dimethylaminopropenoate to yield ethyl-5-(2'-methylphenyl)-4-isoxazolecarboxylate (1.9 g.; 82.6% yield) as an oil having the following analysis:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([CH3:28])=[N:24][N:25]([CH3:27])[CH:26]=1>>[CH3:27][N:25]1[CH:26]=[C:22]([NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[C:23]([CH3:28])=[N:24]1
Reactant: Cc1nn(C)cc1N
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Nc1cn(C)nc1C

Procedure:
Using an analogous procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted with 4-amino-1,3-dimethylpyrazole to give N-(1,3-dimethylpyrazol-4-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (CDCl3) 2.06 (s, 3H), 3.62 (s, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 5.07 (s, 2H), 6.58 (m, 1H), 6.61 (d, 1H), 7.17 (d, 1H), 7.38 (m, 6H), 7.79 (s, 1H); Mass Spectrum: M+H+ 366; which material was hydrogenated to give N-(1,3-dimethylpyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 2.09 (s, 3H), 3.44 (s, 2H), 3.68 (s, 3H), 3.7 (s, 3H), 6.28 (m, 1H), 6.37 (d, 1H), 6.93 (d, 1H), 7.76 (d, 1H), 9.23 (br s, 1H), 9.3 (br s, 1H); Mass Spectrum: M+H+ 276.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11](=[S:35])[CH2:12][C@H:13]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14]1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>CCO>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:19]2[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:14][C@H:13]2[CH2:12][C:11]2[S:35][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=S)C1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Ethyl bromopyruvate (0.070 mL, 0.50 mmol) was added to a solution of tert-butyl (6R,7R)-6-(2-amino-2-thioxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (140 mg, 0.33 mmol) in EtOH (5 mL). The reaction mixture was stirred at 80° C. for 2 hr, triethylamine (0.140 mL, 1.00 mmol) and di-tert-butyl dicarbonate (0.115 mL, 0.50 mmol) were added at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (173 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[N:5]=[S:6]([CH3:18])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:7])[CH3:2].[OH-].[Na+].[Cl-].[Na+]>C1COCC1.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH2:1]([O:3][C:4](=[O:19])[N:5]=[S:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:18])=[O:7])[CH3:2]
Reactant: CCOC(=O)N=S(C)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N=S(C)(=O)Cc1cccc(N)c1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
Titanium(III)chloride solution (about 15% in about 10% hydrochloric acid, 118 mL; Merck Schuchardt OHG) was added to a stirred solution of (rac)-ethyl[methyl(3-nitrobenzyl)oxido-λ6-sulfanylidene]carbamate (5.0 g; 17.5 mmol) in THF (220 mL) at room temperature. The batch was stirred for 18 hours. By adding 2N sodium hydroxide solution the pH value of the reaction mixture, that was cooled with an ice bath, was raised to 8. The batch was saturated with solid sodium chloride and extracted with ethyl acetate (3×). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated to give the desired product (4.2 g) that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Cu])#[N:11].CCOC(C)=O.Cl>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: N#C[Cu]
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(F)c1
Yield: 99.1 %

Procedure:
A mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) and CuCN (7.56 g, 84.4 mmol) in DMF (40 mL) was heated at reflux for 5 h. After being cooled down, EtOAc and 1N HCl were added. The mixture was filtered through celite. The organic phase was separated, washed sequentially with 1N HCl and brine. It was then dried over MgSO4, concentrated in vacuo to give a brown solid (5.69 g), which was pure enough for the next step. MS 137.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Nc1ccccc1
Product: COC(=O)c1ccc(Nc2ccccc2)cc1

Procedure:
Reaction of methyl 4-bromobenzoate with aniline according to general procedure A provided methyl ester of Compound 4 as a yellow oil (84% yield). 1H NMR (CDCl3, 500 MHz): δ=7.92 (d, J=8.8 Hz, 2H), 7.32-7.38 (m, 2H), 7.18 (d, J=7.5 Hz, 2H), 7.09 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.02 (s, 1H), 3.89 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.2, 148.3, 141.1, 131.7, 129.7, 123.4, 121.5, 120.7, 114.9, 51.9.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[C:20]([CH2:38][OH:39])([CH3:37])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:24]=2)[C:20]([CH3:37])([CH:38]=[O:39])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)CC2(C)CO)cc1OC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CN(Cc3ccccc3)CC2(C)C=O)cc1OC1CCCC1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A solution of oxalyl chloride (4.87 mL, 9.73 mmol) in dry CH2Cl2 (20 mL) was chilled to −78° C. under N2 and stirred while being treated with a solution of dimethyl sulfoxide (DMSO, 1.38 mL, 19.5 mmol) in CH2Cl2 (5 mL). Gas evolution was observed. When addition was complete, the solution was stirred for 5 minutes and a solution of [1-benzyl-4-(3-cyclopentyloxy-4-methyoxy-phenyl)-3-methylpyrrolidin-3-yl]-methanol (3.5 g, 8.85 mmol) in CH2Cl2 (10 mL) was added over a period of 10 minutes. The mixture was stirred for 30 minutes, treated with triethylamine (6.7 mL, 44.3 mmol), and allowed to warm to room temperature. Water was added to the mixture, the resulting layers separated, and the aqueous layer extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give an oily product (3.2 g, 92% yield). 1H NMR (300 MGz, CDCl3) δ (ppm): 9.63 (s, 1H, CHO), 7.34-7.21 (m, 5H, aromatic), 6.78-6.68 (m, 3H, aromatic), 4.73 (br, m, 1H), 3.80 (s, 3H, OCH3), 3.78-3.61 (m, 3H), 3.18-3.11 (m, 2H), 2.86-2.81 (m, 1H), 2.58-2.52 (m, 1H), 2.43-2.34 (m, 2H), 1.87-1.59 (m, 8H, cyclopentyl), 0.74 (s, 3H, CH3)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:54][O:55][C:56](=[O:65])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][NH2:64]>[Cl-].[Na+].O.CN(C=O)C>[CH3:54][O:55][C:56](=[O:65])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH:14]=[N:13][N:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:16][CH:17]=1
Reactant: O=C1Nc2ccc(F)cc2C1=NN=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzoic acid (311 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 8-aminocaprylic acid methyl ester hydrochloride (251 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (290 mg, 62% yield) as a brown solid. LC-MS (m/z) 467 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-3-(carboethoxy)-piperidine (800 mg, 3.11 mmol) in dry THF (10 mL) at −78° C. was added a 0.6M solution of sodium hexamethyldisilazide in toluene (5.7 mL). The reaction was stirred for 1 h when benzyl bromide (559 mg, 3.27 mmol) was added. After 1 h, the reaction was warmed to room temperature for 15 h. The reaction was quenched by the addition of 1M HCl (10 mL). The reaction was extracted with EtOAc (4×20 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to an oil. The oil was purified by flash chromatography (SiO2, 5–15% EtOAc in hexanes) to yield 606 mg of the product as a colorless oil. MS (ESI) 348 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Reaction time: 18 h
Yield: 50.6 %

Procedure:
To a solution of methyl 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (550 mg) in ethanol/THF (15 ml/15 ml) was added at room temperature 1N sodium hydroxide solution (1.6 ml), and the mixture was stirred for 18 hours. To the mixture was added 1N hydrochloric acid (1.6 ml), and the mixture was concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with 2-propanol and diethylether to give yellow crystals of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (268.9 mg). The mother liquor was concentrated, and the resulting solid was collected by filtration (177 mg). (Second crystals, Purity: about 50%)
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.[Si]([O:35][CH2:36][CH2:37][CH:38]=O)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:38][CH2:37][CH2:36][OH:35])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and 3-(tert-butyldimethylsilanyloxy)propionaldehyde. The protecting group is cleaved off as already described by means of a 1M TBAF/THF solution. The product was purified by means of reversed-phase chromatography. The fractions were extracted under basic conditions, dried, filtered and evaporated.