Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]2[NH:9][CH2:10][CH2:11][S:12][CH:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:5]1.[CH3:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:26][C:27]1[C:32]([C:33]([N:17]2[CH2:18][CH2:19][CH:14]([CH:13]3[S:12][CH2:11][CH2:10][NH:9][C:8]4[N:4]([CH3:3])[N:5]=[C:6]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:7]3=4)[CH2:15][CH2:16]2)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCNCC1
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C(=O)N1CCC(C2SCCNc3c2c(-c2ccccn2)nn3C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride (0.10 g, 0.25 mmol, Preparation #4), 2-methylpyridine-3-carboxylic acid (0.0341 g, 0.25 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol), 1-hydroxybenzotriazole hydrate (0.0505 g, 0.37 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol) in DCM (50 mL) was stirred overnight at rt. Then the mixture was concentrated in vacuo and purified by column chromatography (SiO2, DCM/methanol/ammonium hydroxide 92:7.5:0.5) to give (2-methyl-3-pyridyl)-[4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]-1-piperidyl]methanone (0.080 g, 71%) as an off white solid: LC-MS (Table 1, Method a) Rt=1.50 min; m/z 449 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 1.17-1.39 (2H, m) 1.44-1.64 (1H, m) 2.08-3.14 (10H, m) 3.22-3.55 (3H, m) 3.74-3.77 (3H, s) 4.58-4.78 (1H, br.d, J=13.0 Hz) 5.06-5.16 (1H, m) 7.05-7.20 (2H, m) 7.36-7.55 (1H, m) 7.62-7.72 (1H, m) 7.89 (1H br.t, J=9.0 Hz) 8.43-8.59 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@@H:7]([OH:21])[CH2:8][NH:9][C@@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@@H:10]([N:9]1[CH2:8][C@@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC[C@H](O)COc1cccc(Cl)c1
Reactant: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C[C@@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 2.06 g of 1(S)-(3-chlorophenoxymethyl)-2-[2-t-butyldimethylsilyloxy-1(S)-methylethylamino]ethanol (prepared as described in Preparation 38), 1.07 g of N,N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide were used, to give 2.11 g of the title compound having an Rf value of 0.18 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =+51.7° (methanol, c=1.03).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][CH2:35][C:36]#[C:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]#[C:36][CH2:35][CH2:34][CH2:33][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:39][CH:40]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCC#Cc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCC#Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
33.4 g (0.205 mol) of N-hydroxyphthalimide and 53.8 g (0.205 mol) of triphenylphosphine were added to a solution of 33.1 g (0.186 mol) of 5-hydroxy-1-(4-fluorophenyl)-1-pentyne in 430 ml of dry tetrahydrofuran. 35.7 g (0.205 mol) of diethyl azodicarboxylate were then added dropwise inthe course of 2.5 hours under temperature control (not more than 40°C.). Stirring was carried out overnight at room temperature, the mixture was evaporated down under reduced pressure and the residue was taken up with 300 ml of dichloromethane. The solution was washed twice with sodium carbonate solution and once with saturated sodium chloride solution. Afterthe solution had been dried and evaporated down, the crude product was purified by chromatography over silica gel. The eluent used was initially dichloromethane/n-hexane and then pure dichloromethane. Yield: 82%; mp.: 85°-88° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH3:20])[O:14][N:13]=1.[C:21](OC)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH2:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:14][N:13]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: COC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O

Procedure:
A solution of lithium bis(trimethylsilyl)amide (10 g, 60 mmol, 3 eq) in toluene (60 mL) was added drop wise during 15 min to a solution of 3,5-dimethylisoxazole-4-carboxylic acid (2.82 g, 20 mmol) and methyl benzoate (2.5 mL, 1 eq) in THF (20 mL) at a temperature not exceeding 40 deg. After 1 h the reaction was quenched by the addition of a water solution of 0.1M HCl (0.3 L) leaving the water phase still basic and the phases was separated. The water phase was washed with toluene and then reduced in volume by evaporation until most of the residual organic solvents were removed. 1M HCl was added dropwise with stirring. The resulting crystals were filtered and dried in vacuum to yield the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3H) 4.75 (s, 2H) 7.43-7.51 (m, 2H) 7.55-7.63 (m, 1H) 7.86-8.12 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[H-].[K+].[C:14]1([C@H:20]2[O:22][C@@H:21]2[CH2:23][OH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:21]([OH:22])[CH2:23][OH:24])[CH:6]=[C:5]2[CH3:11]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: OC[C@H]1O[C@@H]1c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [H-]
Solvent: ClCCl
Product: Cc1cn([C@@H](c2ccccc2)[C@H](O)CO)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) and potassium hydride 50% dispersion in mineral oil (2.8 g, 35.1 mmol) in dichloromethane (40 mL) was stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 mL) was then added and the mixture was stirred at room temperature for 12 hours. After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane) to give (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol. MS (ESI) m/z 300
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.[C:32]([O:36][C:37]([C@@H:39]1[CH2:43][S:42][C@@H:41]([CH2:44]O)[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:46]([OH:49])(=[S:48])[CH3:47]>C1COCC1>[C:46]([S:48][CH2:44][C@H:41]1[CH2:40][C@H:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:43][S:42]1)(=[O:49])[CH3:47]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H]1C[C@H](C(=O)OC(C)(C)C)CS1
Temperature: -20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of triphenylphosphine (391 mg) in THF (3 ml), azodicarboxylic acid diethylester (260 mg) dissolved in THF (1 ml) was added at -15°--10° C. under nitrogen atmosphere. To the mixture, trans-4-tert-butoxycarbonyl-2-hydroxymethyltetrahydrothiophene (compound No. 1-1, 150 mg) and thioacetic acid (114 mg) dissolved in THF (2 ml) were added at -20°--15° C., and the mixture was stirred for 1 hour at -20° C. and for 1 hour at room temperature. The mixture was concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 169 mg (82%) of the titled compound (compound No. 4-1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([O:14][C:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 8 h

Procedure:
A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)-(−)-N—BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from 0° C. to rt. TLC (5% MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (1M, 2×50 mL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8%). MS: 363 (M+Na+); TLC (DCM) Rf=0.3.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16]1[O:20][N:19]=[C:18]([CH3:21])[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[ClH:23]>C(OCC)(=O)C>[ClH:23].[CH3:21][C:18]1[N:17]=[C:16]([CH:8]([NH2:7])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:20][N:19]=1
Reactant: Cc1noc(C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1noc(C(N)Cc2ccccc2)n1

Procedure:
[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamic acid tertbutyl ester (2.4 g, 7.9 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (40 ml). After 5 h at 20° C. the reaction mixture was concentrated in vacuo. The residue was crystallized from ethyl acetate to give 2.05 g of (R) 1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylamine hydrochloride.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].N1C=CC=CC=1.[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>O1CCCC1.O.Cl>[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)Sc2ccccc2C(=O)O)cc1
Yield: 52.7 %

Procedure:
Thiosalicylic acid (1.28 g, 8.3 mmol) was suspended in tetrahydrofuran (10 ml). While stirring, pyridine (1.64 g, 21 mmol) and then a tetrahydrofuran solution (5 ml) of 4-(acetylamino)benzoyl chloride (1.67 g, 9.1 mmol) were dropwise added to the suspension under ice cooling. After the reaction mixture was stirred for 15 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (50 ml×2) with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation and the residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.38 g, 53%).
Reaction SMILES: N1CC(=O)NC1=O.N1C(=O)[C:11]2([C:24]3[CH:23]=[CH:22][S:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)NC1=O>>[S:21]1[CH:22]=[CH:23][C:24]2[CH2:11][C:14]3[C:19]([C:20]1=2)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: O=C1NC(=O)C2(N1)c1ccccc1-c1sccc12
Agent: O=C1CNC(=O)N1
Product: c1ccc2c(c1)Cc1ccsc1-2

Procedure:
Synthesis substrates 4H-indeno[1,2-b]thiophen-4-one and 4H-indeno [1,2-b]thiophene can be prepared according to a general process of MacDowell and Jefferies, J. Org. Chem., 35, 871 (1970). In this process the 4-one substrate is prepared by the Ullmann coupling of ortho-iodo or ortho-bromo, di, tri and tetrasubstituted benzoic acid lower alkyl esters, such as 3-fluoro-2-iodo-benzoic acid ethyl or methyl ester (Chem. Abst.; 27:1339/G) or 2-bromo-4-fluoro-benzoic acid methyl ester (Chem. Abst. 99(1):5630j) or 2-bromo-5-chlorobenzoic acid methyl ester (J. Med. Chem., 13, 567-8 (1970)) with 2-iodo or 2-bromothiophene (Aldrich Chemical, Inc.). Saponification of the coupled product will yield the corresponding substituted 2-(2'-thienyl) benzoic acid (e.g., 5-chloro-2-(2'-thienyl)benzoic acid from 2-bromo-5-chloro-benzoic acid methyl ester). Cyclization of the acid is performed via the aroyl halide using stannic chloride or aluminum chloride to yield to substituted 4H -indeno[1,2-b]thiophen-4-one (B-1) (e.g., 6-chloro-4H-indeno[1,2-b]thiophen-4-one). This 4-one derivative is converted (in accordance with Method I) into a hydantoin derivative such as spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione. See Example XIII for the preparation of spiro-(4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione. The Wolff-Kishner reduction (Method VIII) of (B-1) yields the corresponding 4H-indeno[1,2-b]thiophene. Product isolation is best accomplished by fractional distillation, but may involve other separation methods as are known in the art. The resulting substituted or unsubstituted 4H-indeno[1,2-b]thiophene (which may be further derivatized according to Method V) is metalated by n-butyllithium and carbonated in the methylene bridge to yield the corresponding 4-carboxylic acid which after esterification at reflux with a lower alkyl alcohol such as methanol under acid catalyzed conditions such as concentrated hydrochloric acid yields the corresponding substituted or unsubstituted 4H-indeno[1,2-b]thiophen-4-carboxylic acid lower alkyl ester, e.g., 6-chloro-4H-indeno[1,2-b]thiophen-4-carboxylic acid methyl ester. The ester is utilized according to Methods II, III and IV to yield the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide such as spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,5'-thiazolidine)-2',4'-dione, spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,5'-oxazolidine)-2',4'-dione and spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,3'-succinimide) respectively. The resulting spiro-derivatives may be further derivatized according to Method VI.
Reaction SMILES: [S:1]([C:6]([C:9]([C:12]([O:14][K])=[O:13])([F:11])[F:10])([F:8])[F:7])([O:4][K])(=[O:3])=[O:2].Cl>O>[S:1]([C:6]([F:7])([F:8])[C:9]([F:10])([F:11])[C:12]([OH:14])=[O:13])([OH:4])(=[O:3])=[O:2].[S:1]([C:6]([C:9]([C:12]([OH:14])=[O:13])([F:10])[F:11])([F:7])[F:8])([OH:4])(=[O:3])=[O:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2]
Reactant: O=C(O[K])C(F)(F)C(F)(F)S(=O)(=O)O[K]
Agent: Cl
Solvent: O
Product: O=C(O)C(F)(F)C(F)(F)S(=O)(=O)O

Procedure:
Ten grams of KO3SCF2CF2COOK were dissolved in 30 ml warm water and placed in a 50 cm×2.5 cm glass column containing a 20 cm bed of "Amberlite IR-120" ion-exchange resin in the acid (H+) form, which had been previously prepared by treating the column with 6N hydrochloric acid and rinsing with distilled water. The column was eluted with distilled water. The first 150 ml of eluate was concentrated under reduced pressure to yield the hydrate of 3-sulfoperfluoropropionic acid, HO3SCF2CF2COOH.8H2O.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+]([O-])=O)[CH:12]=2)[C:7]1=[O:19])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[C:26]([F:28])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:29][C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH:12]=2)[C:7]1=[O:19])[CH3:2]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CN1C(=O)c2ccc(Oc3cc(F)cc(F)c3)cc2C1=O

Procedure:
To an 80 mL microwave reaction vessel was added (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (2 g), 3,5-difluorophenol (1.12 g), potassium carbonate (1.39 g), and dimethyl acetamide (27 mL). The resulting mixture was reacted in the microwave at 100° C. for 10 min. Water (280 mL) was added and the resulting precipitate was filtered, washed with water and dried. Further purification by silica gel chromatography generated 0.94 g of the title compound. 1H NMR (200 MHz, CDCl3) δ 7.86 (d, J=8.2 Hz, 1H), 7.41-7.31 (m, 2H), 6.67-6.57 (m, 3H), 4.41 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])[CH2:24][CH2:23]1>C(N(C(C)C)C(C)C)C>[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:28])=[O:27])[CH2:24][CH2:23]1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 90 %

Procedure:
1-[Bis(4-chlorophenyl)methyl]piperazine (10.00 g, 31.13 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (8.30 g, 34.63 mmol) were refluxed in N-ethyldiisopropylamine (50 ml) for 7 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (14.70 g) as an oil (yield based on 1-[bis(4-chlorophenyl)methyl]piperazine: 95.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH:11]([CH3:12])[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: CCC(=O)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(3-nitrophenyl)propan-1-one (1.41 g, 7.90 mmol) in acetic acid (20 mL) was added bromine dropwise (1.27 g, 7.93 mmol) and the mixture was stirred at room temperature for 24 h. The mixture was poured into ice-cold water and the organic layer was extracted with DCM. The organic extract was washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. Evaporation of the solvent under reduced pressure afforded 11z as a white solid which was used in the next step without further purification (1.78 g, 87%). 1H NMR matches literature data.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])=[O:28])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:36])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCCN(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NO)nc1C(=O)NCCN(C)C
Temperature: 43 °C
Yield: 50.2 %

Procedure:
A solution 2-((1R)-1 -{2-[(benzyloxy)amino]-2-oxoethyl}4-cyclohexylbutyl)-N-[2-(dimethylamino)ethyl]-5-methyl-1,3-oxazole-4-carboxamide (Preparation 98) (193 mg, 0.39 mmol) in ethanol (10 ml) was treated with ammonium formate (244 mg, 3.90 mmol) and 5% palladium on barium sulphate (100 mg) and heated at 43° C., under a nitrogen atmosphere for 2 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of 98:2:0.2 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a white solid (80 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:17]2[C:8](=[C:9]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([Cl:20])=[CH:12][CH:11]=3)[CH2:7]1)=[O:5])C.O.[OH-].[Na+]>C(O)C>[OH2:3].[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:21][NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:8]1[C:17]([CH2:18][CH2:19][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[N:16]2.[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:21][NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:8]1[C:17]([CH2:18][CH2:19][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[N:16]2
Reactant: CCOC(=O)C1CCc2nc3cc(Cl)ccc3c(NNc3ccccc3)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2nc3cc(Cl)ccc3c(NNc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.3 %

Procedure:
A mixture of 2.0 g (0.0051 mol) of the compound of Example 10, 6.4 ml of water, 6.4 ml of ethanol, and 0.4 g of NaOH is stirred at ambient temperature overnight, then concentrated in vacuo. The residue is dissolved in water and extracted with ethyl acetate. The aqueous phase is acidified using acetic acid and extracted with methylene chloride. The organic extracts are dried over Na2SO4, and concentrated in vacuo. The resulting powder is triturated with petroleum ether to give 42 mg of the title compound: IR (KBr) 3250 (br), 2940 (br), 2500 (br), 1700, and 1600 cm-1 ; NMR (DMSO-d6) δ 8.18-7.58 (m, 11H), 3.24-2.90 (m, 5H), 2.38-2.22 (m, 1H), and 2.10-1.98 (m, 1H).