Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[S:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(N)C1C=CC=CC=1.CC1SC(C=C[N+]([O-])=O)=CC=1>C1(C)C=CC=CC=1>[CH2:23]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CN(C(=O)OC(C)(C)C)CC3)s1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(C=C[N+](=O)[O-])s1
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyl-3-(5-methyl-thiophen-2-yl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. A mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.54 g) and 300 μL of benzylamine in toluene (10 mL) was heated at reflux for 6 h using a Dean-Stark apparatus. The solution was cooled to RT and 0.47 g of 2-methyl-5-(2-nitro-vinyl)-thiophene was added. The mixture was stirred for 16 h at RT and then was concentrated in vacuo. The residue was chromatographed on SiO2 (1 to 30% EtOAc/hexanes) to afford 281.9 mg of the desired compound. TLC (SiO2, 33% EtOAc/hexanes): Rf=0.54
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:22][C:12]2=[N:13][C:14](Cl)=[C:15]([N+:18]([O-:20])=[O:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[OH2:29].[CH3:30]O>>[CH2:1]([S:8][C:9]1[S:22][C:12]2=[N:13][C:14]([O:29][CH3:30])=[C:15]([N+:18]([O-:20])=[O:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c([N+](=O)[O-])c(Cl)nc2sc(SCc3ccccc3)nn12
Reactant: O
Reactant: CO
Solvent: c1ccncc1
Product: COc1nc2sc(SCc3ccccc3)nn2c(=O)c1[N+](=O)[O-]
Yield: 70 %

Procedure:
Three (3) grams of the thus obtained 2-benzylthio-7-chloro-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved in 50 ml of methanol, and 0.8 g of pyridine was added. The solution was stirred under refluxing for 30 minutes. After the reaction was finished, the reaction mixture was cooled and poured into water. The resulting mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with isopropyl ether. Thus, 2.1 g of 2-benzylthio-7-methoxy-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 70%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=O)[C:14]1=O>C(O)(=O)C>[CH:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]2[C:11]=1[N:12]=[C:16]1[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[N:13]=[C:14]1[NH:1]2.[C:3]1([C:4]([O:6][CH3:7])=[O:5])[C:2]2[N:1]=[C:16]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[N:13]=[C:14]3[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(N)c1N
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]c3nc4ccccc4c-3nc12
Product: COC(=O)c1cccc2nc3c4ccccc4nc-3[nH]c12
Reaction time: 8 h

Procedure:
A suspension of 20 g of methyl 2,3-diaminobenzoate and 17.7 g of isatin in 230 ml of acetic acid was heated under reflux for an hour. After completion of the reaction, the reaction solution was allowed to stand at room temperature overnight, and the resulting precipitate was collected by filtration. The precipitate was purified by silica gel column chromatography to give methyl 4-indolo[2,3-b]quinoxalinecarboxylate and methyl 1-indolo[2,3-b]quinoxalinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][O:5][CH3:6].C(N(C(C)C)C(C)C)C.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][CH2:30][O:31][C:32]1[C:40]2[CH:39]=[CH:38][S:37][C:36]=2[C:35]([CH:41]=[O:42])=[CH:34][CH:33]=1>C1COCC1.ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:5][CH3:6])[CH:41]([OH:42])[C:35]1[C:36]2[S:37][CH:38]=[CH:39][C:40]=2[C:32]([O:31][CH2:30][CH2:29][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:22][C:18]=2[CH3:17])=[CH:33][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Reactant: COCC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 127.6 %

Procedure:
To a solution of 3.17 ml methoxyacetic acid methyl ester (31.4 mmol) in 30 ml of THF, 3.5 ml of titanium tetrachloride (31.4 mmol) was added dropwise within 15 min at 0° C. After stirring the yellow solution for additional 15 min at the same temperature, 6.0 ml of N-ethyldiisopropylamine (34.1 mmol) were added within 5 min and the yellow/orange solution stirred for additional 15 min. A solution of 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.66 mmol) in 70 ml of dichloromethane was added dropwise within 20 min and the reaction mixture was stirred for additional 60 min. The reaction solution was allowed to warm up to r.t. and stirred the same temperature for 90 min, cooled to 0° C. and treated with 50 ml of ice water. The organic layer was separated, washed with 25 ml water, dried over sodium sulfate and evaporated to dryness to yield 8.15 g of crude 3-Hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid methyl ester ((syn/anti=6:4) as an orange oil. After this intermediate was dissolved at r.t. in 50 ml of DMF, 1.20 ml of conc. sulfuric acid (10.5 mmol) were added and the resulting dark brown solution was stirred at 100° C. for 17 h. The reaction solution was cooled to r.t., whereas the product crystallized. 50 ml of ethanol were added and the suspension stirred for 1 h at 0° C. The white crystals were filtered off, washed with 75 ml of cold (−15° C.) methanol in two portions and dried to constant weight (20° C./5 mbar/16 h) to afford 3.82 g (61%) of the title compound with a purity of 98.6% (GC area).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14]C(O)=O)=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:26](=[O:29])([O-])[O-:27].[K+].[K+].[CH3:32]N(C)C=O>O>[C:26]([O:27][CH2:14][C:13]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10][N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=1)(=[O:29])[CH3:32]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Product: CC(=O)OCc1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylacetic acid (2.47 g), methyl iodide (0.75 ml), potassium carbonate (2.21 g) and N,N-dimethylformamide (25 ml) was stirred at room temperature for 1 hr. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylmethyl acetate (2.55 g, yield 99%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 74–75° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:33])([F:34])[F:20])=[N:29][CH:28]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(OCC(F)(F)F)nc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(OCC(F)(F)F)nc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-(2,2,2-trifluoroethoxy)nicotinamide as a white crystalline solid, m.p. 192.0-194.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J=1.9 Hz, 1H), 8.58 (t, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.15 (dd, J=8.6, 2.4 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.1 Hz, 1H), 7.24 (t, J=7.1 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.82 (broad s, 2H), 5.06 (q, J=9.1 Hz, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H); MS (EI) m/e 458.1678 (458.1678 calcd for C22H21N6O2F3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.[C:19]([CH2:21][C@@H:22]1N(C2C=CC(OC)=CC=2)N=[C:24](C2C=CC(C#N)=CC=2)[C@H:23]1C)#[N:20]>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C@@H:22]([CH2:21][C:19]#[N:20])[C@H:23]([CH3:24])[C:6]([C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(N2N=C(c3ccc(C#N)cc3)[C@@H](C)[C@@H]2CC#N)cc1
Reactant: O=Cc1ccc(F)cc1
Reactant: NNc1ccc(Br)cc1
Product: C[C@@H]1C(c2ccc(F)cc2)=NN(c2ccc(Br)cc2)[C@H]1CC#N

Procedure:
2-((4S,5S)-1-(4-Bromophenyl)-3-(4-fluorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile was prepared from 4-fluorobenzaldehyde and (4-bromophenyl)hydrazine following the procedure for the preparation of 4-((4S,5S)-5-(cyanomethyl)-1-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (example 91G). LC-MS [M+H] 372, 374.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[CH3:11][O:12][CH2:13]C(Cl)=O>>[CH3:11][O:12][CH2:13][C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCC(=O)Cl
Product: CCOC(=O)CC(=O)COC

Procedure:
The title compound was prepared in a manner analogous to Intermediate 123 starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and methoxyacetyl chloride.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:4][C:3]2[C:11](=[CH:12][CH:13]=[CH:1][CH:2]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CN2Cc3ccccc3C2)cc1

Procedure:
In Scheme 7A, the commercially available bis-bromomethyl benzoic acid ester ((LI) is reacted with benzylamine in a polar aprotic solvent such as tetrahydrofuran (THF) in the presence of a non-interfering base such as triethylamine to give the N-benzyl dihydroisoindole intermediate (LII). The ester group in intermediate (LII) is then reduced to the corresponding alcohol using lithium aluminium hydride in THF to give the hydroxymethyldihydroisoindole intermediate (LIII). Debenzylation of the hydroxymethyldihydroisoindole intermediate (LIII) is then carried out by hydrogenation over palladium on charcoal catalyst in an alcohol (e.g. ethanol) solvent at a mildly elevated temperature (e.g. up to about 50°) to give the intermediate (LIV). Intermediate (LIV) is then converted to intermediate (LV) by reaction with a reagent suitable for introducing a benzyloxycarbonyl (“Z”) group onto the nitrogen atom of the dihydroisoindole ring. For example, the intermediate (LIV) can be reacted with benzyl chloroformate in a polar non-protic solvent such as THF in the presence of a non-interfering base such as triethylamine to give intermediate (LV).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:33]([S:35]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:37])=[O:36])[CH3:34]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Reaction time: 12 h

Procedure:
The crude 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) was suspended in DMF (8 mL) and treated with triethylamine (0.3 mL, 2.2 mmols), DMAP (0.0056 g, 0.065 mmol), and ethane sulfonyl chloride (0.044 mL, 0.47 mmols) at ambient temperature. After 12 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (10 mL), and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified via preparative HPL, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give 0.080 g of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(O)Cc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccnc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 1.00 equivalent), 2-(pyridin-3-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol, 1.20 equivalents), HATU (10 g, 26.30 mmol, 1.20 equivalents), and DIEA (8.5 g, 65.77 mmol, 3.00 equivalents) in N,N-dimethylformamide (100 mL). After stirring overnight at 20° C., the reaction was quenched with 100 mL of water and extracted with 3×100 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2-1:1) to give the title compound as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19](=O)[CH:20]=[CH:21]N(C)C.C(=O)(O)[O-].[Na+].ClCCl.CCCCCC>C(O)(=O)C.ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]1[N:4]2[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]2[N:2]=[CH:21][CH:20]=1
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ncn2c(-c3cc(Cl)ccc3Cl)ccnc12
Yield: 74.3 %

Procedure:
A stirred mixture of 5.2 g of 4-amino-5-imidazolecarboxamide hydrochloride and 10.0 g of 2',5'-dichloro-3-dimethylaminoacrylophenone (prepared as described in Example 4) in 80 ml of glacial acetic acid was heated at reflux for 4 hours. Evaporation in vacuo gave a dark oil which was dissolved in dichloromethane and treated with saturated sodium bicarbonate. The organic layer was separated, washed with water then dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous magnesium silicate. Evaporation of the eluate gave a semi-solid which was treated with hot dichloromethane-hexane to give a yellow precipitate which was collected by filtration and dried to give 7.3 g of the product of the example, mp 230°-234° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:29])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:43][OH:44]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:29])[CH2:16][C:17]([NH:43][OH:44])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC1CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC1CCCC1
Yield: 91.5 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (1.00 g, 2.53 mmol), carbonyldiimidazole (430 mg, 2.66 mmol) and hydroxylamine hydrochloride (230 mg, 3.29 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide as a white solid (950 mg, 91% yield): mp, 183.0-184.5° C.; 1H NMR (DMSO-d6) δ1.54-1.82 (m, 8H, C5H8), 2.82-2.86 (m, 2H, CH2), 3.70 (s, 3H, CH3), 4.13 (d, J=17.5 Hz, NCHH), 4.55 (d, J=17.5 Hz, 1H, NCHH), 4.73 (m, 1H, CH), 5.74 (t, J=7.6 Hz, 1H, NCH), 6.85-6.93 (m, 3H, Ar), 7.47-7.70 (m, 4H, Ar), 8.84 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ23.50, 32.11, 32.18, 46.20, 51.17, 55.53, 79.52, 112.21, 114.00, 119.14, 122.78, 123.43, 127.85, 131.31, 131.86, 132.27, 141.65, 146.87, 149.07, 166.04, 166.91; Anal Calcd for C23H26N2O5 0.7H2O: C, 65.30; H, 6.53; N, 6.62. Found: C, 65.59; H, 6.38; N, 6.65; H2O, 2.94.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].Cl[C:17]([O:19][CH2:20][CH2:21][Cl:22])=[O:18]>COCCOC.O>[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:17](=[O:18])[O:19][CH2:20][CH2:21][Cl:22])([O-:8])=[O:7]
Reactant: O=C(Cl)OCCCl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCCCl
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
135 g of calcium carbonate are added to a solution of 345.3 g of 2-nitroaniline in a mixture of 1020 g of monoethylene glycol dimethyl ether and 150 g of water and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are then added in the course of 3 hours. The mixture is subsequently stirred at the reflux temperature for 1.5 hours, until the reaction is complete, and is cooled to 35° C., and the product is precipitated with water and ice. The product is filtered off, washed with water and dried.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Br[C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:26]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:25][O:24][N:23]=2)[CH:12]=[CH:13][C:14]=1[F:15].[CH3:44][N:45](C)C=O>C(#N)C.O.[C-]#N.[Zn+2].[C-]#N.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>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:42]=[S:39]1(=[O:43])[CH2:40][CH2:41][N:36]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:26]3[C:22]([C:17]4[N:16]([C:11]5[CH:12]=[CH:13][C:14]([F:15])=[C:9]([CH:10]=5)[C:44]#[N:45])[C:20](=[O:21])[O:19][N:18]=4)=[N:23][O:24][N:25]=3)=[CH:30][CH:31]=2)[CH2:37][CH2:38]1
Reactant: O=c1onc(-c2nonc2NCc2ccc(CN3CCS(=O)(=O)CC3)cc2)n1-c1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(-n2c(-c3nonc3NCc3ccc(CN4CCS(=O)(=O)CC4)cc3)noc2=O)ccc1F

Procedure:
A solution of 4-(3-bromo-4-fluorophenyl)-3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (10 mg, 14 μmol), zinc cyanide (5 mg, 43 μmol), and tetrakis(triphenylphosphine)palladium(0) (8 mg, 7 μmol) in N,N-dimethylformamide (0.25 mL) was heated in the microwave at 150° C. for 5 min. The reaction mixture was diluted with 3:1 acetonitrile/water (2 mL), filtered, and purified by preparative LCMS to give the intermediate 5-[3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile trifluoroacetate. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.1 mL), and stirred for 45 min. The reaction mixture was quenched with acetic acid (50 μL, 0.9 mmol), filtered, and purified by preparative LCMS to give the desired product (1 mg, 11%). LCMS for C22H23FN7O4S (M+H)+: m/z=500.0.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:30]([NH:29][C:25]3[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[O:31])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N(C)Cc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and m-tolyl isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH2Cl2 and slurred with acetone to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-m-tolyl-urea as a solid (0.41 g, 52%): mp 208-210° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.57 (99%); 1H NMR (DMSO-d6): δ 1.99-2.08 (m, 1H), 2.24 (s, 3H), 2.28-2.35 (m, 1H), 2.55-2.62 (m, 1H), 2.85-2.92 (m, 1H), 2.96 (s, 2H), 4.36 (d, J=17.3 Hz, 1H), 4.43 (d, J=17.3 Hz, 1H), 4.64 (s, 2H), 5.10-5.17 (dd, J=5.1, 13.2 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.29-7.25 (m, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 8.38 (s, 1H). 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 21.17, 22.56, 31.17, 34.71, 46.25, 48.38, 51.56, 117.15, 120.57, 121.71, 122.63, 128.12, 128.43, 129.87, 131.92, 133.87, 137.31, 140.13, 140.27, 155.62, 168.01, 171.01, 172.84. Anal Calcd for C23H24N4O4+0.1 H2O: C, 65.42; H, 5.78; N, 13.27. Found: C, 65.25; H, 5.50; N, 13.14.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19].O>CC(N(C)C)=O>[CH2:18]([O:20][C:21]([N:10]([C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[NH2:11])=[O:22])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: NNC(=O)c1ccccc1O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N(N)C(=O)c1ccccc1O
Temperature: 25 °C

Procedure:
30.4 g. of salicylic acid hydrazide are dissolved in 200 ml of dimethylacetamide and 16 g of pyridine and 22 g of chloroformic acid ethyl ester are then added simultaneously over the course of 30 minutes. Thereafter the reaction mixture is heated to 80°-90° C for 5 hours whilst stirring and is then cooled to room temperature, and about 500 ml of water are added carefully. Hereupon the N-salicyloyl-hydrazine-carboxylic acid ethyl ester produced (Stabiliser No. 1) separates out as a micro-crystalline precipitate. The compound is isolated and is purified by washing with water and recrystallised from ethanol. Melting point 126° C.