Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11](=[O:15])OCC)(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=1)=[O:15])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: COc1cc(C)nc(N)n1
Reactant: CCOC(=O)NS(=O)(=O)N(C)S(C)(=O)=O
Solvent: Clc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 50 °C
Yield: 96.4 %

Procedure:
52.0 g of ethyl (N-methylsulfonyl-N-methylamino)sulfonylcarbamate are dissolved in 500 ml of chlorobenzene, 27.8 g of 2-amino-4-methoxy-6-methylpyrimidine are added at room temperature, and the mixture is heated at 50° C. for 5 hours. After cooling to 0° C., the precipitate is filtered off. After washing with 100 ml of chlorobenzene, 68.8 g of the desired product of a purity of 98.9% are obtained; this corresponds to a yield of 96.4% of theory. The melting point of the product is 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][C:38]1[C:42]([C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([CH3:51])[O:40][N:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([C:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:51])=[O:44])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 13) in an analogous manner as described in example 25. LR-MS: 713.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][N:15]2[C:23](=[O:24])C3C(=CC=CC=3)C2=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH2:27].NN>CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][NH:15][C:23]([O:24][C:4]([CH3:5])([CH3:13])[CH3:3])=[O:27])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O
Reactant: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1C(=O)OC
Agent: NN
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound (909 mg) obtained in Example 129-2 was suspended in methanol (22 ml). Hydrazine monohydrate (0.13 ml) was dropped in this suspension. Then, the solution was subjected to thermal reflux for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and then the residue was subjected to extraction with chloroform. The organic layer was washed with water and then washed with saturated saline solution, followed by drying with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was dissolved in DMF (15 ml) and added with triethylamine (0.54 ml) and di-t-butyl dicarbonate (851 mg), followed by stirring at room temperature for 15 hours. After the solvent had been distilled off, the residue was subjected to extraction with chloroform. The organic layer was washed with water and saturated saline solution and then dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (779 mg) as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Yield: 83.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-cyanobenzoic acid (2.03 g) described in Preparation Example 192 and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.81 g) described in Preparation Example 47, the title compound (2.98 g) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:31][CH2:32][CH3:33])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]=1[C:8]([O:10]CC)=[O:9].O.[OH-].[Li+].Cl>O>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:31][CH2:32][CH3:33])[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of 0.20 g of ethyl 4-hydroxymethyl -2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 35(c)] and 0.10 g of lithium hydroxide monohydrate in 3 ml of water was stirred at room temperature for 3 hours, after which it was allowed to stand for 16 hours at the same temperature. The reaction mixture was then mixed with 2.38 ml of 1N aqueous hydrochloric acid and the resulting precipitate was collected by filtration, to give 150 mg of the title compound, melting at 233° C. (with decomposition).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.[I-:22].[Na+]>S1(CCCC1)(=O)=O.O>[I:22][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: [I-]
Reactant: O=C1COCCN1c1ccc(N2C[C@H](CCl)OC2=O)cc1
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1COCCN1c1ccc(N2C[C@H](CI)OC2=O)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
Under an atmosphere of nitrogen to a solution of 1.00 g of 4-[4-[(5R)-5-(chloromethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-morpholinone (MW=310.74; 1 eq.) in 5.3 mL sulfolane were added 0.97 g of sodium iodide (MW=149.89; 2 eq.). The resulting reaction mixture was stirred for 20 h at 110° C. Then the resulting slurry was cooled to room temperature and diluted with 30 mL of water. After stirring for 1 h at ambient temperature, the crystal suspension was isolated by filtration and the filter cake was washed with 20 mL of water. After drying in vacuo at 30° C., 1.05 g of the crystalline title compound (MW=402.19) were isolated. Yield=81.4%.
Reaction SMILES: [C:1]1([CH3:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[CH3:8][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Cc1ccccc1S
Solvent: CN(C)C=O
Product: Cc1ccccc1Sc1cc(C(=O)O)co1
Temperature: 175 °C

Procedure:
In an open flask cuprous oxide (2.25 g., 15.7 mmoles) and o-toluenethiol (3.89 g., 31.4 mmoles) were combined in 40 ml. of dimethylformamide and heated in a 150° C. oil bath until a thick yellow mixture formed. The mixture was cooled slightly and 5-bromofuran-3-carboxylic acid [3.0 g., 15.7 mmoles; Gilman and Burtner, J. Am. Chem. Soc. 55, 2903 (1933)] in 40 ml. of dimethylformamide added. The mixture was heated in a 175° C. oil bath for approximately 16 hours. The reaction mixture was cooled, solids removed by filtration, the filtrate diluted with 500 ml. of water, acidified with 6 N hydrochloric acid and product extracted into three portions of ethyl acetate. The ethyl acetate extracts were combined, evaporated to an oil, the oil taken up in 1 N sodium hydroxide, the basic solution washed with ether, cooled, reacidified and product (650 mg.) recovered by filtration. Recrystallization from methanol/water gave purified 5-(2-methylphenylthio)furan-3-carboxylic acid (485 mg., m.p. 148°-150° C., m/e 234).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C(=O)Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: CC(C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12)c1ccccc1
Yield: 55.8 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide (170 mg, 0.469 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (282 mg, 1.41 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield tert-butyl(3R)-1-(5-bromo-3-(2-phenylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (142 mg, 55.8% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCCl
Product: CC(=O)CC(=O)N(C)c1ccc(Cl)cc1

Procedure:
An appropriately fitted reaction flask was charged with 26.5 g (0.187 mole) of 4-chloro-N-methylaniline [prepared as described by Kadin in The Journal of Organic Chemistry, vol. 38, p. 1348 (1973)] and 90 ml of 1,2-dichloroethane. Dropwise addition of 16.7 g (0.2 mole) of diketene produced an exothermic response. The reaction solution was refluxed for four hours. Additional 1,2-dichloroethane was added and the organic phase was extracted with: (a) dilute hydrochloric acid, (b) water and (c) saturated aqueous sodium chloride. After drying the 1,2-dichloroethane solution over sodium sulfate, the solvent was evaporated under an efficient source of vacuum. The residual oil (38.9 g, 92%) was used in the following reaction without further purification. N.M.R. (CDCl3) ∂1.8 (CH3, enol), 2.2 (CH3, keto), 3.2 (NCH3), 3.7 (CH2), 4.8 (CH), 7.2-7.4 (aromatic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[NH2:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:30](Cl)=[O:31].CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[NH:6][C:30](=[O:31])[C:29]1[CH:33]=[C:34]([CH3:36])[CH:35]=[C:27]([CH3:26])[CH:28]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(-c2ccno2)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)NC(=O)c1cc(C)cc(C)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Crude 3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (660 mg) is dissolved in chloroform (6.6 ml), stirred vigorously with 2N aqueous sodium carbonate (1,4 ml), and after cooling to 10° C., 3,5-dimethylbenzoylchloride (0.7 ml) is added. Stirring is continued for 1 hour at 10° C. and for 2 hours at ambient temperature. Then extraction with dichloromethane/water, washing with 10% aqueous citric acid, and with brine, followed by evaporation gives the crude product. Flash chromatography on silica gel, hexane/ethyl acetate (4:1), gives pure N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.28 (d, 1.8 Hz, 1H), 7.72 (d, 8.2 Hz, 2H), 7.33 (s, 2H), 7.26 (d, 8.2 Hz, 2H), 7.15 (s, 1H), 6.65 (d, 7.3 Hz, 1H), 6.50 (d, 1.8 Hz, 1H), 5.09 (m, 1H), 4.24 (q, 7.1 Hz, 2H), 3.32 (m, 2H), 2.34 (s, 6H), 1.29 (t, 7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:19]([N:21](CC)CC)C>C(#N)C>[C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:13]=1)#[N:21]
Reactant: CCCCCCCCCCCc1cccc[n+]1[O-]
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCc1cccc(C#N)n1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 10.0 g (40 mmol) of 2-n-undecylpyridine N-oxide and 8.10 g (80 mmol) of triethylamine dissolved in 40 ml of acetonitrile was dropwise added 15.8 g of trimethylsilylanilide while stirring at room temperature. After the dropwise addition, the mixture was refluxed for 67 hours, concentrated under a reduced pressure, followed by separation by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 5.40 g of an oily product (yield 52.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.[H-].[Na+].Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]([O:9][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)c(-n2nc(C)n(C(F)F)c2=O)cc1O
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Yield: 98.5 %

Procedure:
In a manner similar to Example 2, Step G, the reaction of 3.0 g (0.01 mole) of 1-(2-chloro-4-methyl-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.25 g (0.01 mole) of sodium hydride and 1.75 g (0.01 mole) of methyl 2-bromopropionate in 100 mL of N,N-dimethylformamide produced 3.7 g of methyl 2-[4-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-methylphenoxy]propionate as an oil, Compound 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]([C:12](=[CH:21]OCC)[C:13]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])#[N:11]>>[C:10]([C:12](=[CH:21][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])#[N:11]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: COc1ccc(N)cc1
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(OC)cc1

Procedure:
Following the above procedure, p-methoxyaniline (0.05 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.05 mol) to yield α-cyano-β-(4-methoxyanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating in tetralin to yield 5-cyano-1-(4-methoxyphenyl)uracil, m.p. 304.5°-306.5°.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.C(OCC)C>O.C(O)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Agent: C=O
Agent: Cl
Solvent: CCOCC
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Temperature: 95 °C
Yield: 111.9 %

Procedure:
Formaldehyde (35 ml of a 37% solution in water, 420 mmol) was added to a solution of ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89 mmol) in formic acid (35 ml) and the reaction was heated at 95° C. for 3 hours. The reaction was cooled, the volatiles we re removed in vacuo and the residue was dissolved in dichloromethane. 3.0N Hydrogen chloride in diethyl ether (40 ml, 120 mmol) was added, together with a little diethyl ether and a solid was precipitated. Collection of the solid by suction filtration followed by drying in vacuo yielded ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 100% yield) as a white solid:
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl.CCCCCC>[CH3:22][S:23]([O:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(I)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 90.5 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-methoxy-7-iodoisoindolinone (250 mg, 0.819 mmol) was dissolved in dichloromethane (5 mL), and the solution was treated with triethylamine (0.685 mL, 4.91 mmol) and methanesulfonyl chloride (0.190 mL, 2.45 mmol). The mixture was added with water and hexane. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-methanesulfonyloxy-5-methoxy-7-iodoisoindolinone (284 mg, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[C:2]1([NH:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNc1ccccc1
Reaction time: 3 h
Yield: 87 %

Procedure:
According to Kotake et al. (Chem. Pharm. Bull. 1995, 43, 829-841), a stirred solution of aniline (15.3 g, 0.16 mol) and DIEA (56 ml, 0.33 mol) in acetonitrile (120 ml) is heated to 60° C. and ethyl bromoacetate (18.2 ml, 0.16 mmol) is added dropwise within 2 h. The reaction mixture is kept stirring at this temperature for another 3 h and is then evaporated to dryness. Water is added to the residue, the solid is filtered and thoroughly rinsed with H2O. Crystallization from toluene provided pure subtitle compound as beige crystals (25.5 g) in 87% yield. tR (LC-3) 2.33 min; ESI-MS (positive ion): m/z 180.27 [M+H]+ (calcd 179.22 for C10H13NO2). 1H-NMR (CDCl3): 1.29 (t, J=7.0 Hz, 3H); 3.90 (s, 2H); 4.25 (m, 3H); 6.61 (d, J=8.2 Hz, 2H); 6.75 (t, J=7.1 Hz, 1H); 7.21 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:6]1[CH2:7][CH2:8]2)=[O:4].[OH-].[Na+]>CCO>[C:35]([O:34][C:32]([N:31]1[C@H:9]2[CH2:8][CH2:7][C@@H:6]1[C@H:5]([C:3]([OH:4])=[O:2])[C@@H:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:23]([Cl:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[Cl:28])=[CH:16][CH:17]=1)[CH2:10]2)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)[C@@H]1[C@@H](c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3C[C@@H]4CC[C@H]([C@@H]3C(=O)O)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a sol. of compound D2 (595 mg, 1.05 mmol) in EtOH (6.00 mL) was added aq. 1M NaOH (2.0 mL), and the resulting mixture was stirred at rt for 1 h, and at 70° C. overnight. The mixture was partially concentrated under reduced pressure, and the aq. residue was acidified with aq. 2M HCl. The mixture was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (573 mg, 98%) that was used further without purification. LC-MS: tR=1.11 min; ES+: 534.91.
Reaction SMILES: OOS([O-])=O.[K+].[N+:7]([C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O)([O-])=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:7][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]1[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]=1
Reactant: Cc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)c(N)c1
Temperature: 20 °C

Procedure:
33.8 g (55 mmol) of oxone [70693-62-8] are added in portions to a solution of 13.5 g (100 mmol) of 2-nitro-4-methylbenzaldehyde [20357-22-6] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 150 ml of DMF and 5 ml of water with stirring and cooling to 20° C. at such a rate that the temperature does not exceed 35° C. The reaction mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 4 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate in 2000 ml of water, stirred for a further 15 min., extracted with three 300 ml portions of dichloromethane in each case, the organic phase is washed twice with 300 ml of water, once with 500 ml of sat. sodium chloride solution and dried over sodium sulfate. The dichloromethane solution is filtered through silica gel, and the dichloromethane is removed in vacuo. The yellow residue is taken up in 500 ml of methanol, blanketed with nitrogen with stirring, 3 g of 10% Pd/C are added, and the mixture is hydrogenated at room temperature in an autoclave at a hydrogen pressure of 2 bar. When the uptake of hydrogen is complete, the catalyst is filtered off via a Celite bed, and the methanol is removed in vacuo. Yield: 18.5 g (83 mmol), 83%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][OH:21].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:19][CH2:20][OH:21])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2s1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1sc2ccc(Br)cc2n1CCO
Reaction time: 48 h

Procedure:
5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.5 g) were stirred in DMF (7 mL) at room temperature and 2-bromoethanol (0.4 mL) added. The mixture was stirred for 48 h. The mixture was poured onto water and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 25% ethyl acetate in isohexane afforded the subtitle compound as a colourless solid (0.540 g).