Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH2:26])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C(N(CC)CC)C.[NH:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43](O)=[O:44])=[CH:42][C:37]=2[N:36]=[N:35]1.CCOC(OC(OCC)=O)=O>C1COCC1.O>[CH3:2][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:43]([C:41]3[CH:40]=[CH:39][C:38]4[NH:34][N:35]=[N:36][C:37]=4[CH:42]=3)=[O:44])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution (5 ml) of (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (200 mg, 0.480 mmol) in THF were added triethylamine (0.199 ml, 1.44 mmol), 1H-1,2,3-benzotriazole-5-carboxylic acid (78.3 mg, 0.480 mmol) and DEPC (0.079 ml, 0.528 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and eluted with hexane:ethyl acetate (1:1-1:9) to give the title compound (187 mg, 80%) as an amorphous form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[C:1]([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3cccnc3)cc2)c1

Procedure:
0.18 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D4) and 62 mg 3-pyridylboronic acid are dissolved in 10 ml DME. A catalytic amount of bis-(triphenylphosphin-palladium (II)-chloride and 0.6 ml of an aqueous solution of sodium carbonate are added and the mixture is heated to reflux temperature overnight. The title compound is isolated by means of chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:28][C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)[C:9]2[C:10]([C:25]([OH:27])=O)=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([C:15]4[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=4)[C:13]=3[CH3:14])[C:25](=[O:27])[N:28]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)c(OC)n1
Solvent: ClCCl
Solvent: CO
Product: COc1ncc(-n2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(C)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 56.2). tR: 4.10 min (HPLC 1); tR: 0.94 min (LC-MS 2); ESI-MS: 507 [M+H]+ (LC-MS 2); Rf=0.44 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.95 (m, 6H) 3.35 (s, 3H) 3.92 (s, 3H) 3.96 (s, 3H) 6.21 (s, 1H) 7.26-7.33 (m, 2H) 7.35-7.44 (m, 3H) 7.75 (d, J=2.7 Hz, 1H) 8.53 (d, J=0.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[CH:15][N:14]=3)/[O:7][C:8]2=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.O.[NH2:23][NH2:24].C(O)(=O)C>C1COCC1.O>[NH2:19][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[C:6]([CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[CH:15][N:14]=1)=[N:23][NH:24][C:8]2=[O:7]
Reactant: Cn1ncnc1/C=C1\OC(=O)c2cc(F)cc([N+](=O)[O-])c21
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cn1ncnc1Cc1n[nH]c(=O)c2cc(F)cc(N)c12
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroiso-benzofuran-1(3H)-one (3) (4.0 g, 135 mmol) in THF (100 mL) was added hydrazine monohydrate (85%) (6 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 hours, then acetic acid (6 mL) was added and the mixture was heated to and kept at 60° C. for 18 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness to afford the title compound as a yellow solid (1.6 g, yield 42%). LC-MS (ESI) m/z: 275 (M+1)+.
Reaction SMILES: C([NH:8][C@H]1CCCC[C@H]1CO)C1C=CC=CC=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([C:30]3[C:31](=[O:49])[N:32]([CH3:48])[C:33](=[O:47])[N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=4)[C:35]=3[CH3:36])=[C:28]([S:50]([OH:53])(=O)=[O:51])[CH:27]=[N:26]2)=[CH:21][CH:20]=1)#[N:18].P(Cl)(Cl)(Cl)=O.O.N>C(#N)C.C(OCC)(=O)C.O.N1C=CC=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([C:30]3[C:31](=[O:49])[N:32]([CH3:48])[C:33](=[O:47])[N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=4)[C:35]=3[CH3:36])=[C:28]([S:50]([NH2:8])(=[O:53])=[O:51])[CH:27]=[N:26]2)=[CH:21][CH:20]=1)#[N:18]
Reactant: OC[C@@H]1CCCC[C@@H]1NCc1ccccc1
Reactant: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (−)-cis-2-benzylaminocyclohexanemethanol salt of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 195) (6.83 g) in acetonitrile (48 ml) were added pyridine (1.47 ml) and phosphorus oxychloride (3.39 ml) and the resulting mixture was stirred at room temperature for two hours. The reaction solution was added dropwise to ammonia water (28%, 48 ml) that cooled to 0° C. and the mixture was stirred for another ten minutes. To the reaction solution were added water (50 ml) and ethyl acetate (100 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with 4% ammonia water (50 ml), saturated saline (20 ml), 1N hydrochloric acid (50 ml×2) and saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the same product as Example 209, (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (4.84 g). UPLC/MS 531 (M+H)/0.87 min. (measurement condition 9)
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:21]=2[CH2:20]1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[C:27]([O:30][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH:28]=[CH:29][C:21]=2[CH2:20]1)[CH3:15]
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc2C1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Product: CCOC(=O)CC1CCCc2cc(OCCCCNC(=O)OC(C)(C)C)ccc2C1

Procedure:
The title compound was prepared according to the procedure of Example 19 except that (4-bromo-butyl)-carbamic acid tert-butyl ester was used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (2-hydroxy-6,7,8,9-tetrahydro-5H-benzo-cyclohepten-6-yl)-acetic acid ethyl ester was used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:24]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([F:23])([F:21])[F:22])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:24]2)[CH:7]=1
Reactant: OO
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2OC(F)(F)F)C1=O
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of 4-[1-(5-bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (7.06 g, 18.00 mmol) in methanol (300 ml) at 35° C. is added 50% aqueous hydrogen peroxide (1.80 ml, 27.00 mmol), immediately followed by 2M aqueous lithium hydroxide (1.80 ml, 3.60 mmol). After stirring at this temperature for 1 hour the reaction mixture is allowed to cool, then quenched with 10% sodium metabisulfite solution (negative KI-starch indicator test). The reaction mixture is extracted with diethyl ether (×3), then the organic phase is further washed with saturated aqueous sodium bicarbonate (×2) then brine. All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 2-(5-bromo-2-trifluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (6.34 g, 86%) as a yellow oil.
Reaction SMILES: [CH:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:6][CH2:5]1)=O.[Cl-].[CH3:21][O:22]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:21]([CH2:1][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:6][CH2:5]1)=[O:22]
Reactant: O=CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reaction time: 0.5 h

Procedure:
8.2 g of 1-((trans-4-(formylmethyl)cyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 12.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 4.1 g of potassium-t-butoxide was added dropwise at an internal temperature of 5 to 20° C., and the solution was stirred for 30 min. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and dried over silicagel. After evaporating the solvent under reduced pressure, the residue was dissolved in 50 mL of THF, and 50 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 7.0 g of 1-((trans-4-(2-formylethyl)cyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (26 mg, 20%).
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])[C:2]1[CH:7]=CC=CC=1.[C:17]([O:22]CCO)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O1CCOCC1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:17]([O:22][CH2:7][CH2:2][O:1][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Reactant: C=C(C)C(=O)OCCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCOC(=O)CC(C)NC(N)=O
Yield: 77.4 %

Procedure:
One hundred gram (450 mmol) of phenoxycarbonylpropyleneurea and 59 g (450 mmol) of hydroxyehtyl methacrylate were dissolved in 900 ml of dioxane at 85° to 90° C. Then, 400 mg of dibutyltin dilaurate was added thereto and allowed to mix for 13 hours with heat. After completion of the reaction, the mixture was concentrated and recrystalized with ether to obtain 90 g of 2-methacryloyloxyethyloxycarbonylpropyleneurea (77.5% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15]>>[Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CCBr)c2ccccc12

Procedure:
1-(2-bromoethyl)naphthalene and sulfonyl chloride can be allowed to react with each other to yield 4-(2-bromoethyl)-naphthalenesulfonyl chloride. Next, 4-(2-bromoethyl)-naphthalenesulfonyl chloride is esterified with methyl alcohol, and is then subjected to dehydrobromination, whereby methyl 4-ethenyl-1-naphthalenesulfonate as a target can be obtained.
Reaction SMILES: O=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1.[ClH:28].Cl.[NH2:30][CH2:31][CH2:32][O:33][NH2:34].N1C=CC=CC=1>C(O)C>[ClH:28].[ClH:28].[NH2:30][CH2:31][CH2:32][O:33][N:34]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1
Reactant: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Reaction time: 3 h
Yield: 47.8 %

Procedure:
A mixture of 1-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]-1,3-dihydro-2-benzimidazolone (3.85 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.89 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. The solvent was evaporated and the residue was taken up in hot 2-propanol and chilled. The precipitate was collected and recrystallized from 2-propanol and then twice from ethanol/ether to give 1.5 g (29%) of product, mp 175°-180° C. (dec).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])=[CH:2][CH:3]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)CC(C)c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(=O)CC(C)c1ccc(C(=O)C(C)C)cc1

Procedure:
As in Example 1 except using 4-phenyl-2-pentanone instead of benzyl acetone, and iso butyryl chloride instead of benzoyl chloride, b.p. 130 - 134 (0.4 mm).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([CH2:40][O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:38])([CH3:37])[CH:31]=[C:30]2[CH3:39]>C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:23][C:22]=1[C:27]1[C:28]([CH2:40][O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:38])([CH3:37])[CH:31]=[C:30]2[CH3:39]
Reactant: COc1ccccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Aluminum chloride (97.0 mg, 0.73 mmol) was added to anhydrous dichloroethane (0.5 mL) and the solution was cooled to 0° C. Phenylacetyl chloride (97 μL, 0.73 mmol) and 6-(2-methoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 13-3, 49.7 mg, 0.12 mmol) were added thereto and the reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (53.6 mg) as a pale yellow amorphous product. (Yield 82%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN1CCN(CCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 1-Methyl-piperazine were converted to yield 3-(4-Bromo-phenyl)-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]isothiazole as colorless oil, MS: 446 (MH+,1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH2:14][CH2:15][C:16](OCC)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][OH:17])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCC1C(C)CCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1CCN(C(=O)OC(C)(C)C)C1C=CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution containing crude 61 (16.7 g, 0.059 mol) in DCM (150 mL) was cooled to −78° C. BF3.Et2O (8.9 mL, 0.07 mol) was added followed by the dropwise addition of DIBAL (2 M/DCM, 200 mL, 0.4 mol). After 2 h, TLC analysis indicated complete consumption of the 61 [TLC analysis: 1:1 hexane/EtOAc, Rf(62)=0.3]. EtOAc (40 mL) was added and the reaction mixture was warmed to −15° C. The reaction mixture was carefully quenched with 1M HCl until pH=2. The product was extracted with DCM. The organic extracts were washed with 1M HCl, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude 62 was purified by silica gel chromatography (2:1 hexanes/EtOAc) to afford 7.2 g (51%) of 62. 1H NMR (CDCl3, 300 MHz) δ5.8-5.5 (m, 2H), 4.18 (m, 2H), 4.0-3.25 (m, 3H), 2.2-1.85 (m, 2H), 1.55-1.3 (m. 1H), 1.43 (s, 9H), 1.15 (d, J=6 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([CH3:43])[C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[NH2:31][S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([N:39]([CH3:43])[C:40](=[O:42])[CH3:41])=[CH:37][CH:38]=3)[N:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 110 °C
Reaction time: 72 h
Yield: 15.7 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.21 mmol), N-(4-aminophenyl)-N-methylacetamide (100 mg, 0.61 mmol) and trimethylsilyl chloride (0.050 mL, 0.40 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 4 h. More trimethylsilyl chloride (0.100 mL, 0.79 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give N-(4-(4-(3-aminosulfonyl-phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide as a solid (20 mg).
Reaction SMILES: Cl.[CH2:2]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]([OH:24])=[O:23])[CH:19]=2)[NH:14]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].[CH3:27]I>C(O)(=O)C.O.C(O)C>[CH3:27][N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH2:21][CH:13]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC1Cc2cc(C(=O)O)ccc2N1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCC1Cc2cc(C(=O)O)ccc2N1C

Procedure:
A mixture of (RS)-2-(n-undecyl)indoline-5-carboxylic acid hydrochloride (6.8 g), sodium hydroxide (6.8 g), water (25 ml), ethanol (75 ml) and methyl iodide (10 ml) was heated under reflux for 1 hour. Methyl iodide (5 ml) was added and the mixture was heated for 30 minutes, then poured into water and acidified with acetic acid. The product was collected and recrystallised from methanol to give (RS)-1-methyl-2-(n-undecyl)indoline-5-carboxylic acid (3.0 g), in the form of white needles, m.p. 102°-104° C.