Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[C:11]2([CH3:19])[CH3:18].O>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][C:11]2([CH3:19])[CH3:18]
Reactant: CC1(C)C(=O)Nc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CNc2ccc(F)cc21
Temperature: 70 °C

Procedure:
Under an argon atmosphere a solution of 9.30 mL (9.30 mmol) of a 1M solution lithium aluminium hydride in THF and 10 mL THF was slowly added dropwise to 1.40 g (7.81 mmol) 5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one in 50 mL THF. Then the reaction mixture was heated to 70° C. for 1 h. After cooling 2 mL water were added. The solution was dried on sodium sulphate and filtered off. The solvent was eliminated i. vac.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(O)C1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
To a solution of 1.002 g (6.9 mmoles) of 2-hydroxy-2-(pyrrolidin-2-yl)acetic acid in a solution of 550 mg (2 equivalents) of sodium hydroxide in 10 ml of water is added 1.18 ml (1.2 equivalents) of benzyloxycarbonyl chloride, and the mixture is stirred at room temperature for 1.5 hours, washed twice with ether, adjusted to pH 2 with 10% hydrochloric acid, and then extracted thrice with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield 1.288 g of α-hydroxy-α-(1-benzyloxycarbonylpyrrolidin-2-yl)acetic acid in 70.3% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:36]>>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)COC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoro-acetate salt (Intermediate 27) with 2,2-dimethylpropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (s, 9H), 1.98-2.01 (m, 4H), 3.00-3.10 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.70-3.80 (m, 2H), 4.14-4.17 (m, 2H), 5.03-5.09 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.37 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=488.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1.[CH3:16]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH3:16])=[O:12])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)c1ccc(Br)cc1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.43 g, 32.59 mmol) in MeOH (200 mL) was added 2,2-dimethoxypropane (10.18 g, 97.77 mmol) and HCl (4.0 M in dioxane, 4.0 mL). The resulting solution was stirred at 40° C. overnight, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 15 to 25% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclopropanecarboxylate (7.7 g, 83%). 1H NMR (400 MHz, CD2Cl2) δ 1.68 (m, 2H), 2.37 (m, 1H), 3.21 (m, 1H), 3.65 (s, 3H), 7.68 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][OH:8].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:4]([I:3])[CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(CO)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(COCC(=O)OC(C)(C)C)cc1I
Yield: 143.6 %

Procedure:
The procedure used in Example 299: step a was followed using sodium hydride (53 mg, 2.2 mmol), 3-iodo-4-methyl-benzyl alcohol (992 mg, 4 mmol), tert-butyl bromoacetate (0.4 mL, 2.5 mmol) in DMF (10 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound (1.30 g, 89%) as an oil. 1H-NMR (CDCl3): δ 7.84 (d, 1H, J=1.4 Hz), 7.27 (d, 1H, J=1.4 Hz), 7.23 (d, 1H, J=7.7 Hz), 4.55 (s, 2H), 3.99 (s, 2H), 2.44 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C([NH:10][S:11](CC)(=[O:13])=[O:12])(C)(C)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]CC>C1COCC1>[CH3:5][CH:4]([S:11]([NH2:10])(=[O:12])=[O:13])[CH2:3][CH2:2][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: [Li]CCCC
Reactant: CCS(=O)(=O)NC(C)(C)C
Reactant: CCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(C)S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
n-BuLi (1.6M, 32 mL) was added dropwise to a 0° C. solution of N-t-butylethanesulfonamide (4.0 g, 24 mmoles) in anhydrous THF (80 mL) under dry N2. The solution was stirred for 30 minutes at 0° C. then warmed to room temperature for 30 minutes. It was then cooled back to 0° C. and a solution of 1-bromotridecane (6.4 mL, 25 mmoles) in 10 mL anhydrous THF (distilled from Na--Ph2CO) was added dropwise. The solution was allowed to warm to room temperature overnight, quenched by addition of 1N HCl (60 mL), and partitioned between ethyl acetate and brine. The organic layer was dried, filtered, and concentrated to an oil, which was dissolved in 40 mL of CF3CO2H and stirred overnight at room temperature. It was then concentrated and the solid residue recrystallized from iPr2O to afford 4.8 g (68%) of 2-pentadecylsulfonamide as a light brown (almond) powder. (b) A solution of 2-pentadecylsulfonamide (2.91 g, 10 mmoles) in DMF (40 mL dried over 3Å sieves) was added dropwise to a stirred, 0° C. suspension of NaH (0.5 g, 21 mmoles of hexane washed) in 10 mL dry DMF. The mixture was stirred 30 minutes at 0° C., then warmed to room temperature for 3 hours. It was then cooled back to 0° C. and a solution of 2,6-diisopropylphenylisocyanate (2.14 mL, 10 mmoles) in 10 mL DMF was added dropwise. The mixture was allowed to warm to room temperature overnight, cooled to 0° C., and quenched by dropwise addition of 1N HCl (60 mL). The mixture was partitioned between EtOAc (300 mL) and H2O (100 mL). The organic layer was further washed with brine, dried, filtered, and evaporated to provide an oil which was flash chromatographed (silica gel, 4:1 hexane-EtOAc) to produce 3 g of an oil which solidified on standing (m.p. 65-75° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5](Cl)=[O:6].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(#N)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([O:19][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([Cl:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.8 g of 2,6-dichloroisonicotinic acid chloride, dissolved in 10 ml of acetonitrile, are added dropwise to a solution, maintained at 15°-20° C. by cooling, of 5.4 g of benzyl alcohol, 0.5 g of 4-dimethylaminopyridine and 3.0 g of pyridine in 50 ml of acetonitrile. After stirring overnight at room temperature the batch is poured onto ice-water, taken up in methylene chloride, washed with water, dried and concentrated by evaporation. The oil that remains crystallises from pentane in the form of white crystals having a melting point of 39°-41° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[C:21]4[N:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19]4=[N:26][N:27]([CH:30]5[CH2:35][CH2:34][CH2:33][O:32][CH2:31]5)[C:28](=[O:29])[C:18]4=[N:17]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.I[Si](C)(C)C.CO.O>ClCCl>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:21]4[N:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19]4=[N:26][N:27]([CH:30]5[CH2:35][CH2:34][CH2:33][O:32][CH2:31]5)[C:28](=[O:29])[C:18]4=[N:17]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(Cn3nc4c(=O)n(C5CCCOC5)nc-4c4cccnc43)cc2)cn1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=c1c2nn(Cc3ccc(-c4ccc(O)nc4)cc3)c3ncccc3c-2nn1C1CCCOC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(±)-5-({4-[6-(Methyloxy)pyridin-3-yl]phenyl}methyl)-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one (Example 14, 20 mg, 0.043 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. and treated with iodotrimethylsilane (26 μL, 0.13 mmol, 3 equiv). After stirring for 15 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was cooled to 0° C. treated with additional iodotrimethylsilane (26 μL, 0.13 mmol, 3 equiv) and after stirring for 15 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with methanol (1 mL), poured into water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 90: 10; dichloromethane:methanol), providing the titled compound as a deep red solid: high resolution mass spectrometry (ES+) m/z 455.1839 [(M+H)+; calculated for C25H23N6O3: 455.1826].
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12]=O)=[C:8]([N:14](C)C)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:17]N>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[N:17][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C)c1cnn(C(C)(C)C)c(=O)c1C=O
Solvent: CCO
Product: CC(C)(C)n1ncc2[nH]ncc2c1=O

Procedure:
2-Tert-butyl-5-dimethylamino-4-formyl-3(2H)-pyridazinone (3.5 g) was added to hydrazine (5.1 g)/ethanol (30 ml) and the mixture was refluxed for 40 hours. The solvent ethanol-hydrazine was then distilled off and the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane-diethyl ether and dried. White powder, 1.9 g. 1H-NMR (CDCl3) δ: 1.71(9H,s), 8.19(1H,s), 8.32(1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[CH2:60][CH2:59][CH2:58][CH2:57]2)[CH:50]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]([CH3:46])[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:50]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1cccc(CN2CCCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3cccc(CN4CCCC4)c3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), DIPEA (0.17 mL, 0.97 mmol) and N-methyl-1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (31 mg, 0.14 mmol) in DCE (1.2 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:43]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21]([N:47]3[CH2:46][CH2:43][NH:45][CH2:49][C:48]3=[O:50])=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CNCCN1C(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1

Procedure:
75 mg (0.21 mmol) of the compound of Example 26A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.23 mmol) of 2-oxopiperazine. 77 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]([CH:18]([CH3:22])[CH2:19][CH2:20]O)[CH:15]=[CH:16][CH:17]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]([CH:18]([CH3:22])[CH2:19][CH2:20][N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[CH:15]=[CH:16][CH:17]=1
Reactant: CC1=C(/C=C/c2cccc(C(C)CCO)c2)C(C)(C)CCC1
Reactant: O=C1NC(=O)c2ccccc21
Product: CC1=C(/C=C/c2cccc(C(C)CCN3C(=O)c4ccccc4C3=O)c2)C(C)(C)CCC1

Procedure:
Conversion of (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butan-1-ol with phthalimide following the method used in Example 18 gave (E)-2-(3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butyl)isoindoline-1,3-dione as a colorless oil. Yield (0.416 g, 93%): 1H NMR (500 MHz, CDCl3) δ 7.75 (m, 2H), 7.64 (m, 2H), 7.18 (s, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.64 (d, J=16.3 Hz, 1H), 6.27 (d, J=16.3 Hz, 1H), 3.67 (t, J=7.1 Hz, 2H), 2.78 (m, 1H), 2.12 (m, 1H), 2.04 (t, J=6.0 Hz, 2H), 1.93 (m, 1H), 1.77 (s, 3H), 1.64 (m, 2H), 1.49 (m, 2H), 1.30 (d, J=7.0 Hz, 3H), 1.08 (s, 6H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Br:8].N([O-])=O.[Na+].[S:16](=[O:18])=[O:17].O.O.[Cl-:21]>Cl.O>[Br:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][C:2]=1[S:16]([Cl:21])(=[O:18])=[O:17]
Reactant: [Cl-]
Reactant: CC(=O)c1ccc(Br)c(N)c1
Reactant: O=S=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(Br)c(S(=O)(=O)Cl)c1

Procedure:
5.35 g of 3'-amino-4'-bromoacetophenone, melting point: 113° C., were diazotized in 50 ml of semi-concentrated hydrochloric acid with 1.75 g of sodium nitrite at 0°-5° C. and then decomposed according to Meerwein with 62 ml of sulfur-dioxide-saturated glacial acetic acid solution and 2 g of copper-II-chloride-dihydrate. chloride-dihydrate. After the addition of 62 ml of water, the 4'-bromo-3'-chlorosulfonylacetophenone was obtained which melted at 107° C. and could be introduced without further purification into about 50 ml of liquid ammonia. After evaporation of the ammonia and treatment with water, 4'-bromo-3'-sulfamoylacetophenone were obtained which melted at 161° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=[O:18].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O>CC#N.O>[OH:18][CH2:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)=[O:3]
Reactant: CC(=O)c1nn(CC(=O)O)c2ccccc12
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)Cn1nc(C(=O)CO)c2ccccc21
Temperature: 90 °C

Procedure:
The title compound was prepared in a similar manner as described by N. Yoshikawa et al., J. Org. Chem., 2002, 67, 2556-2565: A mixture of 2-(3-acetyl-1H-indazol-1-yl)acetic acid (100 mg, 0.46 mmol), TFA (0.71 mL, 0.92 mmol) and bis-(trifluoroacetoxy)-iodobenzene (394 mg, 0.92 mmol) in CH3CN (4 mL) and water (0.6 mL) was heated to reflux (90° C.) for 16 h. Solvents were evaporated and the crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 233 [M+H]+; tR (HPLC conditions k): 2.41 min.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:34]1([C:40](=[O:42])[CH3:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:43][C:44]1[CH:52]=[C:51]2[C:47]([C:48]([N:62]([CH2:69][C:70](O)=[O:71])[CH:63]3[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]3)([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[C:49](=[O:53])[NH:50]2)=[CH:46][CH:45]=1>ClCCl>[C:40]([N:34]1[CH2:39][CH2:38][N:37]([C:70](=[O:71])[CH2:69][N:62]([CH:63]2[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]2)[C:48]2([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[C:47]3[C:51](=[CH:52][C:44]([Cl:43])=[CH:45][CH:46]=3)[NH:50][C:49]2=[O:53])[CH2:36][CH2:35]1)(=[O:42])[CH3:41]
Reactant: O=C(O)CN(C1CCCCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)CN(C2CCCCC2)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To the mixture of DIPEA (43 mg, 0.33 mmol), HATU (64 mg, 0.17 mmol) and 1-piperazin-1-yl-ethanone (22 mg, 0.17 mmol) in dichloromethane (3 mL) was added rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-indol-3-yl]-cyclohexyl-amino}-acetic acid (50 mg, 0.11 mmol). After the mixture was stirred at room temperature for 3 h, the crude was washed with water (3×10 mL). The organic solution was concentrated in vacuo and the residue was puritificated by preparative HPLC to give 24 mg of rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. MS: 557 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccc(F)cc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccc(F)cc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]1OC)[CH2:2][CH3:3].BrCCCCN1[C:26](=[O:27])C2=CC=CC=C2C1=O.Br[CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>>[CH3:26][O:27][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:6][O:7]2
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1ccc(S(=O)(=O)NCCCBr)cc1
Reactant: CCCNC1Cc2ccccc2OC1OC
Product: CCCN(CCCNS(=O)(=O)c1ccc(C)cc1)C1COc2cccc(OC)c2C1
Reaction time: 72 h
Yield: 65 %

Procedure:
Using the procedure described in Example 1, but replacing 3-amino-5-methoxychroman by 3-(N-propylamino)-methoxychroman and N-(4-bromobutyl)phthalimide by -bromo-3-(4-toluenesulfonylamino)propane, and leaving stirring for 72 hours, the expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.C(O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:8]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(N)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 2-methyl-5-nitroanisole (11.56 g, 69.2 mmol) in a mixture of ethyl acetate (200 mL) and ethanol (70 mL) was added portionwise tin (II) chloride dihydrate (109 g, 0.483 mol) and the mixture was stirred at room temperature overnight. The reaction mixture was basified with aq. K2CO3 and filtered over celite. The layers were separated. The aqueous layer was further extracted with ethyl acetate and the combined organics washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 8.02 g of 3-methoxy-4-methyl-aniline (86% yield). 1H NMR (300 MHz; CDCl3): 2.09 (s, 3 H), 3.76 (s, 3 H), 4.01 (br s, 1 H), 6.20 (m, 2 H), 6.90 (d, J=8.4 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:30][Zn]C.ClCCl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 50 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.040 g, 0.098 mmol) in 3 mL of tetrahydrofuran under an atmosphere of nitrogen was added dimethylzinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol). The mixture was heated at 50° C. for 3 hr and then cooled to ambient temperature. Additional dimethyl zinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol) were added and the mixture was heated at 50° C. for an additional 12 hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 387.4 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92-7.84 (m, 3H), 7.69 (s, 1H), 7.65-7.61 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 4.87-4.73 (m, 2H), 4.53 (s, 2H), 4.23-4.16 (m, 1H), 3.81-3.75 (m, 1H), 2.77 (s, 3H), 2.23-2.20 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.84 (m, 2H), 1.84-1.64 (m, 1H), 1.55-1.33 (m, 3H) ppm.