Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[OH:3][C:4]([CH3:30])([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C>[OH:3][C:4]1([CH3:30])[CH:11]([Br:1])[CH:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[O:8][C:6](=[O:7])[CH2:5]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C=CCCCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(O)CC(=O)OC(CCCc2ccc(OCc3ccccc3)cc2)C1Br

Procedure:
According to the method described in Example 25 (b), the reaction was carried out by using 0.13 ml of bromine and 0.74 g of the carboxylic acid which was prepared from 0.80 g of ethyl 3-hydroxy-3-methyl-8-(p-benzyloxyphenyl)-4-octenoate, 8 ml of ethanol and 1 ml of 4 N sodium hydroxide, and the product was recrystallized from ethyl ether to give 0.32 g of the desired compound melting at 100°-101° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:29][CH3:30])[C:14]([N:21]3[CH2:26][CH:25]([CH3:27])[NH:24][CH:23]([CH3:28])[CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:10]=1)=[O:8].Cl[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][N:24]1[CH:23]([CH3:28])[CH2:22][N:21]([C:14]2[C:13]([O:29][CH3:30])=[C:12]3[C:17]([C:18](=[O:19])[C:9]([C:7]([NH:6][CH2:5][C:4]4[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:3]=4[Cl:2])=[O:8])=[CH:10][N:11]3[CH2:31][C:32]([F:34])([F:35])[F:33])=[CH:16][C:15]=2[F:20])[CH2:26][CH:25]1[CH3:27])[CH3:47]
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(CC(F)(F)F)c12
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CN1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1C

Procedure:
810.0 mg (1.29 mmol) of N-(2,4-dichlorobenzyl)-7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinoline-3-carboxamide hydrochloride (Example 38A), 396.5 mg (3.24 mmol) of ethyl chloroacetate, 64.5 mg (0.39 mmol) of potassium iodide and 804.9 mg (5.82 mmol) of potassium carbonate are stirred under reflux in 20 ml of acetonitrile overnight. The Work-up takes place in analogy to the general working instructions 1, and after purification via preparative RP-HPLC (method 5) 1050 mg of the target compound are obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>O1CCCC1.ClCCl>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11]([C:10]2[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:14][CH3:15])=[N:8][CH:9]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: CSc1ncc(C(=O)Cl)c(NC(C)C)n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cnc(SC)nc2NC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a 0° C. suspension of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid chloride (as prepared in the above example, Preparation 16) in 30 mL of tetrahydrofuran is added 6.0 mL (46.3 mmol) of 4-methoxybenzylamine and 30 mL of tetrahydrofuran. The reaction suspension is allowed to warm briefly to room temperature, then stored at 0° C. overnight. The reaction mixture is diluted with dichloromethane, washed with 1N HCl and water. The combined aqueous phase is washed with dichloromethane. The combined organic phase is washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue is crystallized from ethyl acetate/hexane to give 3.27 g (61%) of the title compound: mp 176-177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]([CH3:26])[CH:7]=1)=[O:5]
Reactant: CI
Reactant: COC(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1cn(C)c2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.1 %

Procedure:
A 0° C. suspension of (6-benzyloxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (2.70 g, 8.73 mmol) in dimethylformamide (25 mL) is treated with sodium hydride (437 mg, 10.9 mmol). The mixture is stirred at 0° C. for 20 minutes. Methyl iodide (1.00 mL; 16.1 mmol) is added. The reaction mixture is stirred at 0° C. for 30 minutes and quenched with water (100 mL). The mixture is extracted with EtOAc (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography eluting with 60% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to afford the title compound (0.68 g, 24%). ES.MS m/e 324.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([O:24][C:25]2[C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[N:21]=[CH:20][N:19]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:9]=1[C:18]1[N:19]=[CH:20][N:21]=[C:22]([O:24][C:25]2[C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[CH:23]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)OC(C)(C)C)ncn3)cccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reaction time: 16 h

Procedure:
To {2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}carbamic acid tert-butyl ester, (Example 150) (0.35 g, 0.60 mmol) was added 4 M HCl in dioxane (25 mL). The mixture was stirred for 16 h and then was concentrated in vacuum. The residue was dissolved in ethyl acetate (40 mL) and washed with saturated NaHCO3 (2×70 mL), dried over Na2SO4 and concentrated in vacuum. Purification by silica gel chromatography (2:1, EtOAc:hexanes) afforded the title compound as thick yellow oil. Mp: 160–161° C. MS (ESI, pos. ion) m/z: 446 (M+1). Anal. Calcd for C20H14F3N5O2S.0.4H2O: C, 53.07; H, 3.30; F, 15.47; N, 12.59. Found: C, 53.12; H, 3.27; F, 15.19; N, 12.70.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC12
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2-hydroxyphenylacetic acid (1.06 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.23 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 125 cc fractions. Fractions 4 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (15 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-hydroxyphenyl)acetyl]-4-perhydroisoindolone (0.8 g) is obtained in the form of white crystals melting at 232° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[CH3:12][NH:13][C:14](=O)[C@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][CH:17]=[CH2:18].ClCCl>O1CCCC1.CO.ClCCl>[CH3:12][NH:13][CH2:14][C@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][CH:17]=[CH2:18]
Reactant: C=CC[C@H](C(=O)NC)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: C=CC[C@H](CNC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Cool a solution of lithium aluminum hydride (42.6 mL, 1.0 M in tetrahydrofuran, 42.6 mmol) to about −10° C. Add dropwise a solution of sulfuric acid (2.1 g) in tetrahydrofuran (5 mL) while maintaining the temperature of the reaction mixture at less than 0° C. After 20 minutes, warm to ambient temperature. Add a solution of (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid, N-methyl amide (4.8 g, 18.8 mmol) and tetrahydrofuran (25 mL). After the addition is complete, heat the reaction mixture abbot t 35° C. After 15 hours, cool in an ice bath and carefully quench by the addition of water (5 mL) and tetrahydrofuran (5 mL). Add tetrahydrofuran (60 mL) and filter, and evaporate the filtrate in vacuo to give a residue. Combine the residue and dichloromethane, extract with water, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1% methanol/dichloromethane, 2% methanol/dichloromethane, 3% methanol/dichloromethane, and 4% methanol/dichloromethane to give (S)-N-methyl-(2-(3,4-dichlorophenyl)pent-4-enyl)amine: Rf=0.54 (silica gel, 9/1/0.1 dichloromethane/methanol/concentrated aqueous ammonia).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.3 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (3.14 g), 2-pyridylmethyl chloride (3.28 g), potassium carbonate (5.52 g) and DMF (20 ml) was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate to give 3-fluoro-4-nitrophenyl 2-pyridylmethyl ether (0.86 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>C(#N)C.CCOCC.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[N:23]=[N:24][N:25]=[C:9]23)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: O=c1cc(C(F)(F)F)n2nnnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (1.1 g) was dissolved in a mixture of acetonitrile (20 ml) with ether (20 ml) and was added with sodium azide (0.24 g) under ice-cooled condition. The thus obtained mixture was stirred for 30 minutes at room temperature and was added with saturated brine (50 ml). The mixture was extracted with ether and then dried on anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. The residue was purified by a preparative thin-layer plate of silica gel (developing solvent: ethyl acetate/hexane=1.5/8.5) to give the compound of interest (0.7 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH2:22][CH3:23])[O:10][C:9](=O)[C:8]=2[CH:25]=1)([OH:3])=[O:2].[OH-].[NH4+:27]>[OH-].[Na+]>[C:1]([C:4]1[CH:25]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:12]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[O:21][CH2:22][CH3:23])[NH:27][C:9]2=[O:10])([OH:3])=[O:2]
Reactant: CCOc1c(OC)cccc1-c1nc2ccc(C(=O)O)cc2c(=O)o1
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: CCOc1c(OC)cccc1-c1nc2ccc(C(=O)O)cc2c(=O)[nH]1

Procedure:
The yield is 5 g of 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-4H-3,1-benzoxazin-4-one (m.p.=175°-177° C.), which are reacted at room temperature first with 70 ml of 32% ammonium hydroxide for 4 hours and then with 20 ml of 2N NaOH overnight. After acidification with 4N HCl, the precipitate is filtered off and crystallized from ethanol to give 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline (3 g; m.p. 228°-229° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=[O:14].[CH2:19](Br)[CH2:20][CH3:21]>CC(=O)CC.O>[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH3:21])[CH:13]=[O:14]
Reactant: CCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCOc1ccc(C=O)cc1O
Yield: 23.2 %

Procedure:
Anhydrous potassium carbonate (5.9 g, 0.043 mmol) and sodium iodide (0.434 g, 4.3 mmol) were added to 3,4-dihydroxybenzaldehyde (4.0 g, 28.9 mmol), in butanone (100 ml), at room temperature. The reaction was stirred for 10 min after which propyl bromide (2.628 ml, 28.9 mmol) was added dropwise and the reaction was refluxed for 3 h. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×50 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) afforded 1.21 g (23.3%) of 3-hydroxy-4-propoxybenzaldehyde as an off-white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]([C:36](O)=[O:37])[CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36]([CH:28]5[CH2:29][C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[O:26][CH2:27]5)=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1COc2ccccc2C1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1COc2ccccc2C1

Procedure:
The title compound, white solid (28.5 mg, 71%), MS (ISP) m/z=491.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and chroman-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1
Reactant: COc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To [6-Methoxy-5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine (31, 0.0340 g, 0.0598 mmol) was added tetrahydrofuran (5 mL) followed by tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 66 μL, 0.0658 mmol). The reaction was allowed to stir at room temperature for 2 hours, then poured into 1:1 water:saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and the volatiles were removed by rotary evaporation. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane followed by 1% methanol in dichloromethane and finally 3% methanol in dichloromethane. This provided 20 mg of the desired compound as a white solid (P-0012, 0.048 mmol, 81%). MS(ESI) [M+H+]+=413.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:37](=O)[N:38]([CH2:40][CH2:41][NH2:42])C)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:42][CH2:41][CH2:40][NH:38][CH3:37])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with TFA and neutralisation, the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:30](#[N:33])[CH:31]=[CH2:32]>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:32][CH2:31][C:30]#[N:33])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CC#N
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCN(CCC#N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (260 mg) obtained in Example 23-4 was dissolved in methanol (5.0 ml) and added with distilled water (1.0 ml) and acrylonitrile (87.4 μl) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off and the resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (332 mg) as a colorless oily substance.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:34]=[C:35]([NH:36]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:37]=[CH:38][CH:39]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)CCNCc1cccc(N)c1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-(2-ethoxycarbonyl-ethylaminomethyl)-aniline in DMF.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C.C(OCC)(=O)C>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1
Reactant: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CN)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 45 h

Procedure:
A dispersion of Lindlar catalyst (0.150 g) in ethanol (10 ml) was hydrogenated at atmospheric pressure for 15 min. Then, a solution of the product of step c) (0.187 g, 0.38 mmol) in ethyl acetate (3 mL) was added with a syringe, and the resulting mixture stirred vigorously for 45 h. The solution was filtered through Celite® (a silica gel) and the solvents evaporated. Chromatography on silica (ethyl acetate/methanol/ammonium hydroxide; 80/20/2; v/v) furnished 20.1 mg of 3-[1-(3-aminomethylbenzyl)-indol-3-yl]-4-(1-methyl-indol-3-yl)-pyrrole-2,5-dione which was dissolved in ethanolic HCl (1.5 M), evaporated, dissolved in methanol, evaporated to dryness, dissolved in water and freeze dried to afford the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([CH:36]([OH:39])[CH2:37][NH2:38])[CH:33]=[CH:32][C:31]=1[OH:40]>>[OH:39][CH:36]([C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[C:30]([O:29][CH3:28])[CH:35]=1)[CH2:37][NH:38][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: COc1cc(C(O)CN)ccc1O
Product: COc1cc(C(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(NC(C)=O)cc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-normetanephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.06 (m, 2H), 2.06 (s, 3H), 2.50-3.50 (m, 5H), 3.55-3.65 (m, 2H), 3.77 (s, 3H), 4.70-4.80 (m, 1H), 5.70-5.85 (brs, 1H), 6.70-6.90 (m, 7H), 7.59 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 8.95 (brs, 1H), 10.37 (s, 1H); MS (ES) m/z: 555.2 (MH+); HRMS Calcd. for C28H35N4O6S(MH+): 555.2277. Found: 555.2265.