Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][CH2:19][CH:18]([OH:25])[CH2:17]2)=[C:12]([OH:26])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][CH2:19][C:18](=[O:25])[CH2:17]2)=[C:12]([OH:26])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCC1CCC(O)CC1c1ccc(C(C)(C)CCCCCC)cc1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(2-propenyl)cyclohexanol (2.15 g, 6.03 mmole) (mixture of isomers) in dichloromethane (15 ml) was added pyridinium chlorochromate (2.59 g, 12.1 mmole). The reaction mixture was stirred for 2 hours at room temperature, diluted with ether, diatomaceous earth added and the mixture filtered through magnesium sulfate. The evaporated filtrate was purified via column chromatography on 200 g of silica gel eluted with 20% ether-pentane to yield 250 mg of crude title compound. This was further purified via preparative layer chromatography on two 20 cm×20 cm×2 mm silica gel plates eluted twice with 20% ether-pentane to yield 200 mg (9.3%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC2CCCCC2)CC1

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound, cyclohexanone (0.73 ml) and sodium cyanoborohydride (0.86 g) were reacted and treated in the same manner as in Example 136 to give 1.42 g of 4-amino-5-chloro-N-((1-(5-(cyclohexylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([OH:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl>CC(C)=O.O>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([OH:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCNC(=O)OCc1ccccc1)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 22.5 °C
Reaction time: 15 h
Yield: 111.1 %

Procedure:
A 0.5 L round-bottom flask is loaded with 22.6 g of 3-aminopropionyl-histidine, 150 ml of water and 30 ml of acetone. The solution is adjusted to pH 13.00 with 30% sodium hydroxide, then cooled to 0-5° C., at which temperature 18.7 g of benzyl chloroformate are dropwise added in about 1 h, keeping pH at 12-13 with sodium hydroxide. Afterwards, the mixture is stirred for 15 h at 20-25° C., acidified to pH 2.0-2.5 with 37% hydrochloric acid, then concentrated under vacuum, at 50° C. maximum, carrying out repeated evaporations with isopropanol to a white solid residue. 40 g of a residue are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[I:15]I>O1CCCC1>[I:15][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: II
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1cc2ccccc2o1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of benzofuran (3.0 g, 25.4 mmol) in tetrahydrofuran (36 mL) at about −78° C. was added a 2.5M solution of n-butyllithium in hexanes (10.2 mL, 25.4 mmol). The solution was allowed to warm to about −10° C. and was stirred for about 2 hours. Iodine (6.41 g, 25.4 mmol) was added gradually and the mixture was stirred at about −10° C. for about 30 min. The solution was allowed to warm to room temperature, was quenched by the addition of aqueous ammonium chloride, and was extracted with diethyl ether. The combined organic extracts were washed with aqueous sodium bisulfite and brine, dried (MgSO4), filtered and concentrated under vacuum. The resulting oil was distilled (b.p. 90° C./1.05 mm Hg) to provide Example 651. 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1H), 7.20 (m, 2H), 7.48 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCNCCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCNCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-[(2-aminoethyl)amino]ethanol. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, J=7.6 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1 H), 7.61-7.57 (m, 2 H), 7.43-7.38 (m, 2 H), 7.24 (d, J=7.6 Hz, 1 H), 6.02 (s, 1 H), 5.12 (s, 2 H), 4.51 (brs, 2 H), 3.69 (t, J=5.2 Hz, 2 H), 3.55-3.52 (m, 2 H), 3.49 (t, J=6.0 Hz, 2 H), 3.01 (t, J=6.0 Hz, 2 H), 2.83 (t, J=5.6 Hz, 2 H), 2.38 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28]#[N:29])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([OH:33])(C)C>[OH-].[K+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28](=[O:33])[NH2:29])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3c2CCCC3)CC1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(N)=O)c3c2CCCC3)CC1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
4-(4-Cyano-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (545 mg, 1.30 mmol) was dissolved in a mixture of isopropanol (2 ml) and 2N KOH (4 mL). The reaction was stirred for 5 days at 80° C. The isopropanol was removed in vacuo and the residue was diluted with H2O (20 mL). The mixture was charged to a separatory funnel and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to a white solid that was triturated with dichloromethane to afford 4-(4-carbamoyl-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester F-29 as a white solid. Wt.: 340 mg (60%). 1H NMR (300 MHz, D-DMSO) δ 7.81 (m, 2H), 7.72 (d, 1H), 7.52 (s, 1H), 7.23 (d, 1H), 3.72 (m, 2H), 3.09 (m, 3H), 2.81 (m, 2H), 2.71 (m, 2H), 1.70 (m, 4H), 1.55 (m, 2H), 1.36 (s, 9H), 1.25 (m, 2H); LC/MS m/z 436 (M−H)−. The aqueous extract was acidified to pH 2 with IN HC1 and extracted twice with dichloromethane. The combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration in vacuo afforded 4-(4-carboxy-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Wt.: 76 mg (13%). 1H NMR (300 MHz, d6-DMSO) δ 7.72 (d, 1H), 7.33 (s, 1H), 7.23 (d, 1H), 3.72 (m, 2H), 3.09 (m, 3H), 2.81 (m, 2H), 2.71 (m, 2H), 1.70 (m, 4H), 1.55 (m, 2H), 1.36 (s, 9H), 1.25 (m, 2H); LC/MS m/z 437 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>ClCCl.CO>[CH3:16][C:2]([CH3:1])([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([C:13]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:15])[CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 76 %

Procedure:
Prepared analogously to Example A15a) from 1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid and 1-methylpiperazine in the presence of TBTU in a yield of 76% of theory. Colourless, amorphous substance, Rf=0.64 (eluant: dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH3:49])[C:18](=[O:48])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:36]3[N:35]=[C:34]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])=[C:21]([O:46][CH3:47])[CH:20]=1)(O)=[O:2].[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:47][O:46][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH:25][C:26]([C:28]1[C:36]2[N:35]=[C:34]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27])[C:18]([N:17]([CH3:49])[C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([N:60]1[CH2:61][CH2:62][N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:56])[CH2:58][CH2:59]1)=[O:2])=[O:48]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-[2-(tert-butoxycarbonylamino)methyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (200 mg), 4-(tert-butoxycarbonyl)piperazine (66.3 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68.3 mg) and 1-hydroxybenztriazol (48.1 mg) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature overnight and the mixture was diluted with ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column (chloroform) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-tert-butoxycarbonylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (250 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][P:6](=[O:18])([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:19].[H][H]>C(O)C.[Pd]>[ClH:19].[CH2:1]([N:3]1[CH2:4][CH2:5][P:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)(=[O:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCP(=O)(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCN1CCP(=O)(c2ccc(N)cc2)CC1
Reaction time: 5 h

Procedure:
1-Ethyl-4-(4-nitro-phenyl)-perhydro-1,4-azaphosphorine 4-oxide (269.80 mg, 1.0058 mmol) dissolved in Ethanol (50 mL) and treated with palladium on carbon 10% (90:10, carbon black:Palladium, 30 mg, 2 mmol), 2.5 M of hydrogen chloride in ethanol (1.21 mL, 3.02 mmol) and 50 PSI of hydrogen gas. The mixture was shaken on a Parr apparatus for 5 hours. The mixture was degassed and backflushed with nitrogen. The mixture was filtered through a plug of diatomaceous earth and washed with ethanol. The filtrate was evaporated. 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)aniline hydrochloride was isolated (401 mg, 145%). MS=238 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:29][CH:16]([C:7]1[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 107.7 %

Procedure:
In carbon tetrachloride (15 mL) was dissolved Intermediate 10 (1.46 g, 5.0 mmol) and NBS (1.33 g, 7.5 mmol). The solution was treated with benzoyl peroxide (~2 mg) and warmed to 60° C. and stirred for 18 hours. The mixture was cooled to room temperature and filtered free of insolubles. The filtrate was evaporated in vacuo to give 2.0 g (>100%) of the crude product as an oil.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][O:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COc1c(B(O)O)ccc2c1CCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc2c(c1OC)CCCC2
Temperature: 25 °C
Yield: 20.1 %

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid, methyl ester, (2.06 g, 9.61 mM), 1-methoxy-5,6,7,8-tetrahydronaphthalene-2-boronic acid, (2.08 g, 10.09 mM), tetrakis(triphenylphosphine)palladium(0) (0.583 g, 0.5 mM), and 2M aqueous sodium carbonate solution (10.5 mL, 21.0 mM) in THF (50 mL) was stirred at reflux for 48 hours in the absence of light. The mixture was cooled to room temperature, the THF removed in vacuo, and the resulting aqueous residue dissolved in ethyl acetate and brine. The solvent layers were separated, the aqueous layer extracted with ethyl acetate (4×25 mL), the combined ethyl acetate extracts washed successively with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant black oil was purified by column chromatography on silica gel (elution with 5–15% ethyl acetate/hexane) to afford 0.656 g (20%) of the title compound 2-(1-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-nitrobenzoic acid, methyl ester as a yellow solid (MW 341.37, C19H19NO5).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19])[CH3:15]>C1COCC1>[CH3:19][C:18]([O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:20])[C:17]([O:16][CH2:14][CH3:15])=[O:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a solution of potassium t-butoxide (1M in THF, 531 ml, 0.531 moles, 1 eq) precooled to 0° C. (ice bath) was added phenol (50 g, 0.531 moles, 1 eq) in dry THF (50 ml) dropwise via an addition funnel over 20 minutes maintaining the internal temperature of the reaction below 5 degrees centigrade. Ethyl-2-bromoisobutyrate (70.14 ml, 0.9 eq, 0.478 moles) in dry THF (20 ml) was added dropwise over 10 minutes maintaining the internal reaction temperature below 5° C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was brought to reflux and maintained at this reflux temperature for 8 hours. Following the cooling of the reaction to 0° C. the volatiles were removed in vacuo. The residue was then partitioned between EtOAc and 1N NaOH. The phases were separated and the organic phase was washed with 1N NaOH, H2O, brine and dried over Na2SO4. After filtration the solution was concentrated under reduced pressure to yield 83 g (75%) of clean title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C., where it was stirred for 25 min. The reaction mixture was then treated with 2-aminopyridine (91 mg, 0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide (106 mg, 58%) as a white foam: mp 92-95° C. (foam to gel); FAB-HRMS m/e calcd for C20H23N3O5S (M+H)+ 418.1436, found 418.1430.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([F:38])[F:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Cl.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C:45](Cl)=[O:46]>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([F:38])[F:37])(=[O:34])=[O:35])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:45]([C@@H:41]4[CH2:42][CH2:43][CH2:44][NH:40]4)=[O:46])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(F)F)n2)c(OC(C)C)cc1C1CCNCC1
Reactant: O=C(Cl)[C@@H]1CCCN1
Agent: Cl
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(F)F)n2)c(OC(C)C)cc1C1CCN(C(=O)[C@@H]2CCCN2)CC1

Procedure:
Prepared according to the method of Example 1 by replacing N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine with 5-chloro-N4-(2-(difluoromethylsulfonyl)phenyl)-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine and replacing2-(dimethylamino)acetyl chloride hydrochloride with (S)-pyrrolidine-2-carbonyl chloride hydrochloride, product was obtained. MS (ES+): 663.23 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([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:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 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 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (89.7 mg, 67%)
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:3](=[O:8])C(OC)=O.[OH:19]O.Cl>[OH-].[Na+]>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:2]([CH3:1])[C:3]([OH:8])=[O:19])=[CH:10][CH:11]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)C(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 0 °C
Yield: 79 %

Procedure:
Methyl 3-methyl-3-(4-isobutylphenyl)pyruvate (1.19 g, 4.8 mmol) was dissolved in a 1N sodium hydroxide aqueous solution (15 ml), and a 35% hydrogen peroxide aqueous solution (5.0 ml) was dropwise added under cooling (0° C.) and stirring. The temperature of the mixture was returned to room temperature, and the mixture was stirred overnight. Then, mixture was acidified with hydrochloric acid and extracted with ether, whereby 2-(4-isobutylphenyl)propionic acid (0.78 g, yield: 79%) was obtained.