Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8]=2[CH:7]=[C:6]([O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH:5]=1>C(OCC)(=O)C>[Cl:1][CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:6]1[CH:5]=[C:4]([O:3][CH3:2])[C:17]2[C:16](=[O:18])[C:15]3[C:10]([O:9][C:8]=2[CH:7]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1cc(OCC2CO2)cc2oc3ccccc3c(=O)c12
Reactant: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OCC(O)CCl)cc2oc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-methoxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (25 mg, 0.08 mmol) prepared in Step 4 of Example 9, followed by stirring at room temperature for 30 minutes, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (20 mg, 71.3%) as a reddish brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]=1[C:17]([OH:19])=[O:18])[OH:6].[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22].S(=O)(=O)(O)O.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[OH-].[Ca+2].[OH-]>C1(C)C=CC=CC=1.O>[C:20]([O:1][CH2:2][CH2:3][N:4]=[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]=1[C:17]([OH:19])=[O:18])[OH:6])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)C1=C(C(O)=NCCO)c2ccccc2CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OCCN=C(O)C1=C(C(=O)O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
24.3 g (0.1 mol) of N-(2'-hydroxyethyl)-3,4-dihydronaphthalene-1,2-dicarboxylic acid imide, 12.9 g (0.15 mol) of methacrylic acid, 1.6 ml of concentrated sulphuric acid and 1.0 g of 2,6-di-tert.-butyl-p-cresol are dissolved in toluene and the solution is refluxed for 2 hours, the water formed being separated off by means of a water separator downstream of the reaction vessel. The reaction solution is then cooled to room temperature, 5.52 g (0.075 mol) of calcium hydroxide are added and the mixture is stirred thoroughly for 5 minutes. After filtering, the filtrate is concentrated to dryness in vacuo at 60° C. This yields 28.8 g (95.7% of theory) of N-(2'-methacryloyloxyethyl)-3,4-dihydronaphthalene-1,2-dicarboxylic acid imide.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[C:22](=[O:36])[CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:26])=O)(C)(C)C>Cl.C(OCC)(=O)C>[ClH:20].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[C:22](=[O:36])[CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:26]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(Cl)c(Cl)c2)C(=O)CCC(=O)NCc2ccccc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(Cl)c(Cl)c2)C(=O)CCC(=O)NCc2ccccc2F)c1
Yield: 162.3 %

Procedure:
A 2 N hydrochloric acid/ethyl acetate solution (10 ml) of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(3,4-dichlorobenzyl)-N′-(2-fluorobenzyl)succinamide (0.50 g, 0.7 mmols) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The solid precipitated was taken out through filtration, and washed with ethyl ether to give an amorphous solid of N-[2-(3-aminomethylphenoxy)-4-chlorophenyl]-N-(3,4-dichlorobenzyl)-N′-(2-fluorobenzyl)succinamide hydrochloride (0.37 g, 82.2%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:47].[Li+]>O1CCCC1.O>[Br:47][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(CO)c2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 6 g of N-[3-(hydroxymethyl)phenyl]-N-[[4-(tetradecyloxy)phenyl]methyl]acetamide in 100 ml of tetrahydrofuran is added 1.56 g of triethylamine and 1.76 g of methanesulfonyl chloride followed by stirring at ambient temperature for 1 hour. Added 11.14 g of lithium bromide and continued stirring for an additional hour. The mixture is poured into water and extracted with ether. The organic layer is washed with a solution of saturated sodium bicarbonate and brine then dried and evaporated to a residue which is crystallized from petroleum ether to give 6.6 g of the desired product as a white solid, m.p. 56°-58° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([OH:30])=O)[CH:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:28](=[O:30])[NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH:13]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1SC(c1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: Cc1ccccc1C
Product: O=C(NC1C(=O)Nc2ccccc2SC1c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
2.7 g of the N-benzyloxycarbonyl-S-(2-aminophenyl)-β-phenylcysteine obtained in Example 1 was suspended in 60 ml of xylene and the resulting suspension was heated under reflux for 3 hours. Thereafter, the apparatus was cooled to room temperature. The precipitated crystals were separated by filtration and washed with ethanol to obtain 1.9 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[O:12][CH:13]=[C:14]([CH3:16])[N:15]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[O:12][C:13]([Cl:17])=[C:14]([CH3:16])[N:15]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(C)co2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(C)c(Cl)o2)CC1

Procedure:
A solution of trans-4-(4-methyl-oxazol-2-yl)-cyclohexanecarboxylic acid methyl ester (277 mg, 1.24 mmol) and N-chlorosuccinimide (182 mg, 1.36 mmol) in N,N-dimethylformamide (2.5 ml) was stirred for 6 h at room temperature. The reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with one 25-ml portion of tert-butyl methyl ether. The combined organic layers were washed with three 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (285 mg, 89%) as light yellow solid, which was used in the next step without further purification. MS m/e: 258 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-]>Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)nc1
Temperature: 5 °C
Yield: 76.3 %

Procedure:
6-bromopyridine-3-carboxylic acid (50 g, 0.25 mol) in thionyl chloride (4a, 130 ml, 1.76 mol) was heated at reflux for 3 hours. The mixture was then concentrated under vacuum and the residue was co-evaporated with benzene to remove the thionyl chloride. The resulting acid chloride was dissolved in benzene (120 ml, 1.33 mol) and treated with AlCl3 (82.5 g, 0.6 mol) portion wise with stirring at 5° C. After heating at reflux for 6 hours, the reaction mixture was cooled to room temperature and poured into 20% HCl (500 ml), stirred for 1 h, and layers were separated. The aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, 50% KOH, and water (100 mL each), dried (Na2SO4), filtered and concentrated under reduced pressure to afford the product, 4-b, (50 g, 77%). 1H NMR (CDCl3, 300 MHz,): δ 8.72 (d, J=2.4 Hz, 1H), 8.04 (dd, J1=8.4 Hz, J2=2.7 Hz, 1H), 7.74 (m, 2H), 7.61 (m, 1H), 7.48 (m, 3H).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(CCC(N[C@H](C(=O)NCCCCC)CC1C=CC(OC(C(O)=O)C(O)=O)=CC=1)=O)(O)=O.C1(CCCCN)C=CC=CC=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.C(OC(C1C=C(C[C@H](NC(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)C(O)=O)C=CC=1OCC(OCC)=O)=O)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)N=C=NC(C)C
Agent: CCCCCNC(=O)[C@H](Cc1ccc(OC(C(=O)O)C(=O)O)cc1)NC(=O)CCC(=O)O
Solvent: CN(C)C=O
Product: COc1ccccc1C=O
Reaction time: 9.5 h

Procedure:
The production of the library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme 3). The AMEBA resin was then treated with 4-phenylbutyl amine and NaBH(OAc)3 to give the corresponding reductive amination product. The tyrosine scaffold (5) was then coupled to this amine resin using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1:1). The resin was then plated in a 96 well Robbins block and coupled to the corresponding acid with DIC and HOBT in DMF. After thorough washing, the resin was subjected to the coupling conditions a second time. The diethyl ester was hydrolyzed with excess LiOH in THF: MeOH (1:1) for 5-14 h at rt to yield the dicarboxylic acid on resin. The product was then cleaved from the resin with 20% TFA/CH2Cl2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=3)[CH:12]=[C:11]2[C:24]([O:26]CC)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:26]=[C:24]1[C:11]2=[CH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:18]=3[N:10]2[CH2:9][C:3]2([CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH2:2][NH:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CCOCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCOCC1)CNC3=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of the crude diethyl 1-{[4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methyl}-1H-indole-2,6-dicarboxylate from the preceding step in ethanol (800 mL) is added triethylamine (16.16 mL, 115.9 mmol) and K2CO3 (16.1 g, 115.9 mmol). The reaction mixture is heated at 80° C. for 2 h and is cooled to room temperature and stirred for an additional 16 h. The solid K2CO3 is removed by filtration and the filtrate is concentrated. The crude compound is purified by flash column chromatography using 3% methanol in CH2Cl2 to afford the title compound (4.2 g, 30% for 3 steps) as a white solid.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](Cl)[CH:12]=1.CS(C)=O>O>[CH2:2]([O:5][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:6])[CH:12]=1)[CH:3]=[CH2:4]
Reactant: C=CCO
Reactant: Clc1cncc(Cl)c1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1cncc(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium (4.7 g, 203 mmol) was added to allyl alcohol (57.5 ml, 84.5 mmol). After complete reaction, the excess of allyl alcohol was evaporated. 3,5-Dichloropyridine (25.0 g, 169 mmol) and dimethyl sulfoxide (75 ml) were added to the crude mixture. The mixture was stirred at 60° C. overnight. Water (100 ml) was added followed by extraction twice with ethyl acetate (100 ml). The product was isolated in quantitative yield.
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])(=O)C.O>S(=O)(=O)(O)O.O.CO>[N+:15]([C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[CH2:5][SH:4])([O-:17])=[O:16]
Reactant: CC(=O)SCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CS)c([N+](=O)[O-])c1
Yield: 98.5 %

Procedure:
A stirred suspension of S-(2,4-dinitrobenzyl) thioacetate 16b (8.2 g, 32 mmol) in concentrated sulfuric acid--water (1:1 v/v; 14.08 cm3) and methanol (128 cm3) was heated, under reflux, for 1.5 h. The cooled products were poured into water (300 cm3) and the resulting mixture was extracted with ether (2×400 cm3). The combined organic extracts were washed with water (300 cm3), dried (MgSO4) and evaporated under reduced pressure to give 2,4-dinitrobenzyl mercaptan 17b as a yellow oil (6.75 g, 98 %) (Found: M+ =214.0084 12 C11H614N216O432S requires: 214.0048); δH [CDCl3 ] 2.21 (1 H, t, J 8.7), 4.10 (2 H, d, J 8.7), 7.75 (1 H, d, J 8.7), 8.44 (1 H, dd, J 2.4 and 8.5), 8.77 (1 H, d, J 2.4); δC [CDCl3 ] 26.2, 121.0, 127.8, 133.0, 143.6, 146.9, 148.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 70 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 70% of theory, Rf value: 0.16 (silica gel; dichloromethane/ethanol=4:1) C26H27N7O3 (485.6) ##EQU27##
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O.Cl>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of pentane-2,4-dione (4.4 g) in N,N-dimethylformamide (10 mL) was added dropwise over a period of 15 minutes to a stirred suspension of sodium hydride (60% in oil, 1.7 g) in N,N-dimethylformamide (50 mL) at −5° C. The mixture was warmed to room temperature over 20 minutes and a solution of 1-bromomethyl-4-methanesulfonylbenzene (10 g) in N,N-dimethylformamide (20 mL) was added dropwise over a period of 10 minutes. The resulting mixture was stirred at room temperature for 17 hours and then diluted with 1.0 M aqueous hydrochloric acid (100 mL). The resulting mixture was extracted with a mixture of diethyl ether and ethyl acetate (1:1 by volume) and the combined extracts washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (2:1 to 1:2 by volume) gave title compound as a colourless gum, 3.7 g.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([C:53]([O:55][CH3:56])=[O:54])=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:47]1([CH:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:39][NH:38][C:34]2[N:33]=[C:32]([C:53]([O:55][CH3:56])=[O:54])[N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[C@H:11]2[C@H:10]([OH:9])[C@H:14]([OH:15])[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Yield: 97.6 %

Procedure:
A solution of methyl 9-{(2R,3R,4R,5S)-3,4-bis(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 8) (3.4 g, 4.5 mmol) and sodium carbonate (50 mg) in dry methanol (60 ml) was stirred at room temperature for four hours. Solvent was removed under reduced pressure and the residue taken up in a mixture of dichloromethane:methanol (95:5, by volume, 60 ml). Inorganic salts were filtered off and the filtrate evaporated under reduced pressure. The residue was triturated with diethyl ether, filtered off and dried to yield the title compound as a white solid, (2.4 g, 98%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([C:9]([OH:11])=O)[CH2:2]2.S(Cl)(Cl)=O.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9]([C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)=[O:11])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)[C@H]1CN2CCC1CC2
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)[C@H]1CN2CCC1CC2

Procedure:
9.17 g (about 47.8 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid are heated together with 160 ml of thionyl chloride under reflux for 1 h. The excess thionyl chloride is removed under reduced pressure, and residues are removed by azeotropic distillation together with toluene. The crude acid chloride obtained in this way is stirred together with 8.19 g (47.60 mmol) of 4-bromoaniline and 24.6 ml (190.4 mmol) of N,N-diisopropylethylamine in 59 ml of DMF at RT for 72 h. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/triethylamine 70:30:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 5.5 g (37% of theory) of the title compound are obtained. The absolute configuration was assigned by crystal structure analysis of single crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:37][N:38]([CH3:69])[NH:39][C:40]([C:42]1([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:47][CH2:46][N:45]([C:48](=[O:61])[CH:49]([NH2:60])[CH2:50][C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][CH:52]=2)[CH2:44][CH2:43]1)=[O:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[NH:60][CH:49]([CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1)[C:48]([N:45]1[CH2:44][CH2:43][C:42]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:40]([NH:39][N:38]([CH3:69])[CH3:37])=[O:41])[CH2:47][CH2:46]1)=[O:61])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(N)Cc2c[nH]c3ccccc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methylpropionic acid (0.18 g, 0.88 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.12 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.88 mmol) and the mixture was stirred for 30 min. Then 1-(2-amino-3-(1H-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide (0.46 g, 0.73 mmol) and diisopropylethylamine (0.50 ml, 2.92 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.31 g of (1-(2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:11](Cl)=[N:10][C:9]=12)=[O:4].[C:23]([O-:26])([O-])=O.[Na+].[Na+]>C(COC)OC.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]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:23]=[O:26])=[CH:16][CH:15]=3)=[N:10][C:9]=12)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(Cl)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Temperature: 90 °C

Procedure:
2.3 g (7.1 mmol) 5-Chloro-6-(2,6-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester are given in 24 mL dimethoxyethane. 13.9 mL Na2CO3 solution (10%) and 1.18 g (7.8 mmol) 4-formylboronic acid are added. After addition of 0.26 g (0.32 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture is purged 3× with argon and heated at 90° C. for 2 hours. The reaction mixture is cooled down, treated with water and extracted 3 times with dichloromethane. The organic phase is washed with brine and dried (Na2SO4). The solvent is removed and the crude product purified via chromatography (silicagel, dichloromethane/methanol). 2.57 g (64.4%) of the slightly contaminated compound are obtained.