Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:38](=[O:40])[CH3:39])[CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:38](=[O:40])[CH3:39])[CH2:32]2)=[O:7])=[C:4]([NH:11][C:12]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: CC(=O)N[C@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCCN(C(=O)c2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Yield: 17.6 %

Procedure:
The mixture 4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (150 mg, 0.298 mmol), (S)-N-Piperidin-3-yl-acetamide (63 mg, 0.446 mmol), EDC.HCl (85 mg, 0.446 mmol), HOBt (60 mg, 0.446 mmol) and DIPEA (154 mg, 1.190 mmol) in dichloro-methane (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 33 mg N-((S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COCCN1C(=O)CCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3)ncc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A microwave vessel was charged with 8-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (51.3 mg, 0.219 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (56.8 mg, 0.182 mmol), 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). The reaction mixture was quenched with a slurry of saturated, aqueous NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (50.0 mg, 54%) as a white powder that had the following properties: mp: 185-187° C.; LC/MS (ESI+): 509 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.30-9.17 (m, 2H), 8.29 (br s, 1H), 8.13 (s, 1H), 7.45-7.38 (m, 2H), 7.35 (m, 1H), 7.30-7.18 (m, 2H), 6.92 (d, J=7.9, 1H), 4.05 (br s, 2H), 3.28 (br s, 2H), 3.09 (s, 3H), 2.70 (d, 3H, J=4.3), 2.55 (m, 2H) 2.25 (2, 3H), 2.20-1.80 (series of m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1cccc(N)c1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(Nc2nnc(Cc3ccncc3)c(C)c2C)c1

Procedure:
The compound is prepared starting from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g meta-methylaniline in the manner described in Example 82A. After heating for 20 h to 130° C., siginificant quantities of 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine are still present (TLC). For this reason, a further 0.129 g meta-methylaniline is added and heated for another 24 h to 130° C. Processing is in the manner described for Example 82A. Title compound of about 90% purity is obtained after FC in CH2Cl2/methanol 19/1; m.p. 68-90%°. 1H-NMR (250 MHz, CDCl3): δ=8.45 (d, 2H); 7.70 (t, 1H); 7.50 (s, 1H); 7.40-7.10 (m, 4H)); 6.90 (d, 1H); 6.15 (s, wide, 1H); 4.30 (s, 2H); 2.35 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H). The starting material is prepared as follows:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:15][CH:25]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCC(OS(C)(=O)=O)c1ccc(C(=O)OCC)cc1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (140 mg, 0.585 mmol) in N,N-dimethylformamide (2 mL) was added to a suspension of 60% sodium hydride (27.2 mg, 0.679 mmol) in N,N-dimethylformamide (2 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. A mixture of ethyl 4-(1-(methylsulfonyloxy)butyl)benzoate (0.170 g, 0.566 mmol) in N,N-dimethylformamide (3 mL) was then added at room temperature. The reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-15% ethyl acetate in heptanes) gave ethyl 4-(1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylamino)butyl)benzoate (25.0 mg, 10%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.98-8.05 (m, 4 H), 7.67 (d, J=8.19 Hz, 2 H), 7.53 (d, J=9.36 Hz, 1 H), 7.44 (d, J=8.19 Hz, 2 H), 6.57 (d, J=9.36 Hz, 1 H), 5.56-5.67 (m, 1 H), 4.82-4.93 (m, 1 H), 4.34 (q, J=7.22 Hz, 2 H), 1.79-2.01 (m, 2 H), 1.36 (t, J=7.22 Hz, 3 H), 1.28-1.54 (m, 2 H), 0.96 (t, J=7.32 Hz, 3 H). MS (M+1): 444.1.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH3:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1>CN(C=O)C>[CH3:5][C:6]1[CH:11]=[C:10]([O:2][CH3:1])[N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)nc2ccnn12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanol (5 ml) was added to a suspension of 0.40 g of 60% sodium hydride in 10 ml of DMF. Then a solution of 1 g of 5-methyl-7-chloropyrazolo[1,5-a]pyrimidine in 5 ml of DMF was added dropwise thereinto at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and the crystals precipitated were collected by filtration and recrystallized from diethyl ether to provide 0.40 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Br:60])[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Br:60][C:56]1[CH:55]=[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])[CH:59]=[CH:58][CH:57]=1
Reactant: CC(=O)SCC(Cc1cccc(Br)c1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1.88 g of L-Tryptophan in the form of the hydrochloride is introduced into 25 ml of anhydrous methylene chloride and 2.14 ml of triethylamine, 3.1 g of BOP then 2.217 g of the product obtained in Stage 4 above, dissolved in 25 ml of anhydrous methylene chloride, are added. The solution is agitated for 2 hours at ambient temperature, then the solvent is evaporated off, the product obtained in the form of a yellow oil, is then purified by chromatography on silica, with chloroform-ethyl acetate: 85-15 as eluant. After evaporation of the solvent and washing, a yellow gum is obtained. In this way 2.69 g of expected product is obtained (mixture of two diastereoisomers).
Reaction SMILES: Br[CH:2]([CH2:26][CH2:27][Cl:28])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]([NH2:32])=[S:31].C(O)C>O>[NH2:32][C:30]1[S:31][C:2]([CH2:26][CH2:27][Cl:28])=[C:3]([C:5]2[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:7][CH:6]=2)[N:29]=1
Reactant: NC(N)=S
Reactant: N#Cc1ccc(OCCCCCOc2ccc(C(=O)C(Br)CCCl)cc2)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(OCCCCCOc2ccc(-c3nc(N)sc3CCCl)cc2)cc1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
16.9 g (36.3 mmol) of 4-{5-[4-(2-bromo-4-chlorobutyryl)phenoxy]pentyloxy}-benzonitrile compound (9) of Preparative Example 1-4 and 5.53 g (72.6 mmol) of thiourea were added to 100 ml of ethanol, and the mixture was refluxed at 80□ for 12 hrs. The reaction solution was cooled to room temperature, added with purified water for recrystallization, and filtered under reduced pressure to obtain 3.3 g (yield: 21%) of a title compound (16).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][C:13]([C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)[CH:17]=[CH:16][N:15]=3)=[C:7]2[CH:6]=1)#[N:4].[CH3:34]I>CN(C)C=O>[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][C:13]([C:14]3[N:19]=[C:18]([N:20]([CH3:34])[C@@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)[CH:17]=[CH:16][N:15]=3)=[C:7]2[CH:6]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccnc(-c2cnn3ccc(C#N)cc23)n1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 102 mg, 2.55 mmol) was added to a cooled (0° C.) solution of tert-butyl (3R)-3-{[2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl) pyrimidin-4-yl]amino}piperidine-1-carboxylate (Preparation 7a, 0.83 g, 1.98 mmol) in NIP-dimethylformamide (5 mL) and the reaction mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.135 mL, 2.17 mmol) was then added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent was evaporated to give the title compound (0.39 g, 80%) as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[N:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[N:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1nc(N)ccc1F
Product: Cc1ccc(Nc2ccc(F)c(C)n2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 2-Amino-5-fluoro-6-methylpyridine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a light yellow solid, MS (ISP): m/e=341 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH:21]([F:23])[F:22]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][CH:21]([F:23])[F:22])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)CI
Reactant: COC(=O)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCC(F)F)ccc1Cl

Procedure:
To a suspension of methyl 2-chloro-5-hydroxybenzoate (50 mg) and potassium carbonate (111 mg) in acetone (1 mL) was added 2-iodo-1,1-difluoroethane (35 μL), and the suspension was reacted at 120° C. for 10 minutes in a microwave synthesizer (Biotage, Initiator). After reaction at 130° C. for additional 15 minutes, the reaction mixture was directly purified on silica gel column chromatography to obtain the titled compound (55 mg) as yellow oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:9][C:8](=O)[CH:7]([CH2:20][OH:21])[CH:6]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:3])[CH3:2].COC[O:33][CH:34]1CC(=O)CC[CH2:35]1>>[C:1]([O:4][CH:5]1[CH:10]([O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[CH2:9][C:8]2=[CH:35][C:34](=[O:33])[O:21][CH2:20][CH:7]2[CH:6]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])(=[O:3])[CH3:2]
Reactant: COCOC1CCCC(=O)C1
Reactant: CC(=O)OC1C(O[Si](C)(C)C(C)(C)C)CC(=O)C(CO)C1O[Si](C)(C)C(C)(C)C
Product: CC(=O)OC1C(O[Si](C)(C)C(C)(C)C)CC2=CC(=O)OCC2C1O[Si](C)(C)C(C)(C)C
Yield: 34 %

Procedure:
Example 4 was repeated except that 4-acetoxy-3,5-bis(tert-butyldimethylsilyloxy)-2-hydroxymethylcyclohexanone was used instead of 2-hydroxymethyl-3,4-dimethylmethylenedioxy)-5-(methoxymethoxy)cyclohexanone to give 7-acetoxy-6,8-bis(tert-butyldimethylsilyloxy)-1,5,6,7,8,8a-hexahydro-3H-2-benzopyran-3-one having the following property (yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:45](O)=[O:46])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:45]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:4]([N:5]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:3]([O:2][CH3:1])=[O:25])=[O:46])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(C)cc1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine methyl ester (369 mg, 1 mmol, example 65, step C) in THF/K2CO3(1M) (3 mL/3 mL) was added Nα-(4-methylbenzenesulfonyl)-L-phenylalanine N-hydroxysuccinimmide ester (500 mg, 1.2 mmol). The reaction mixture was stirred overnight, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude was purified by flash chromatography using hexane/EtOAc as eluent to afford the desired product (77% yield).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=2[O:27]1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:31]2[CH:30]=[CH:29][C:28]3[O:27][CH2:26][O:34][C:33]=3[CH:32]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc3c(c2)OCO3)c2c(c1)ncn2-c1ccccc1

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3,4-methylene dioxyphenylboronic acid (83 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and product was crystallised from dichloromethane/diethyl ether to the title compound (75 mg, 44%) m/z, 339.8 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)C1(NC(=O)OC(C)(C)C)CCC1
Yield: 93 %

Procedure:
A 70.21 g (257 mmol) portion of ethyl 1-tert-butoxycarbonylamino-β-oxocyclobutanepropanoate was dissolved in 500.0 ml of ethanol. Thereto was added 4.86 g (514 mmol) of sodium borohydride in small portions under ice cooling. After 2 hours of stirring at the same temperature, water was added and the solvent was evaporated. The resulting residue was extracted with chloroform, washed with saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, 65.25 g (93%) of the title compound was obtained.
Reaction SMILES: [OH-].[Na+].[CH:3]1([O:7][C:8]2[CH:13]=[C:12]([C:14]3([O:32][C@H:31]([CH2:33][O:34]C(=O)C)[C@@H:26]([O:27]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[OH:15])[CH:11]=[C:10]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=3)[C:9]=2[CH3:47])[CH2:6][CH2:5][CH2:4]1.Cl>CO.C1COCC1>[CH:3]1([O:7][C:8]2[CH:13]=[C:12]([C:14]3([O:32][C@H:31]([CH2:33][OH:34])[C@@H:26]([OH:27])[C@H:21]([OH:22])[C@H:16]3[OH:17])[OH:15])[CH:11]=[C:10]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=3)[C:9]=2[CH3:47])[CH2:6][CH2:5][CH2:4]1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC3CCC3)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC3CCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (0.15 mL, 4 mol/L) is added to 1-cyclobutoxy-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (80 mg) dissolved in methanol (1 mL) and THF (0.5 mL). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1:0->6:1).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:23])[CH2:2][CH2:3][CH3:4].[I:24]NC(=O)CCC(N)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.C(Cl)Cl>[CH2:1]([N:5]1[C:13]([CH2:14][C:15]2[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=2[I:24])=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(Cc2cccc(OC)c2)nc2c(N)ncnc21
Reactant: NC(=O)CCC(=O)NI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCn1c(Cc2cc(OC)ccc2I)nc2c(N)ncnc21
Reaction time: 3 h

Procedure:
4.1 To a solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (1.24 g, 4 mmol) in AcOH (6 ml) was added N-iodo-succinamide (NIS) (1.8 g, 8 mmol). After 3 h at r.t., additional NIS (1.8 g, 8 mmol) was added, and the mixture was stirred for another 24 h. The reaction mixture was diluted with CH2Cl2 (500 ml), and carefully neutralized with a solution of sat. aq. K2CO3 (2×100 ml), then washed with 0.1 N Na2S2O3 (3×100 ml), brine (3×100 ml), dried (Na2SO4), evaporated, and purified by flash chromatography (CH2Cl2:MeOH=100:5) to give the 9-Butyl-8-(2-iodo-5-methoxy-benzyl)-9H-purin-6-ylamine (4.1), as a colorless powder (0.53 g, 30%); rt=7.7 min.; 1HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J=7.9 Hz, 1H), 5.62 (s, 2H), 4.33 (s, 2H), 4.06 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 1.67 (quint., J=7.7 Hz, 2H), 1.36 (sext., J=7.5 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).