Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)[CH2:10][N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][S:36]([CH2:39][C:40]#[N:41])(=[O:38])=[O:37])=[O:34])=[C:29]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:28]=2)=[CH:23][CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-:56].[K+].[K+].OO.Cl>CS(C)=O>[NH2:41][C:40](=[O:56])[CH2:39][S:36]([NH:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][N:11]([CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:26][CH:25]=2)=[CH:28][C:29]=1[O:42][CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)=[O:34])(=[O:38])=[O:37]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CC#N)c(OC3CCCCC3)c2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CC(N)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of tert-butyl [(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl][2-[4′-[[[(cyanomethyl)sulfonyl]amino]carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl]carbamate (52.9 mg) in dimethyl sulfoxide (1.0 ml) was added potassium carbonate (28.3 mg), 30% aq. hydrogen peroxide solution (100 μl) at 0° C. After stirring for 16 hours at room temperature, 1N hydrochloric acid was added to the reaction mixture. The products were extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=95/5) to give tert-butyl [2-[4′-[[[(2-amino-2-oxoethyl)sulfonyl]amino]-carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]-carbamate (30.0 mg).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 125-3 (3.4 g, 11 mmol), Pd/C (0.5 g) and methanol (100 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 125-4 as purple solid. MS m/z 279.2 (M+1).
Reaction SMILES: C1(C[O:8][P:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]2C(=O)C3=CC=CC=C3C2=O)([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)C=CC=CC=1.[OH2:55].NN>O1CCOCC1.C1(C)C=CC=CC=1>[C:14]1([CH2:13][O:55][N:11]([PH:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:8])[C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: NN
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)N(OCc1ccccc1)[PH](=O)CCCCCCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-[N-[(phenylmethoxy)(6-phthalimidohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After 24 hours, the mixture is diluted with toluene and the solvents decanted and evaporated to dryness. The residue is purified by extraction and flash chromatography to give N-[(phenylmethoxy)[(6-aminohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]O.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:6]
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of N,N-dimethylethanolamine (890 mg, 10 mmol) and triethylamine (1520 mg, 15 mmol) in anhydrous CH2Cl2, kept under nitrogen atmosphere, at 0° C., methansulphonyl chloride (1220 mg, 11 mmol) was added. The mixture was kept under stirring and at 0° C. for 1 hour, and then concentrated by evaporation. The residue was dissolved in CH2Cl2, washed with Na2CO3 saturated solution and with deionized water. The organic phase was dried under Na2SO4 and the solvent removed by evaporation. The product was used as obtained, without purification, for the following step b) (1330 mg, yield 80%).
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.[Li]CCCC.[Cl:38]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:38][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: [Li]C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.300 g, 0.624 mmol; Example 15, Step B) was placed in THF (10 mL) and cooled to −78° C. MeLi (1.17 mL, 1.87 mmol) was then added, and the reaction was stirred for 10 minutes. Excess THF (10 mL) was added to aid solubility. n-BuLi (0.525 mL, 1.31 mmol) was then added and stirred for an additional 10 minutes, followed by the addition of a hexachloroethane (0.296 g, 1.25 mmol) solution in THF (3 mL). The reaction was then stirred for an additional 10 minutes at 0° C., poured into water, and extracted into DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by reverse phase HPLC (50-75% ACN in water) to give the product (R)-tert-butyl 1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.100 g, 36.7% yield).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([CH2:20][NH:21][C:22]([C@H:24]([O:26]C(=O)C)[CH3:25])=[O:23])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Li+].[OH-]>CO>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:22](=[O:23])[C@H:24]([OH:26])[CH3:25])[O:17]3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O[C@H](C)C(=O)NCC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](O)C(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 542.1 %

Procedure:
(R)-Acetic acid 1-[(7-benzenesulfonyl-chroman-2-ylmethyl)-carbamoyl]-ethyl ester (7.59 mg) was dissolved in 1 mL MeOH, and water (0.25 mL) and LiOH (200 mg) were added. The reaction was stirred at room temperature for two hours, then quenched by addition of water. Crystals formed and were collected by filtration, washed with water and dried under vacuum to give 37 mg of (R)—N-(7-Benzenesulfonyl-chroman-2-ylmethyl)-2-(R)-hydroxy-propionamide. MP=129.5-131.5° C.; MS (M−H)=374.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26]>C1(C)C=CC=CC=1>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2([CH3:1])[O:26][CH2:25][CH2:24][O:3]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: OCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
A mixture of 4-nitroacetophenone (1.65 g, 10.0 mmol), p-toluenesulfonic acid (172 mg, 1.00 mmol) and ethylene glycol (1.7 mL, 30 mmol) in dry toluene (20 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Recrystallisation from ether and hexanes afforded 2-(4-nitrophenyl)-2-methyl-1,3-dioxolane (25) as a pale yellow crystals (1.52 g, 73%; yield based from the first crop of crystals). 1H nmr (300 MHz, CDCl3) 1.66 (s, 3H, CH3), 3.71-3.83 (m, 2H, OCH2), 4.02-4.13 (m, 2H, OCH2), 7.63-7.73 (d, J=8.8 Hz, 2H, 2×ArH), 8.16-8.26 (d, J=8.8 Hz, 2H, 2×ArH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23])[CH2:19][CH3:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCN=C=O
Product: CCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 52.2 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.073 mL (0.78 mMol) propyl isocyanate, 0.107 gm (52%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[C:17]([NH2:18])=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:11][C:12]3=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[C:17]3[N:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: O=C(O)c1ccnc(Cl)c1
Product: O=[N+]([O-])c1cnc2[nH]c(-c3ccnc(Cl)c3)nc2c1

Procedure:
was prepared as described for example 4-1, starting from 2-chloropyridine-4-carboxylic acid and 2,3-diamino-5-nitropyridine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](C(=O)C)[CH:9]=[CH:10][C:3]=12.CO>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(=O)n1ccc2c(I)ccnc21
Solvent: CO
Solvent: CCO
Product: Ic1ccnc2[nH]ccc12
Yield: 234.2 %

Procedure:
A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0° C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0° C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30% K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0° C. for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58%) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50° C., and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70° C. This reaction solution was stirred at 75° C. for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0° C., followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to yield 2.7 g (80%) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85° C. for 12 hr and then cooled to room temperature, and 10% Na2CO3 (28 mL) and 10% NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28% sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92%). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.89 (d, 1H, J=5.0 Hz), 7.59 (t, 1H, J=3.1 Hz), 7.51 (d, 1H, J=5.0 Hz), 6.27 (d, 1H, J=3.4 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][C:12]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][C:16](=[O:17])[O:15][C:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCC(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 116.5 %

Procedure:
Racemic α-(aminomethyl)benzenemethanol (13.7 g) and bis(1,1-dimethylethyl)carbonate (21.8 g) were dissolved in methanol (200 ml) and 10% aqueous sodium carbonate (200 ml) added. The mixture was stirred at room temperature for 24 h, poured into 2M hydrochloric acid and extracted with ethyl acetate. Evaporation of the extract and trituration with ethyl acetate/hexane gave the sub-title compound as a pale yellow solid (27.6 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61]Br)=[N:53]1)=O)(C)(C)C>CN(C=O)C.C1COCC1>[NH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:4]2=[O:34])=[N:53]1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of 0.35 g (0.77 mmol, 1.0 equiv) of 2-(2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 36, in 7 mL of DMF is cooled in an ice/water bath. 0.85 mL (0.84 mmol, 1.1 equiv) of 1M NaN(TMS)2 in THF is added and the solution stirred at 0° C. for 10 min. A solution of 0.26 g (0.84 mmol, 1.1 equiv) of N-tert-butoxycarbonyl-3-bromomethyl-indazole in 3 mL of DMF is added and the resulting yellow solution stirred at RT for 1 h. The reaction is quenched with H2O, extracted with EtOAc (×3), washed with H2O (×2) and brine, dried over MgSO4 and concentrated to a brown oil. Purification by silica gel flash chromatography using EtOAc/hexane 1/1 as eluent followed by Si60 MPLC using EtOAc/hexane 1/1 as eluent gave 0.23 g of a white powder; low resolution MS (FAB) 689 (MH+). A portion of this compound is dissolved in 4N HCl in dioxane and stirred at 0° C. for 30 min, and then concentrated to a white foam. Purification by RP-18 MPLC using MeCN/H2O 3/2 containing 0.1% HCl as eluent gave 33 mg of the title compound HCl salt as an amorphous white powder: 1H NMR (d6 -DMSO, 400 MHz) δ8.47 (d, 1H, J=3.5), 8.0-7.0 (m, 15H), 4.79 (m,1H), 4.20 (m, 2H), 3.79 (s, 3H), 3.51 (dd, 1H, J=7, 15), 3.39 (dd, 1H, J=5, 15), 0.97 (dd, 6H, J=7, 14); low resolution MS (FAB)m/e 589 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([OH:9])[CH:8]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH2:29][N:28]1[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39]>CN(C)C(=O)C>[CH3:35][N:34]([CH3:36])[C:33]([O:32][C@H:30]1[CH2:29][N:28]([C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39])[C@H:27]([CH2:26][CH2:25][O:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:31]1)=[O:37]
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Reactant: COc1ccc(CCc2ccccc2)c(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1cc(OC)ccc1CCc1ccccc1
Yield: 99.4 %

Procedure:
670 mg of 5-methoxy-2-(2-phenylethyl)phenol (prepared as described in Preparation 1) were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 360 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1500 mg (yield 99%) of the title compound as an oily substance.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([N:47]=[N+:48]=[N-:49])(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[N:47]=[N:48][NH:49][N:33]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2nn(CCCCCCCCc3nn[nH]n3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 72.3 %

Procedure:
A mixture of 3,4,5-triphenyl-lH-pyrazole-1-nonanenitrile (1.25 g, 2.9 mmol) and tri-n-butyltin azide (1.15 g, 3.5 mmol) was heated with stirring at 140° C. under an atmosphere of nitrogen. After 2.5 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and washed with 0.5 N HCl (3 x) and saturated sodium chloride solution before being dried and concentrated in vacuo. The residual oil was chromatographed on a column of silica gel using first a mixture of ethyl acetate and hexane (1:1) and subsequently methanol/chloroform (1:9) as eluent. The recovered oil was dissolved in CH2Cl2 and stirred with a concentrated aqueous solution of potassium floride. After 24 hours, the layers were separated and the aqueous layer extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated in vacuo to give an oil that solidified. Recrystallization from a mixture of hexane and dichloromethane (2:1) afforded the title compound (1.00 g, 73%); m.p.=158°-160° C. MS(CI): m/e =477 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[C:13]([CH2:21][C:22](OCC)=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:22](=[O:23])[CH2:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCOc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CC(=O)c1ccccc1)NCCOc1ccc(Cl)cc1Cl
Temperature: 160 °C

Procedure:
To a solution of 2-(2,4-Dichloro-phenoxy)-ethylamine 29 (412 mg, 2.0 mmol) in toluene (1.5 mL) is added ethyl benzoylacetate 34 (384 mg, 2.0 mmol). The mixture is heated to 160° C. for 10 minutes in a microwave. The resulting mixture is concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford N-[2-(2,4-dichloro-phenoxy)-ethyl]-3-oxo-3-phenyl-propionamide 35 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.98 (d, J=7.2 Hz, 2H), 7.60-7.35 (m, 5H), 7.15 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.10 (t, J=5.2 Hz, 2H), 3.98 (s, 2H), 3.76 (q, J=5.3 Hz, 2H). MS calculated for C17H16Cl2NO3 (M+H+) 352.0, found 352.1.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[C:11]([CH2:13][N:14]=[CH:15]OC)#[N:12]>CO>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:13]2[NH:14][CH:15]=[N:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: COC=NCC#N
Agent: [Na]
Solvent: CO
Product: N#Cc1ccc(Oc2cnc[nH]2)cc1
Temperature: 127.5 °C

Procedure:
Sodium metal (1.10 g, 47.8 mmol) was dissolved in anhydrous methanol and 4-cyanophenol (5.70 g, 47.8 mmol) was added. The resultant solution was concentrated and dried under vacuum overnight. A mixture of this sodium salt and 4-cyanophenol (25 g, mp 110-113° C.) was heated to 125-130° C. and neat methyl N-(cyanomethyl)methanimidate (5.0 g, 51 mmol; Hosmane, R. S. et al, J. Org. Chem., 1212, 1984) was added dropwise over a period of 10 minutes under a slow stream of dry argon. The resultant mixture was stirred at 120° C. for 2 hours, cooled, and the reaction product partitioned between methylene chloride (500 mL) and aqueous sodium hydroxide (1 M, 500 mL). The aqueous layer was separated and extracted with methylene chloride (3×100 mL). The organic extracts were combined, washed with brine (100 mL), dried (K2CO3), and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 3:7 acetone in CHCl3) to afford the title compound as a white powder.