Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.[CH2:17]1[S:19][CH2:18]1>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[OH:16][CH2:15][C:11]1[CH:10]=[N+:9]([CH2:17][CH2:18][SH:19])[CH:14]=[CH:13][CH:12]=1
Reactant: C1CS1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: OCc1cccnc1
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F
Product: OCc1ccc[n+](CCS)c1
Yield: 93.9 %

Procedure:
Trifluoromethanesulfonic acid (1.327 mL, 0.015 mol) was added dropwise to 3-pyridinemethanol (2.91 mL, 0.030 mol), followed by ethylene sulfide (0.89 mL, 0.015 mol). The resulting homogeneous mixture was heated (oil bath) at 50°-70° C. under N2 for 20 h. The reaction mixture was then taken up in H2O (15 mL) and extracted with CH2Cl2 (5×5 mL). The aqueous phase was concentrated in vacuo and then applied to a C18 reverse-phase column. Elution with H2O followed by evaporation of the relevant fractions gave a pale yellow oil. This material was rechromatographed to give a nearly colourless oil. After drying in vacuo (P2O5) this afforded the product (4.50 g, 94%) as a viscous oil. ir (film) νmax : 3450 (s, OH), 2560 (w, SH) cm-1 ; 1Hmr (d6 -acetone)δ: 9.10-8.05 (m, 4H, aromatic), 5.01 (t, J= 5.5 Hz, 2H, N-CH2), 4.93 (s, 2H, --CH2OH), 4.43 (br S, 1H, -OH), 3.43-3.18 (m, 2H, S-CH2), 2.34-2.10 (m, 1H, SH).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=O)[O:23]C(C)=C)[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[N:29]1CCOCC1.N.CO>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH2:29])=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Reactant: CN1CCOCC1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Temperature: 55 °C
Reaction time: 5 h
Yield: 614.9 %

Procedure:
To a solution of prop-1-en-2-yl 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-ylcarbamate (109 mg, 0.298 mmol) and 4-methylmorpholine (3.3 μL, 0.030 mmol) in dry THF (27 mL) was added a solution of NH3 in MeOH (0.6 mL, 1M, 0.6 mmol) and the reaction mixture heated to 55° C. Further aliquots of the methanolic NH3 solution were added after 1 hr (0.6 ml, 0.6 mmol) and after 5 hr (1.0 mL, 1 mmol) and after a further 16 hr the reaction mixture was evaporated in vacuo. The residue was taken up into THF (3.0 mL) and NMM (3.3 μL, 0.030 mmol) and NH3 in MeOH (0.6 mL, 1M, 0.6 mmol) were added and the reaction mixture was heated to 55° C. Further aliquots of the methanolic NH3 solution (1M, 1.0 mL, 1.0 mmol) were added after 2 hr and after 3 hr. After 3.5 hr additional aliquots of NMM (3.3 μL, 0.030 mmol) and methanolic NH3 (1M, 1.0 mL, 1.0 mmol) were added and the reaction mixture was maintained at 55° C. for 15 hr. The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound as a yellow solid (60 mg, 61%); Rt 1.87 min (Method 2); m/z 326 (M+H)+ (ES+).
Reaction SMILES: [OH-:1].[Li+].Cl.[C:4](O)(=O)[CH2:5][C:6]([CH2:11][C:12](O)=O)([C:8]([OH:10])=[O:9])O.[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:6]([O:10][C:8]([C:6]1[CH:5]=[CH:4][C:18]([CH2:19][CH2:20][C:21]([OH:17])=[O:1])=[CH:12][CH:11]=1)=[O:9])([CH3:11])([CH3:8])[CH3:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: [OH-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Product: CC(C)(C)OC(=O)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product of Ex. A-23, Part F, (14 g, 55.5 mM) was dissolved in 90 mL of tetrahydrofuran. 1N Lithium hydroxide (90 ml) was added and the reaction stirred at room temperature for 20 min. The reaction mixture was poured into 200 mL of 1:1 mixture of 1N HCl and saturated citric acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to yield a white solid (13 g 100%). 1H NMR (CDCl3) δ 1.59 (s, 9H), 2.70 (t, J=7 Hz, 2H), 3.00 (t, J=7 Hz, 2H), 7.24 (d, J=8 Hz, 2H), 7.90, (d, J=8 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:5]=[C:4]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=[CH:24][C:3]=12.[CH3:31][NH:32][CH3:33]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([N:32]([CH3:33])[CH3:31])=[C:3]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:4]3=[N:5][C:6]=2[C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1
Reactant: CNC
Reactant: Clc1ccc(-c2nc3c(cnn3-c3ccccc3)c(Cl)c2-c2ccc(Cl)cc2)cc1
Product: CN(C)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
4-Chloro-5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine from step A (15 mg, 0.033 mmol) is treated with dimethylamine (2 M in THF, 1 mL, 2 mmol) in a sealed tube at 100° C. for 14 h. After cooling down to room temperature, the mixture is concentrated and the residue is purified by flash column chromatography (silica gel, 0%˜15% EtOAc/hex) to provide the titled compound [5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-dimethyl-amine (11 mg, 73%). 1H NMR (CDCl3) δ(ppm) 8.35 (s, 1H), 8.32 (d, 2H), 7.47(t, 2H), 7.27(t, 1H), 7.23(d, 2H), 7.16(d, 2H), 7.11(d, 2H), 7.03(d, 2H), 2.91(s, 6H); HPLC-MS calculated for C26H20Cl2N4 (M+H+): 459.1. Found: 459.1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15](ON1C(=O)CCC1=O)=[O:16]>CN(C=O)C>[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:16]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 151.8 %

Procedure:
After 109.2 g (0.27 mol) of H-Arg-CHA.2HCl was dissolved in 290 ml of DMF, 70.2 ml (0.54 mol) of NEM was added to the solution. Further 81.7 g (0.3 mol) of BOC-Gly-OSu was added thereto at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, DMF was distilled under reduced pressure. The residue was dissolved in 500 ml of MeOH and the solution was reprecipitated in 8 liters of AcOEt. The precipitated crystals were taken by filtration and dried to give 135.8 g (100%) of BOC-Gly-Arg-CHA.HCl.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:18][CH2:19][OH:20])([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.C(N(C(C)C)CC)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:15][CH2:16][O:17][S:31]([CH3:30])(=[O:33])=[O:32])([CH2:18][CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(NC2CC3CCC2C3)SC1(CCO)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5,5-bis(2-hydroxyethyl)thiazol-4(5H)-one (280 mg, 0.94 mmol) and diisopropylethylamine (Aldrich, 412 mg, 3.19 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (344 mg, 3.00 mmol, 3.2 eq), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated in vacuo to provide the title compound which was used without further purification. MS (ESI, pos. ion) m/z: 455 (M+H).
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.Cl.[NH2:34][CH2:35][C:36]([NH2:38])=[O:37]>>[NH2:38][C:36](=[O:37])[CH2:35][NH:34][C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NCC(N)=O
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Agent: Cl
Product: NC(=O)CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 49.4 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and glycinamide hydrochloride (95 mg, 0.84 mmol) were reacted to give the title compound as colorless oil (40 mg, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].CO.Cl>C1COCC1>[N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1NCCOC1C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)C1CNCCO1
Yield: 90.5 %

Procedure:
To 33 g of 2-[α-(2-nitro-phenoxy)-benzyl]-morpholin-3-one dissolved in 60 ml of anhydrous THF there was added dropwise under stirring 16.7 ml of a 0.9 M solution of BH3 in THF. The whole was heated at reflux for 3 hours and dropwise addition under cold conditions (0°-5° C.) was then made of 3 ml of methanol and then of 3 ml of 23% HCl. The solvent was removed under reduced pressure. The residue was diluted with H2O, made alkaline and extracted with chloroform. The organic extracts were washed to neutrality, dried and evaporated to dryness, to obtain 28.6 g of 2-[α-(2-nitrophenoxy)-benzyl]-morpholine. Yield 94%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][N:13]=[N+:14]=[N-:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1(CCBr)CCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(CCN=[N+]=[N-])CCCC1
Yield: 87 %

Procedure:
A solution of 1-[2-bromoethyl]cyclopentanecarboxylic acid methyl ester (49.6 g, 211 mmol) and sodium azide (54 g, 831 mmol) in DMF (200 mL) was stirred at 50° C. for 5 h under nitrogen atmosphere. Then, the solids were filtered and the filtrate was concentrated to near dryness. The residue was diluted with ethyl acetate (500 mL) and the undissolved solids were collected by filtration and the filtrate was concentrated to give the crude ethyl 1-(2-azidoethyl) cyclopentanecarboxylate which was purified by chromatography over 250 g of silica gel, eluting with 5% ethyl acetate in hexane to give 36.2 g (87% yield) of 1-[2-azidoethyl]cyclopentanecarboxylic acid methyl ester as a light brown oil. EI(+)-HRMS m/e calcd. for C9H15N3O2 (M−H)+ 196.1086, obsd. 196.1342.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>>[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([C:34]([N:8]2[CH2:13][CH2:12][C@H:11]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C@H:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=3)[CH2:9]2)=[O:35])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCOCC2)[C@H](c2ccc(Cl)c(F)c2)C1

Procedure:
The title compound, MS: m/e=539.3 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(4-chloro-3-fluoro-phenyl)-piperidin-4-one, morpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:22])([C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)[CH2:12]2)=O)(C)(C)C.C(Cl)[Cl:24]>Cl.O1CCOCC1>[ClH:24].[N:18]1[CH:17]=[C:16]([C:11]2([OH:22])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)[CH:21]=[N:20][CH:19]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cncnc1)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2cncnc2)CC2CCC(C1)N2
Temperature: 45 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-3-pyrimidin-5-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.14 g, 0.46 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1.5 mL). The mixture was stirred for 1 hour at 45° C., DCM (3 mL) added and stirred for 5 minutes. The solvent was removed by evaporation under vacuum afford the title compound. LCMS m/z 206.3 [M+H]+. R.T.=2.90 min (Analytical Method 3).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:15][C:13]([NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]([NH:20][CH:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:26]([O:28][CH3:29])=[O:27])=[O:12])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Boc-Phe-OH (2 g, 13.77 mmol), H-Leu-OMe (11 g, 41.32 mmol), HOBt (5.58 g, 41.32 mmol), and HBTU (15.67 g, 41.32 mmol) were dissolved in DMF (69 mL) and then DIPEA (7.2 mL, 41.32 mmol) was added under argon. The reaction was stirred for 8 hrs at room temperature. The reaction was extracted by EtOAc and wash with 5% NaHSO3, sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, and concentrated by rotary evaporation. The crude was purified by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.3) to give methyl 2-(2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylamino)-4-methylpentanoate as white solid (4.5 g, 8%).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[CH:35]N(C)C)[C:22]([CH3:40])([CH3:39])[CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[OH2:42].[NH2:43][NH2:44]>C(O)C>[C:8]([O:42][C:6](=[O:5])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:43][NH:44][CH:35]=[C:23]5[C:22]([CH3:39])([CH3:40])[CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:12])([CH3:11])[CH3:9]
Reactant: CN(C)C=C1C(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2CC1(C)C
Reactant: O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3C(C)(C)C4)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of tert-butyl(1-(4-(6-((dimethylamino)methylene)-7,7-dimethyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (180 mg, 0.33 mmol) in anhydrous ethanol (4 mL) was added hydrazine hydrate (48 μL, 1 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 99:1 to 60:40) and PREP HPLC (Method A) to give the desired product as a white solid (8 mg, 5% yield). 1H NMR (500 MHz, CDCl3) 8.12 (s, 1H), 7.27-7.48 (br m, 5H), 7.25-7.18 (br m, 5H), 5.03 (br s, 1H), 3.16 (s, 2H), 2.23-2.68 (br m, 4H), 1.97-2.12 (m, 1H), 1.75-1.88 (m, 1H), 1.11-1.57 (br s, 9H+6H). LCMS (Method A): RT=6.62 min, M+H+=521.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:30][CH2:31]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(NS(=O)(=O)CCO)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide (0.30 g, 0.64 mmol) in methylene chloride (6 mL) was added a solution of boron tribromide (0.12 mL, 1.29 mmol) and 2,6-lutidine (0.15 mL, 1.29 mmol) in methylene chloride (1 mL) dropwise. The reaction mixture was stirred at 0° C. for 2 h and at ambient temperature for 1 h, then cooled to 0° C. and quenched with saturated sodium bicarbonate solution (15 mL). The mixture was diluted with methylene chloride (15 mL), layers were separated, and the aqueous layer was extracted with methylene chloride (2×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 75% gradient of ethyl acetate in hexanes to afford the title compound as colorless solid (0.07 g, 25%): 1H NMR (300 MHz, CDCl3) δ 8.71 (br. s, 1H), 7.64-7.52 (m, 1H), 6.64-6.50 (m, 1H), 4.22-4.07 (m, 2H), 3.86-3.74 (m, 2H), 3.56 (s, 2H), 2.57 (s, 1H), 2.09-1.99 (m, 4H), 1.84-1.63 (m, 12H), 1.00-0.89 (m, 2H), 0.69-0.59 (m, 2H); MS (ES+) m/z 452.3 (M+1).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].CCN(CC)CC.C(OC(C)C)(C)C.[NH2:41][C@H:42]([C:49]([NH:51][C@H:52]([C:65]([O:67][CH3:68])=[O:66])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1>CN(C=O)C>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:65]([O:67][CH3:68])=[O:66])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 8 h

Procedure:
1.32 g of Z-Ile-OSu [G. W. Anderson et. al., J. Amer. Chem. Soc. 86, 1839 (1964)] are dissolved in the above solution of H-His-Lys(Boc)-OMe in approximately 10 ml of DMF and mixed with 0.41 ml of NEt3. The whole is left to stand for 8 hours at room temperature, 15 ml of diisopropyl ether are added, and the whole is homogenised and filtered. The residue obtained by filtering with suction is dissolved in 15 ml of methanol and added at 0° to 23 ml of aqueous NaHCO3 solution. The resulting precipitate is filtered off, washed with H2O, dried and dissolved and reprecipitated from MeOH/ethyl acetate/petroleum ether, yielding Z-Ile-His-Lys(Boc)-OMe in the form of amorphous powder; Rf (B)=0.65; Rf (I)=0.48.
Reaction SMILES: [CH:1]([O:11][C:12]1[N:17]=[CH:16][C:15](Br)=[CH:14][N:13]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:19]1([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:11][C:12]1[N:17]=[CH:16][C:15]([C:28]2[CH:29]=[CH:30][C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:26][CH:27]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Reactant: CCCCCCCCC=COc1ncc(Br)cn1
Product: CCCCCCCCCCOc1ncc(-c2ccc(-c3ccccc3)nc2)cn1

Procedure:
The synthesis was carried out analogously to Example 27 from 2-decenyloxy-5-bromopyrimidine and 2-phenylpyridine-5-boronic acid.
Reaction SMILES: CO[CH2:3][N:4]1[CH2:9][N:8]([N+:10]([O-:12])=[O:11])[CH2:7][N:6]([N+:13]([O-:15])=[O:14])[CH2:5]1.C([Cl:19])(=O)C.[C:20]([Br:23])(=O)C>>[Cl:19][CH2:3][N:4]1[CH2:9][N:8]([N+:10]([O-:12])=[O:11])[CH2:7][N:6]([N+:13]([O-:15])=[O:14])[CH2:5]1.[Br:23][CH2:20][N:4]1[CH2:5][N:6]([N+:13]([O-:15])=[O:14])[CH2:7][N:8]([N+:10]([O-:12])=[O:11])[CH2:9]1
Reactant: COCN1CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Reactant: CC(=O)Cl
Reactant: CC(=O)Br
Product: O=[N+]([O-])N1CN(CBr)CN([N+](=O)[O-])C1
Product: O=[N+]([O-])N1CN(CCl)CN([N+](=O)[O-])C1

Procedure:
Dunning and Dunning (J.Chem.Soc., 2925(1950)) have reported that treatment of 1-methoxymethyl-3,5-dinitro-1,3,5-triazacyclohexane with acetyl chloride and acetyl bromide gave 1-chloromethyl-3,5-dinitro-1,3,5-triazacyclohexane and 1-bromomethyl-3,5-dinitro-1,3,5-triazacyclohexane, respectively. This chemistry was applied to the current work on the eight-membered ring derivatives. Treatment of (Compound 3) with acetyl bromide gave a quatitative yield of 1-bromomethyl-3,5,7-trinitro-1,3,5,7-tetrazacyclooctane (Compound 4). Attempts to convert Compound 4 to Compound 5 with sodium azide were unsuccessful. Thus, a novel method Eq. 2 was needed and invented for the conversion of Compound 4 to Compound 5. ##STR2##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.Br[CH2:30][C:31](Br)=[O:32]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11]3=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]3[C:31](=[O:32])[CH2:30]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Br)CBr
Reactant: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)c2nc3ccccc3n21
Temperature: 25 °C
Yield: 8.4 %

Procedure:
A mixture of N-(4-nitrophenyl)-1H-benzimidazol-2-amine (947 mg) and N,N-diisopropylethylamine (1.45 g) in THF (10 mL) at −78° C. was treated dropwise with a solution of bromoacetyl bromide (826 mg) in THF (2.0 mL) then the resulting mixture was allowed to warm to ambient temperature overnight. After this time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were washed with brine (50 ml), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 2:3 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (92 mg) as a yellow solid.