Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:21][CH2:20][C:19]2([CH3:25])[C:22]([CH3:24])([CH3:23])[CH:15]1[CH2:16][C:17]1[CH:29]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:27]=[CH:26][C:18]=12)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:7]([O:11][C:12]([N:14]1[CH2:21][CH2:20][C:19]2([CH3:25])[C:22]([CH3:23])([CH3:24])[CH:15]1[CH2:16][C:17]1[CH:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=[CH:26][C:18]=12)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3CC1C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(-c4ccccc4)cc3CC1C2(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Aqueous 2 M Na2CO3 solution (5 mL) is added to a mixture of 6,11,11-trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (1.00 g) and phenylboronic acid (0.34 g) in N,N-dimethylformamide (5 mL) in argon atmosphere. The resulting mixture is flushed with argon and then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.18 g) is added. The mixture is heated to 100° C. and stirred at this temperature for 4 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1->1:1) to give the product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: [H][H]
Reactant: Nc1cc(Br)c(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Br)c(Br)cc1N
Reaction time: 0.42 h

Procedure:
Five grams of 4,5-dibromo-2-nitroaniline were suspended in 200 ml. of anhydrous ethanol to which was added about 10 g. of Raney Nickel. The hydrogenation mixture was placed in a low pressure hydrogenation apparatus at a hydrogen pressure of 55 psi. A rapid uptake of hydrogen occurred which ceased after about 25 minutes, at which time the deep yellow color originally present was discharged indicating complete reduction of the nitro group to an amine group. The hydrogenation was continued for another half hour and the hydrogenation mixture was then worked up by filtering off the catalyst, washing the filtered catalyst, and stripping the volatile constituents from the filtrate. A yield of 4.1 g. of 4,5-dibromo-o-phenylenediamine was obtained.
Reaction SMILES: [Cl:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=1.Cl.[NH2:14][C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17].O.[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[CH2:24]([C@H:15]([NH:14][C:9]([C:7]1[NH:6][C:5]2[S:12][C:2]([Cl:1])=[CH:3][C:4]=2[CH:8]=1)=[O:11])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)c1cc2cc(Cl)sc2[nH]1

Procedure:
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-morpholin-4-yl-3-phenyl-propan-1-one hydrochloride (See, for example, Suzuki, K.; Fujita, H.; Sasaki, Y.; Shiratori, M.; Sakurada, S.; Kisara, K., Chem. Pharm. Bull., 36, 4834-40 (1988)) were coupled according to Procedure C (solution of product in ethyl acetate washed with water, dried over MgSO4, concentrated).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[CH:22]([N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27]Cl)([CH3:24])[CH3:23]>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:30][CH2:29][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]2)(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: CC(C)N(CCCl)CCCl
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C(C)C)CC2)cc1
Yield: 64 %

Procedure:
Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-isopropyl-4-piperidine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (6 g, 20.3 mmol) and isopropyl [bis(2-chloroethyl)]amine hydrochloride (4.88 g, 22.3 mmol); 5.28 g brown oil. Yield 64%; MS: 408.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17].O>C(O)C>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:11][CH:12]=1)[CH:16]=[CH2:15]
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(CCC(C)=O)cc1

Procedure:
p-Hydroxy benzylacetone (1.5 g.), KOH (6 g.) and allyl bromide (1.2 g.) were stirred in ethanol (50 ml) overnight. Water was added and the mixture extracted with ether, which was evaporated to give the compound (1.6 g.) as an oil purified by column chromatography.
Reaction SMILES: [N+]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]1)([O-])=O.[CH:12]1(N)[CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([N:4]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Reactant: NC1CCC1
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCC2)cn1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
1,4-Dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) was added to a solution of cyclobutylamine (107 mg, 1.5 mmol) in methanol (10 mL) at 23° C. The reaction mixture was stirred for 16 h, then the solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to afford 230 mg (92% yield) of 1-cyclobutyl-4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCl3) δ7.81 (s, 1H), 7.45 (s, 1H), 4.64 (m, 1H), 2.6 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H); MS (AP/Cl): 168.2 (M+H)+. Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be stored in a freezer at all times it is not in use. Thermodynamic measurements have shown that it can potentially generate enough energy at 35° C. under adiabatic conditions to violently explode. Extreme caution should be exercised at all times using this material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.C(O)C.[BH4-].[Na+].Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc([C@H]2CC[C@H](O)CC2)c(O)c1
Reaction time: 16 h

Procedure:
4-(2,4-Dihydroxyphenyl)cyclohexanone (18 mg) was placed in a round-bottomed flask equipped with magnetic stirrer. Ethanol (5 ml) was added, followed by sodium borohydride (3.3 mg), and the reaction mixture was stirred for 16 hr. Aqueous HCl (20 ml, 1M), followed by ethyl acetate (20 ml), was added, and the organic phase removed and washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered, and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 60:40, v/v) to afford the title compound (14 mg, 78%) as a white solid. δH (CD3OD) 1.38-1.56 (4H, m), 1.85-1.88 (2H, m), 2.04-2.07 (2H, m), 2.80 (1H, tt), 3.58-3.65 (1H, m), 6.24-6.29 (2H, m), 6.90 (1H, d); m/z (ES−) 267 ((M+AcOH)−1)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3])[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-carboxyphenylboronic acid (1 5 g, 0.09 mol), 99% ethanol (150 mL) and concentrated sulphuric acid (0.5 mL) was heated to reflux for two days. The volume was reduced to approximately 20 mL. The residue was triturated with petroleum ether to give 13.4 g of the desired material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:18]1([O:1][C:2]2[CH:3]=[C:4]([C:10]3[NH:11][CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1OC1CCCC1
Temperature: 70 °C
Yield: 30.4 %

Procedure:
A mixture of 2-(3-hydroxy-4-methoxyphenyl)-imidazole-4-formamide (110 mg, 0.47 mmol), cyclopentyl bromide (60 μl, 0.56 mmol) and K2CO3 (162 mg, 1.2 mmol) in DMF (10 ml) were heated at 70° C. overnight. A further quantity of cyclopentyl bromide (60 μl, 0.56 mmol) and K2CO3 (162 mg, 1.2 mmol) were added and the reaction mixture was cooled to room temperature, diluted with water (50 ml), extracted with ethyl acetate (2×100 ml). The combined organics were washed with brine (30 ml) dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2 ; CH2Cl2 :EtOH (9:1) (1% NH3)) afforded 2-(3-cyclopentyloxy-4-methoxyphenyl)-imidazole-4-formamide (43 mg,) as a white solid, mp d.>195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].C([O-])(O)=O.[Na+].[C:21](=O)([O:30]N1C(=O)CCC1=O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:11][C:12]([NH:15][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:13])[CH3:14]
Reactant: CC(C)(N)COc1cccc(N)c1C#N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile (Example 24d, 30.5 g, 148.6 mmol) in THF/H2O (1:1, 400 mL) was added NaHCO3 (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (44.0 g, 176 mmol) at room temperature. The reaction was stirred at room temperature for 4 h then the organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine and dried over MgSO4. After filtration, the solvent was evaporated and the crude oil was purified by chromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give the title compound as yellow oil (44.8 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0 Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21 (m, 6H). MS 340 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([OH:10])=[O:15]
Reactant: O
Reactant: Cc1ccnc(Br)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccnc(Br)c1

Procedure:
160 g (0.93 mol) of 2-bromo-4-methyl-pyridine is added in drops to 152 g (0.96 mol) of potassium permanganate in 4 l of water. Then, it is stirred under reflux for one hour before 152 g (0.96 mol) of potassium permanganate is added once more. After two additional hours of stirring under reflux, it is suctioned off in a hot state over Celite and washed with water. The aqueous phase is shaken out three times with dichloromethane. The aqueous phase is concentrated by evaporation to one-half its original volume, and the pH is set at 2 with concentrated hydrochloric acid. The precipitated solid is suctioned off and dried at 70° C. in a vacuum. 56.5 g of white solid product accumulates.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH:26]1([NH:32][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CNC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NaB(OAc)3H (11.0 mmol, 2.33 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (10.0 mmol, 1.51 g), cyclohexylamine Compound 10a (10.5 mmol, 1.2 mL) and glacial acetic acid (5 drops) in CH2Cl2 (40 mL) and the resulting suspension was allowed to stir at room temperature for 12 hrs. An aliquot of the reaction mixture showed the formation of product (MS m/e 235, 100%). The reaction mixture was basified with 2N NaOH solution and was extracted with CH2Cl2. The organic layer was washed with brine, separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo to yield cyclohexyl-(4-nitro-benzyl)-amine Compound 10b as yellow oil (1.56 g, 67% yield), which was used in the next step without purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:42]=[C:17]2[N:18]([CH3:41])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:42]=[C:17]2[N:18]([CH3:41])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.77 g), sodium hydrogen carbonate (2.84 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(2,4-dimethyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.41 g, 53%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[N+:27]([O-:29])=[O:28])[CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1c1ccc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of Example 12C (625 mg, 4.03 mmol) in acetonitrile (5 mL) was added 1-fluoro-4-methyl-2-nitrobenzene (1.00 g, 4.03 mmol) and potassium carbonate (1.11 g, 805 mmol). The reaction was heated in an oil bath at 60° C. overnight. The solution was concentrated onto silica gel and purified via flash chromatography (0-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.55-7.60 (m, 1 H), 7.22-7.43 (m, 7 H), 3.55-3.65 (m, 1 H), 3.41-3.59 (m, 2 H), 3.36 (s, 3 H), 3.09-3.21 (m, 1 H), 2.77-2.88 (m, 1 H), 2.22-2.62 (m, 7 H); MS (APCI+) m/z 384 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:11]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=O)[CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].C1N2CN3CN(C2)C[N:28]1C3.[Br-].[NH4+]>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:11]2[N:5]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](=[O:4])[CH2:2][N:28]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:12]=2[CH:22]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1N(CC(F)(F)F)C(=O)CBr
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(F)(F)F

Procedure:
Reflux 1.13 g. (0.0025 moles) of 2-[2-bromo-N-(2,2,2-trifluoroethyl)-acetamido]-5-chloro-2'-fluorobenzophenone, 1.4 g. (0.01 mole) of hexamethylenetetramine, and 0.98 g. (0.01 moles) of ammonium bromide together for 43/4 hours. Pour the reaction mixture into water and extract with dichloromethane. Dry the dichloromethane solution over anhydrous sodium sulfate, filter and evaporate. After recrystallization, the so-obtained 7-chloro-1,3-dihydro-1-(2,2,2-trifluoroethyl)-5-(2'fluorophenyl)-2H-1,4-benzodiazepin-2-one melts at 123°-125° C. Thin layer chromatography shows the product to be pure single spot material.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[O:26])=[CH:20]N=1)[C:5](N[C@@H](C(C)C)C(O)=O)=[O:6].C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4C=CC(NC([C@@H:71]5[CH2:75][CH2:74][CH2:73][C@H:72]5[C:76]([OH:78])=[O:77])=O)=CC=4)=CC=3)=O)N=2)C=CC=CC=1.I[C:84]1C=CC(NC(C2N=C(C3C=CC=CC=3)OC=2C(F)(F)F)=O)=CC=1.CC1(C)C(C)(C)OB(C2C=CC(N)=CC=2)O1.C(OC(C1CCCC1C(O)=O)=O)C1C=CC=CC=1>>[C:36]1([C:29]2[O:30][C:31]([C:32]([F:33])([F:35])[F:34])=[C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:84][C:18]([C:17]4[CH:2]=[CH:3][C:4]([C:5]([C@@H:71]5[CH2:75][CH2:74][CH2:73][C@H:72]5[C:76]([OH:78])=[O:77])=[O:6])=[CH:15][CH:16]=4)=[CH:23][CH:22]=3)=[O:26])[N:28]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Nc1ccc(-c2ccc(NC(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)[C@H](NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(=O)O
Reactant: O=C(Nc1ccc(I)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C(O)C1CCCC1C(=O)OCc1ccccc1
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid above, racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-phenyl)-amide, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and cyclopentane-1,2-dicarboxylic acid monobenzyl ester. The benzyl ester was then removed by hydrogenolysis. The racemic mixture was separated by chiral SFC to afford (1R,2R)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid (or enantiomer). LCMS calcd for C30H24F3N3O5 (m/e) 563, obsd 564 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])=[S:48])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=S)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To the solution of methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XIV (610 mg, 1.12 mmol) in THF (10 mL) under argon was added Lawesson's reagent (680 mg, 1.68 mmol) and DMAP (13 mg, 0.11 mmol). The mixture was stirred at r.t. for 2 h and then refluxed over weekend. An additional two portions of Lawesson's reagent (900 mg, 2.24 mmol) and was added and the reaction was refluxed for another 4 h. The solvent was evaporated under reduced pressure and the crude product was purified on a silica gel column (1:6 EtOAc/hexane) to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamothioyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XV (290 mg, 0.51 mmol, 45% yield). ESIMS found for C25H46N4O8S m/z 563 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[CH3:13][NH2:14]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[CH3:13][NH:14][C:8]([C:7]1[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: COC(=O)c1cc(Br)cnc1N
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cccnc1
Product: Nc1ccc(Br)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
A slurry of the above methyl 2-amino-5-bromopyridine-3-carboxylate (3.0 g, 13 mmol) in methanol was cooled to 0° C., and methylamine gas was passed through the solution at a moderate rate for 5 min. The mixture was stirred in sealed tube at 50 ° C. for 24 h, and the methanol was removed in vacuo to provide 2-amino-5-bromopyridine-N-methylpyridine-3-carboxamide as a white solid (2.5 g, 80.6% yield): 1H NMR (400 MHz; DMSO-d6): 8.54 (br s, 1H); 8.19 (d, 1H); 8.08 (d, 1H); 7.25 (s, 1H); 2.72 (d, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[OH:20][C:21]([C:24]1[O:28][N:27]=[C:26]([C:29](O)=[O:30])[CH:25]=1)([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:26]3[CH:25]=[C:24]([C:21]([OH:20])([CH3:22])[CH3:23])[O:28][N:27]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: CC(C)(O)c1cc(C(=O)O)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cc(C(C)(C)O)on1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 5-(2-hydroxypropan-2-yl)-isoxazole-3-carboxylic acid (0.22 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 40 mg. 1H NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.62 (s, 6H), 4.36 (m, 2H), 4.59 (m, 1H), 6.57 (m, 1H), 6.82 (dd, 1H), 7.54 (m, 2H), 8.00 (m, 1H), 8.20 (m, 1H).