Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:13])[CH2:7][CH2:6][N:5]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:4]12.[CH3:31]C(C)([O-])C.[K+].CI>O1CCCC1>[ClH:1].[ClH:1].[CH3:31][N:14]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][N:8]1[CH2:7][CH2:6][N:5]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:4]2[CH2:3]1
Reactant: COc1cc(NC(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(N(C)C(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
0.9 g of the compound obtained in Example 2 is dissolved in 50 ml of tetrahydrofuran and, under argon, there are added 0.265 g of potassium tert-butoxide and then, after 1 hour's stirring, 0.15 ml of methyl iodide. Stirring is maintained for 1 hour and the solvent is removed in vacuo. The residue is taken up in a mixture of water/dichloromethane, extracted, decanted and then dried over Na2SO4 and evaporated to dryness in vacuo. The product is converted to the hydrochloride using ethanolic hydrogen chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:18][CH3:19])[C:11]=1[O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:6]([OH:8])=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:28]
Reactant: COc1cc(C(=O)O)cc(OC)c1OCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OCC=C(C)C)c(OC)c1
Yield: 89.3 %

Procedure:
In a manner identical to Example 15, 3,5-dimethoxy-4-prenyloxybenzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.39 g), thereby yielding 1.01 g(89%) of the aimed compound.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:9][CH2:10][N:11]1[C:20]2[C:19](=[O:21])[N:17]([CH3:18])[C:16](=[O:22])[N:15]([CH3:23])[C:14]=2[N:13]=[CH:12]1.C(N(CC)CC)C.CCCCCCC.C(Cl)Cl>C(Cl)Cl>[C:1]([O:9][CH2:10][N:11]1[C:20]2[C:19](=[O:21])[N:17]([CH3:18])[C:16](=[O:22])[N:15]([CH3:23])[C:14]=2[N:13]=[CH:12]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cn1c(=O)c2c(ncn2CO)n(C)c1=O
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCn1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To 0.71 g (0.0053 mole) of hexanoyl chloride in 10 ml of CH2Cl2 there was added 1.10 g (0.0052 mole) of 7-hydroxymethyl theophylline; no reaction occurred and the reaction mixture was a suspension. Then 0.58 g (0.0057 mole) of triethylamine was added and a clear, colorless solution was obtained. The solution was stirred at room temperature for 15 minutes then concentrated in vacuo. The residue was titrated with 200 ml ether and filtered. The filtrate was concentrated in vacuo to give an oil which was titrated with heptane CH2Cl2 (50:10). The resulting suspension was filtered while hot and concentrated to 20 ml, then cooled to room temperature. A gelatinous mass precipitated which was filtered and dried to give 0.70 g (mp 67°-72° C., 43% yield) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:23][CH2:22][CH2:21][Cl:20])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: O=C1COc2c(F)cc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2c(F)cc(Br)cc2N1CCCCl
Yield: 72.1 %

Procedure:
6-Bromo-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF44) (0.091 g, 0.37 mmol), Cs2CO3 (0.180 g, 0.55 mmol) and 3-chloro-1-iodopropane (0.083 g, 0.41 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF50(2084)) (0.086 g, 72%). 1H NMR (CDCl3) δ 7.02-6.96 (m, 1H), 6.85 (d, J=5.2 Hz, 1H), 4.65 (s, 2H), 4.04-4.11 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.10-2.18 (m, 2H); 13C NMR (CDCl3) δ 163.8, 151.7 (d, J=250.9 Hz), 133.1 (d, J=14.6 Hz), 131.5 (d, J=3.8 Hz), 115.1 (d, J=21.5 Hz), 114.2 (d, J=10.0 Hz), 113.4 (d, J=3.4 Hz), 67.6, 42.2, 39.5, 30.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>CN(C)C=O.O>[CH3:14][O:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-hydroxyquinoline (10.3 g) in dimethylformamide (140 ml) was ice-cooled. To the solution was added sodium hydride (3.0 g, 62.6% in oil) and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added methoxymethyl chloride (6.5 ml) and then the mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added ice. The reaction mixture was stirred and then diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1N aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate, and then concentrated to give the title compound (10.4 g) having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([CH3:29])=[N:24][N:25]([CH2:27][CH3:28])[CH:26]=1>>[CH2:27]([N:25]1[CH:26]=[C:22]([NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[C:23]([CH3:29])=[N:24]1)[CH3:28]
Reactant: CCn1cc(N)c(C)n1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Product: CCn1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2OC)c(C)n1

Procedure:
Using an analogous procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted with 4-amino-1-ethyl-3-methylpyrazole to give N-(1-ethyl-3-methylpyrazol-4-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.29 (t, 3H), 2.1 (s, 3H), 3.5 (s, 2H), 3.75 (s, 3H), 3.96 (q, 2H), 5.09 (s, 2H), 6.54 (m, 1H), 6.63 (d, 1H), 7.06 (d, 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 7.8 (s, 1H), 9.29 (s, 1H); Mass Spectrum: M+H+ 380; which material was hydrogenated to give N-(1-ethyl-3-methylpyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.28 (t, 3H), 2.1 (s, 3H), 3.45 (s, 2H), 3.7 (s, 3H), 3.96 (q, 2H), 6.28 (m, 1H), 6.37 (d, 1H), 6.93 (d, 1H), 7.8 (s, 1H), 9.22 (br s, 1H), 9.29 (br s, 1H); Mass Spectrum: M+H+ 290.
Reaction SMILES: O=S(Cl)[Cl:3].[C:5]1([CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]2[CH2:17][CH2:16][CH:15]([CH2:18]O)[CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][Cl:3])[CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 70.1 %

Procedure:
Step 2): SOCl2 (0.6 ml, 8.2 mmol) was added dropwise to a solution of 1-diphenylmethyl-4-hydroxymethylpiperidine (1.0 g, 3.6 mmol) in benzene (7 ml) at room temperature. The mixture was refluxed for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with 5% NaOH solution, dried (MgSO4) and concentrated. The residue was recrystallized (ethyl acetate/ether/hexane) to give 1-diphenylmethyl-4-chloromethylpiperidine (70.1%): mp 73°-75° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:26][C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)=[C:29]2[NH:38][CH:39]=[C:40]([C:41](=[O:45])C(O)=O)[C:28]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[F:26][C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)=[C:29]2[NH:38][CH:39]=[C:40]([C:41](=[O:45])[C:18]([N:15]3[CH2:14][CH2:13][CH:12]([C:11]4[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[N:9][N:10]=4)[CH2:17][CH2:16]3)=[O:20])[C:28]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnnn2-c2ccccc2)CC1
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=C(C(=O)N1CCC(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
Part C: To a solution of tert-butyl 4-(1-phenyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.165 g, 0.50 mmol) in 1,4-dioxane (10 mL) at 25° C. was added 4.00 N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at 25° C. for 16 h. The mixture then was concentrated under vacuum. The resulting solids were dissolved in DMF (10 mL). To this solution was added sequentially 2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.137 g, 0.50 mmol), N-methylmorpholine (0.165 mL, 1.50 mmol), and TBTU (0.176 g, 0.55 mmol), and the mixture was stirred at 25° C. for 24 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in hot methanol, and the solution then was allowed to cool slowly to room temperature. The precipitate was recovered by filtration, washed with methanol, and dried under vacuum to provide 1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperidin-1-yl)ethane-1,2-dione (0.142 g) as an off-white solid; mp: 257-258° C.; HRMS: 487.1740 (M+H)+ [calc'd: 487.1755]; 1H NMR (500 MHz, DMSO-D6) δ 13.06 (br s, 1H), 9.02 (s, 1H), 8.32 (d, 1H, J=1.8 Hz), 8.30 (s, 1H), 8.12 (s, 1H), 7.58 (s, 5H), 4.37 (m, 1H), 3.67 (m, 1H), 3.32 (m, 1H), 3.25 (m, 1H), 3.03 (m, 1H), 2.01 (m, 1H), 1.88 (m, 1H), 1.83-1.70 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1.[Na]>O>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(C(C)C)C2)ncc1Cl
Temperature: 120 °C
Yield: 20.7 %

Procedure:
10-Isopropy-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (30 mg, 0.14 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (45 mg, 0.14 mmol) and 4N HCl in dioxane (28 μl, 0.15 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 8 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (14.85 mg, 20%) as a beige foam. 1H-NMR (CDCl3) δ 9.08 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.13 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.21 (m, 2H), 7.08 (d, J=7.8 Hz), 6.93 (s, 1H), 4.52 (d, J=2 Hz, 1H), 3.08 (br s, 1H), (3.02 br s, 1H), 2.71 (m, 2H), 2.63 (d, J=5.3 Hz, 3H), 2.56 (m, 3H), 2.30-2.20 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 0.87 (q, J=1.8, 6.6 Hz, 6H); LC/MS (ESI+): 513 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:49])[CH:5]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[C:22](=[O:33])[N:23]([CH3:32])[C:24]([CH3:31])=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[CH:18]=[C:17]([Br:34])[CH:16]=1)[CH3:7])C.[OH-].[Na+]>>[Br:34][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]2[C:22](=[O:33])[N:23]([CH3:32])[C:24]([CH3:31])=[CH:25][C:26]=2[C:27]([F:28])([F:30])[F:29])[CH:18]=1)[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:6]([CH3:7])[CH:5]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:4]([OH:49])=[O:3]
Reactant: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(Br)cc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)c(-c2cc(Br)cc(OCCCCCCC(C)C(Oc3ccccc3CCC(=O)O)C(=O)O)c2)c(=O)n1C
Yield: 52.6 %

Procedure:
A similar procedure as described in Example 1, step 3 was used, starting from 4-[3-{6-[3-bromo-5-(1,6-dimethyl-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-phenoxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (537 mg, 0.71 mmol) and 1.0 N aqueous sodium hydroxide (7.1 mL) to give 4-[3-{6-[3-bromo-5-(1,6-dimethyl -2-oxo-4-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-phenoxy]-hexyl}-(2-(2-carboxy-ethyl)-phenoxy)-butyric acid (260 mg, 52%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C33H37BrF3NO7 (M+Na)+ 718.1597, found 718.1601.
Reaction SMILES: [C:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.C(N(CC)CC)C>CC#N>[NH2:24][C:19]1[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:11]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccccc1)[C@H]1CCCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)Nc3ccccc3)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To (3S)—N-phenyl-3-piperidinecarboxamide (327 mg, 1.6 mmol) in CH3CN (10 mL) was added 4,6-dichloro-2-pyrimidinamine (289 mg, 1.760 mmol) and triethylamine (0.446 mL, 3.20 mmol), and the solution was allowed to stir overnight at 50° C. The reaction was then quenched with water (2 mL), and extracted 3× with EtOAc. The organics were combined, dried (Na2SO4), filtered and concentrated to afford the crude title compound (350 mg) as a solid. LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=2[NH:6][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([N:6]1[C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[NH:3][C:2]([CH3:1])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(=[O:34])[CH3:33]
Reactant: COC(=O)C1=C(C)Nc2ccccc2NC1c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)Nc2ccccc2N(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester (800 mg., 2.36 mmole) in dichloromethane (8 ml.) is treated with pyridine (280 mg., 3.53 mmole), acetic anhydride (479 mg., 4.72 mmole) and 4-dimethylaminopyridine (5 mg.). The reaction is stirred at room temperature for 16 hours. A light yellow solid precipitates out of the reaction. The reaction is diluted with dichloromethane/methanol (100 ml. of 95:5 mixture) and the resulting solution is washed with 10% citric acid, 5% sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate, the solvent is evaporated to give a yellow foam. This foam is triturated with ether to give 705 mg. of yellow crystals. Recrystallization from dichloromethane-methanol-isopropanol gives an analytically pure sample of 1-acetyl-2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester as yellow crystals; m.p. 231°-232.5°. TLC(silica gel; acetone:hexane, 40:60) Rf = 0.28.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[S:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[C:3]=1[N:24]=O.C1(CN2C(N)=C(N)C(=O)N(CC3CCCCC3)C2=S)CCCCC1.[CH:50]([C:52]1[CH:62]=[CH:61][C:55]([CH:56]=[CH:57][C:58]([OH:60])=[O:59])=[CH:54][CH:53]=1)=O>C(O)C>[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:50]([C:52]4[CH:62]=[CH:61][C:55](/[CH:56]=[CH:57]/[C:58]([OH:60])=[O:59])=[CH:54][CH:53]=4)[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[S:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=S)n1CC1CCCCC1
Agent: Nc1c(N)n(CC2CCCCC2)c(=S)n(CC2CCCCC2)c1=O
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=S)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
In the manner of step (d) of example 8, 6-amino-1,3-bis(cyclohexylmethyl-1,2-dihydro-5-nitroso-2-thioxo-4(3H)-pyrimidinone (from step (c), 3.00 g, 8.20 mmol) was reduced to 1,3-bis(cyclohexylmethyl)-5,6-diamino-1,2-dihydro-2-thioxo-4(3H)-pyrimidinone, which was then combined with 4-formylcinnamic acid (Aldrich, 1.44 g, 8.20 mmol) in ethanol (150 mL). The resulting yellow mixture was dried by evaporation of several portions of absolute ethanol, and the residual yellow powder (Schiff base intermediate) was heated at reflux in nitrobenzene (150 mL) until no more water distilled off. The reaction mixture was then cooled to ambient temperature, and stirred in ether (200 ml). The resulting pale yellow precipitate was filtered off, washed with hot ethanol (100 mL), followed by ether (100 mL), and dried under vacuum at 110° C. to afford (E)-4-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-6-oxo-2-thioxo-9H-purin-8-yl)cinnamic acid as a yellow powder (2.32 g, 65%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:18]=3[CH:36]=2)=[CH:4][CH:3]=1.[OH:37]O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)([CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[C:18]=3[CH:36]=2)=[O:37])=[CH:4][CH:3]=1
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:25]([O-])=O)[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>[Pd].C(OCC)(=O)C.CO>[CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)N1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)N1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid dimethylamide (1.0 g, 2.4 mmol) in 4:1 ethyl acetate/methanol (100 ml) under nitrogen, was added 5% palladium on carbon (240 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-[2-(3,4-diamino-phenyl)-1H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid dimethylamide as an orange solid that was used in the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:21])=[CH:16][CH:15]=1.I[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:21])=[CH:16][CH:15]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccccc4C)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-N-(2-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(2-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, m), 7.77,(1H, m), 7.59-7.43,(5H, m), 7.22,(4H, m), 4.71-4.53,(2H, m), 2.93-2.87,(3H, m), 2.55,(3H, s), 2.32-2.29,(3H, m). LCMS; retention time 3.48 min, MH+ 412.
Reaction SMILES: [H-].[Na+].C(OCC)=O.[CH:8]1([CH2:11][O:12][CH2:13][C:14]([O:16]CC)=O)[CH2:10][CH2:9]1.S(O)(O)(=O)=O.[CH3:24][S:25][C:26](=[NH:28])[NH2:27].[CH3:29]SC(=N)N.[O-]CC.[Na+]>C1COCC1.CCO.C(O)(=O)C>[CH:8]1([CH2:11][O:12][C:13]2[C:14]([OH:16])=[N:28][C:26]([S:25][CH3:24])=[N:27][CH:29]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)COCC1CC1
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC=O
Product: CSc1ncc(OCC2CC2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
To a stirred suspension of NaH (35.20 g, 0.88 mol, 60% in mineral oil) in anhydrous THF (1000 mL) was added ethyl formate (88.80 g, 0.90 mol) and the title compound of step 1 (126.0 g, 0.80 mol) in anhydrous THF (100 mL). The mixture was stirred at r.t. for 0.5 hour and refluxed for 3 h. In a separate flask, S-methylthiopseudourea hemisulfate (133.44 g, 0.96 mol) and sodium ethoxide (65.28 g, 0.96 mol) in EtOH (200 mL) were stirred at r.t. for 1 h, whereupon this mixture was added to the above mixture. There combined mixture was refluxed for 15 h, cooled, and the pHwas adjusted to 5 with acetic acid. After concentration under vacuum, silica gel chromatography (DCM: MeOH=50/110/1) gave the title compound (30.00 g, 17.7% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 12.08 (s, 1H), 7.49 (s, 1H), 3.83-3.80 (m, 2H), 2.55 (s, 3H), 1.37-1.28 (m, 1H), 0.65-0.62 (m, 2H), 0.37-0.34 (m, 2H).