Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][C:5](=[O:7])[CH3:6])([O-:3])=[O:2].C(O[CH:11]=[C:12]([C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C([O-])(=O)C.[Na+]>C(O)C>[OH:7][C:5]1[CH:6]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CC(=O)C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c([N+](=O)[O-])cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of nitro-2-propanone (63.50 g, 0.616 mol), (ethoxymethylene)oxalacetic acid, diethyl ester (151.1 g, 0.616 mol) and ethanol at 5° C. under a nitrogen atmosphere is treated with sodium acetate (101.1 g, 1.23 mol), stirred overnight at room temperature, and concentrated in vacuo. The resultant residue is chromatographed (silica gel, 1% ethyl acetate:hexanes eluent). The chromatographed material is taken up in ethyl acetate and extracted with an equivalent of aqueous sodium hydroxide. The basic layer is acidified to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract is dried and concentrated in vacuo to give the title product as a yellow oil, 16.0 g, identified by NMR and mass spectral analyses.
Reaction SMILES: C([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=2[CH2:36][CH2:37][F:38])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=2)=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[Cl:32][C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:33]=[CH:34][C:35]([CH2:36][CH2:37][F:38])=[C:19]([S:16]([N:12]3[CH2:13][CH2:14][CH2:15][CH:9]([OH:8])[CH2:10][CH2:11]3)(=[O:18])=[O:17])[CH:20]=2)[CH:30]=[CH:29][C:28]=1[F:31]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1ccc(CCF)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(F)c(Cl)c1)c1ccc(CCF)c(S(=O)(=O)N2CCCC(O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 3-(4-benzyloxyazepan-1-yl)sulfonyl-N-(3-chloro-4-fluoro-phenyl)-4-(2-fluoroethyl)benzamide (65.00 mg, 115.44 umol, 1.00 Eq) in MeOH (15 mL) was added Pd/C (30.00 mg, 115.44 umol, 1.00 Eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 25° C. for 16 hr. TLC showed the starting material was consumed completely. The reaction mixture was filtered and the filter was concentrated, purified by prep-TLC (eluting with PE:EA=1:1) to afford product N-(3-chloro-4-fluoro-phenyl)-4-(2-fluoroethyl)-3-(4-hydroxyazepan-1-yl)sulfonyl-benzamide (24.00 mg, 50.75 umol, 43.96% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>CN(C)C=O>[C:24]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide prepared in Reference Example 2 was dissolved in 200 ml of N,N-dimethylformamide. 2.1 ml (15 mmol) of triethylamine and 1.06 ml (15 mmol) of acetyl chloride were added to the mixture while cooling with ice, followed by stirring overnight. The reaction product was concentrated under vacuum to obtain a crude product, which was recrystallized from hot methanol to obtain 0.86 g of 4-acetylamino-1-benzyl-5-imidazolecarboxamide (yield 33%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ncc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of 2-methyl-pyrimidine-5-carbaldehyde (5 g, 41 mmol) in MeOH (100 mL) was added NaBH4 (2.3 g, 61.5 mmol) at 0° C. in portions and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give the remains, which was suspended in H2O (20 mL) and extracted with EtOAc (5×50 ml). The organic layer was dried over Na2SO4 and concentrated to afford the title compound (2 g, yield: 39%). 1H NMR (CDCl3 400 MHz): δ8.64 (s, 2H), 4.72 (s, 2H), 2.73 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])c1cncc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cncc(Cl)c1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
To 5-chloronicotinate (10.5 g) was added 1N NaOH (84.9 mL) at ambient temperature. The mixture was heated at 60° C. for 1 hour. The reaction mixture was adjusted to pH 4–5 with HCl. The precipitate was filtered to give 5-chloronicotinic acid (6.9 g) a colorless solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:16])[CH2:12][CH:13](O)[CH:14]=1)([OH:3])=[O:2].[SH:17][CH2:18][CH2:19][OH:20].C[O-].[Na+]>CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:16])[CH2:12][CH:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=1)([OH:3])=[O:2]
Reactant: OCCS
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(SCCO)CC1=O

Procedure:
In the manner of Example 281 a methanol solution of 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one [Prostaglandins, 3, 921 (1973)] and β-mercaptoethanol is treated with sodium methoxide solution, acidified, concentrated, and extracted to provide the subject compound as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(N(C)C)=O.C(O)C>[N:22]1([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: C1CNCCN1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCNCC2)c2ccccc21
Yield: 70 %

Procedure:
A warm solution of 6.0 g of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in 12 ml of dimethylacetamide and 40 ml of ethanol was added dropwise with stirring to a refluxing solution of 8.6 g of piperazine in 50 ml of ethanol. Then, the reaction mixture was refluxed for 1 hour and the mixture was evaporated to dryness in vacuo. The residue was chromatographed over silica gel and the eluent was then evaporated to dryness in vacuo. The residue was crystallized from acetonitrile to obtain a 70% yield of 5,11-dihydro-11-[3-(1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one with a melting point of 280°-282° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:29]1[N:34]=[C:33]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH:32]=[CH:31][N:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:29]2[N:34]=[C:33]([O:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[CH:32]=[CH:31][N:30]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 100 °C

Procedure:
To 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 59 mg, 0.19 mmol) in a scintillation vial was added dioxane (0.97 ml), cesium carbonate (126 mg, 0.39 mmol), and tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (67 mg, 0.21 mmol). The system was purged and flushed with argon (3×) before adding XantPhos (17 mg, 0.029 mmol) and palladium(II) acetate (5 mg, 0.021 mmol). The system was purged and flushed with argon (3×) before sealing the system and heating to 100° C. overnight. The reaction was cooled to room temperature, filtered through celite and diluted with water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. Purification via reverse phase chromatography (10-80% acetonitrile in water, linear gradient) provided tert-butyl 4-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate. This material was treated with 2 ml of 1:1 trifluoroacetic acid:dichloromethane solution for 1 hr. The reaction was concentrated to dryness and purified by reverse phase chromatography (5-60% acetonitrile in water) to provide 16 mg (0.027 mmol, 14% yield) of 4-[5-(3-methyl-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one as the TFA salt. MS APCI: [M+H]+ m/z 480.2. 1H NMR (500 MHz, dmso) δ 9.70-9.49 (m, 1H), 8.72-8.37 (m, 2H), 8.34-8.08 (m, 1H), 7.70-7.61 (m, 1H), 7.61-7.54 (m, 1H), 7.54-7.47 (m, 1H), 7.41-7.33 (m, 1H), 6.96-6.91 (m, 1H), 6.41-6.13 (m, 1H), 5.42-5.15 (m, 1H), 4.17 (s, 2H), 3.96-3.65 (m, 2H), 3.36-3.14 (m, 2H), 3.14-2.93 (m, 2H), 2.27 (s, 3H), 2.22-2.07 (m, 2H), 2.01-1.84 (m, 2H), 1.84-1.63 (m, 2H), 1.21-1.01 (m, 2H). TFA salt proton was visible. rhSyk=+++.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:28](=O)[CH3:29].Cl>>[CH2:28]([N:11]([C@@H:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:17]1)[CH3:29]
Reactant: CC=O
Reactant: C[C@@H](CCc1ccccc1)N[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: CCN([C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)[C@@H](C)CCc1ccccc1

Procedure:
Coupling of 6-{trans-4-[(S)-1-methyl-3-phenylpropylamino]cyclohexyl}-3H-benzoxazol-2-one (196 mg, 0.538 mmol) and acetaldehyde (24 mg, 0.538 mmol) following the procedure described in Example 24, followed by formation of the HCl salt, gave 6-(trans-4-{ethyl-[(S)-1-methyl-3-phenylpropyl]-amino}cyclohexyl)-3H-benzoxazol-2-one (110 mg, 50%), as a pale yellow solid (a mixture of diastereomers): mp 221-246° C.; IR (KBr): 3424, 2929, 1771, 1495 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.52 (s, 2H), 9.11 (s, 2H), 7.35-7.21 (m, 10H), 7.18 (m, 4H), 7.00 (s, 2H), 3.20 (m, 2H), 2.81 (m, 2H), 2.54 (m, 2H), 2.20-1.51 (m, 28H), 1.44 (d, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 126 (m, 6H); API-MS (methane) (m/z): 393 [M+H]+; HPLC: method C, 5.88 minutes (97.4%), method D, 11.32 minutes (>99%); Anal. Calcd for C25H32N2O2.HCl.H2O: C, 67.17; H, 7.89; N, 6.27. Found: C, 67.18; H, 7.69; N, 5.98.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1.[CH2:31]([S-:33])[CH3:32].[Na+]>CS(C)=O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:33][CH2:31][CH3:32])[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCSc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv) in DMSO (5 mL), and sodium ethanethiolate (100 mg, 1.19 mmol, 1.70 equiv). The resulting solution was stirred for overnight at 90° C. in an oil bath. The mixture was concentrated under vacuum. The residue was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg (crude) of N-(3-(trifluoromethyl)benzyl)-2-(5-(ethylthio)-2-nitrophenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1C=CC=CC=1.S(Cl)(Cl)=O.[NH3:39]>O1CCOCC1.O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:39])=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)CC1
Reactant: N
Solvent: c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(C(N)=O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.1 g of crude p-[trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexyl]benzoic acid, 50 ml of benzene and 0.9 ml of thionyl chloride was heated to boiling for 2 hours. Benzene and excess thionyl chloride were distilled off in vacuo. The residue was taken up twice in 50 ml of toluene and concentrated each time. The crude acid chloride obtained (3.5 g) was dissolved in 50 ml of dioxan and the solution was allowed to flow into a mixture of 18 ml of concentrated ammonia and 75 ml of dioxan. The resulting suspension was stirred at room temperature for 1 hour, then diluted with water and suction filtered. The material on the suction filter was washed neutral with water and then dried by concentration with toluene. 2.6 g of crude p-[trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexyl]benzamide were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([N:8]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of 1.0 g (0.005 mole) of (rac)-3-cyclopentylamino-butanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.0 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester (IV-3)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.IC.[C:25]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:25])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc2c(=O)n(-c3cccc(Br)c3C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (535 mg, 1.48 mmol), iodomethane (0.185 mL, 2.96 mmol) and Cs2CO3 (965 mg, 2.96 mmol) in THF (20 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was dissolved in DCM, washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g silica), eluting with EtOAc-hexanes (gradient from 0-100%), to give 3-(3-bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione (442 mg). Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 7.31-7.22 (m, 2H), 7.22-7.19 (m, 1H), 7.17-7.13 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:33])[CH2:6][N:7]1[C:12](=[O:13])[C:11]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.CO>[C:23]([O:22][C:20]([N:10]1[C:11]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:13])[N:7]([CH2:6][C:5]([OH:33])=[O:4])[C@H:8]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:9]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)O)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24 mg (1.0 mmol) lithium hydroxide in 1 ml of water were added to 0.22 g (0.5 mmol) (R)-tert-butyl 4-(2-methoxy-2-oxoethyl)-5-oxo-3-phenyl-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 10 ml MeOH. The reaction mixture was stirred overnight at RT and then the MeOH was distilled off. The residue was mixed with water and acidified with an aqueous 4N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[C:23]1([C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:33][CH2:32]1)(=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1ccccc1)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with phenyl(piperazin-1-yl)methanone (1.2 equiv) to give 194 (M+1 486.0)
Reaction SMILES: C(N(C(C)C)CC)(C)C.I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:40])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([O:38][CH3:39])[CH:28]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[CH3:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([NH:23][C:24](=[O:40])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:36])=[C:29]([O:38][CH3:39])[CH:28]=2)[CH2:21][CH2:22]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Reactant: CCCCCI
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Reaction time: 16 h

Procedure:
30 ml of diisopropylethylamine and 1.3 ml of 1-iodopentane were added to a solution of 1.84 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy )- 3-methoxycinnamamide (Example 172) in 50 ml of methylene chloride. The solution was stirred for 16 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.56 g of N-(trans-4-methylcyclohexyl)-4-(pentyloxycarbonylmethoxy) -3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
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](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C=O)C>[CH:45]1([CH2:51][CH2:52][NH:53][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: NCCC1CCCCC1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCC4CCCCC4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl 4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-cyclohexylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(2-cyclohexylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=[O:14])=[CH:4]2.[OH-].[Na+].Cl>C(O)C>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=[O:14])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 64.047 g (260.0 mM) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in 400 ml of ethanol was added 156 ml (312 mM) of 2N-aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for one hour. To this reaction mixture was added concentrated hydrochloric acid with stirring to bring pH into the range of 4-5 and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.