Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([Cl:11])[CH:7]=[C:6]([F:12])[C:5]=1[N:13]1[C:17](=[O:18])[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=2[C:14]1=[O:23])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:32])C=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[Cl:11][C:8]1[C:9]2[O:10][CH:2]([CH2:3][OH:32])[CH2:1][C:4]=2[C:5]([N:13]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=3[C:14]2=[O:23])=[C:6]([F:12])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c(Cl)cc(F)c1N1C(=O)C2=C(CCCC2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(Cl)c2c1CC(CO)O2
Temperature: 25 °C

Procedure:
A solution of 0.67 g of 19C and 475 mg of 80% MCPBA in 15 mL of 1,2-dichloroethane was heated on an oil bath at 70° C. for 2.5 hours. A few milligrams of PTSA was added, the mixture was cooled to room temperature, washed with a saturated aqueous solution of sodium sulfite, followed by a saturated aqueous solution of sodium bicarbonate, dried (Na2SO4), filtered and stripped of solvent. The residue was flash chromatographed on silica gel with a 40:60 v:v mixture of ethyl acetate and hexane as eluent, to give the title compound, as white crystals, m.p.: 193°-195° C.
Reaction SMILES: [Mg].CCOCC.BrBr.ClC1C=CC(C[O:15][C:16]2[C:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:19])=CC=1>C1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:23]2[C:16]([OH:15])=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2)c1OCc1ccc(Cl)cc1
Agent: BrBr
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=Cc1cccc(OCc2ccc(Cl)cc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To magnesium (0.098 g, turnings, 4.0 mmol) in a mixture of anhydrous ether (20 mL) and benzene (20 mL) at 0° C., bromine (0.10 mL, 2.0 mmol) was added dropwise. When the reaction had started, stirring was commenced and the addition of bromine continued until complete. The ice bath was removed and the reaction mixture was heated until the solution was almost colorless. After cooling down, the reaction mixture was slowly added to a solution of 2,3-bis-(4-chloro-benzyloxy)-benzaldehyde (627, 0.78 g, 2.0 mmol) in benzene (60 mL) at room temperature while stirring vigorously. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, then refluxed for 36 hours. After the reaction mixture was cooled down to room temperature, a solid was collected by filtration and washed with benzene, then boiled in hydrochloric acid (100 mL, 1.0 M) for 30 minutes. After cool down, the solution was extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. An off-white solid was obtained after removal of the solvent (628, 0.32 mg, 60%). MS (ESI) [M−H−]=261.25.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:6])[CH3:5])[CH3:2].[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15](Cl)[N:14]=[C:13]2[OH:19]>>[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:6])[CH3:5])[N:14]=[C:13]2[OH:19]
Reactant: CCNC(C)C
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Product: CCN(c1nc(O)c2cccc(Br)c2n1)C(C)C
Temperature: 170 °C
Yield: 97.1 %

Procedure:
A slurry of N-ethylisopropylamine (1.40 mL, 11.56 mmol) and 8-bromo-2-chloroquinazolin-4-ol (407c; 0.10 g, 0.385 mmol) was sealed in a microwave tube and heated to 170° C. for 30 min. The reaction was judged complete and clean. The reaction was partitioned between satd aq ammonium chloride and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(ethyl(isopropyl)amino)quinazolin-4-ol (0.116 g, 0.374 mmol, 97% yield) as a brown semi-solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (2H, m), 6.96 (1H, t, J=7.7 Hz), 4.81 (1H, dt, J=13.4, 6.7 Hz), 3.51 (2H, q, J=7.0 Hz), 1.13-1.24 (9H, m). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].[O:11]=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH:22]([C:35](=[O:37])C)[CH:23]([NH:31][C:32]([CH3:34])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[O:11]=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH:22]([CH:35]([OH:37])[CH2:10][N+:7]([O-:9])=[O:8])[CH:23]([NH:31][C:32]([CH3:34])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(C)=O)N1CCc2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)C[N+](=O)[O-])N1CCc2ccccc2C1=O
Yield: 64.1 %

Procedure:
To 1.15 g (10.0 mMol) of KOtBu (potassium tertbutoxide) in dimethylformamide (30 mL) at 0° C. under nitrogen and nitromethane (1.75 mL, 32.5 mMol) was added 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-4-oxo-pentanoic acid, tert-butyl ester (3.6 g, 10.0 mMol). After 3 hours at 0° C. the reaction was quenched by addition of 1.5 mL of acetic acid and partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed with saturated aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated under reduced pressure. Purification of the residue over silica (elution with dichloromethane/methanol 20:1) gave 2.7 g of 3-(1, 2, 3, 4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-4-hydroxy-5-nitro-pentanoic acid, tert-butyl ester as 1:1 mixture of diastereomers.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.[NH2:13][C:14]([NH2:16])=[O:15]>>[NH:13]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:10])[NH:16][C:14]1=[O:15]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NC(N)=O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2

Procedure:
The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formula I, II or III can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of cyclohexanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclohexanecarboxy late. Reaction of ethyl 2-oxocyclohexanecarboxylate with urea at 175-185° C. produced 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione. Reaction of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazol. Reaction of 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazoline with methyl 3-(bromomethyl)benzoate in DMF , followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H )-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43][NH:44][S:45]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])(=[O:47])=[O:46])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43][NH:44][S:45]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])(=[O:46])=[O:47])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 83 %

Procedure:
Ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid (light-brown solid) in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:12](O)(=O)[CH3:13]>Cl>[CH3:5][N:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=2[N:1]=[C:12]1[CH3:13]
Reactant: CNc1cccc(OC)c1N
Reactant: CC(=O)O
Agent: Cl
Product: COc1cccc2c1nc(C)n2C
Yield: 87.5 %

Procedure:
A suspension of 2-amino-3-methoxy-N-methylaniline (671 mg) and acetic acid (265 mg) in 4N hydrochloric acid (3.5 ml) was refluxed for 10 hours. Insoluble material was filtered off, and the filtrate was adjusted to pH 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (dichloromethane:methanol=40:1, v/v) to give 1,2-dimethyl-4-methoxy-1H-benzimidazole (680 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:29][C:30]1[CH:43]=[CH:42][C:33]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1>O1CCCC1>[C:36]1([C:34]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:43][CH:42]=2)=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (35 ml,dry) was added to a mixture of 2,2-bis-trifluoromethyl 2-hydroxyacetic acid (1.08 g,5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was refluxed for 0.5 hrs and cooled to 23° C. The reaction was treated with 4-aminobenzophenone (1.01 g, 5.1 mmol), stirred at 23° C. for 1.5 hrs, and then at reflux 18 hrs. The reaction was evaporated to a yellow oil-solid mixture. The mixture was dissolved in ethyl ether, treated with hydrogen chloride in ethyl ether, and filtered. The filtrate was evaporated to a yellow oil-solid mixture. Chromatography of this mixture on silica gel, eluting with 5% ethylether in methylenechloride provided the title compound as an off-white solid; mp 143°-146° C. 1H-NMR (250 MHz,d6 -DMSO): 7.67(m, 2H, ArH), 7.83(m, 5H, ArH),7.96(d, J=8.8, 2H, ArH), 9.82(s, 1H, OH), 10.82(s, 1H, NH). MS(CI,CH4): 392 (M+1). Analysis for C17H11F6NO3: Calculated: C, 52.18; H, 2.83; N, 3.58 Found: C, 52.25; H, 3.10; N, 3.50
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[C:10]([Cl:21])[CH:9]=1)(C)(C)C.O.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[Cl:21][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=1[N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(N)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
298 mg. (0.92 mmol) of [3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 65b) are dissolved in 5 ml of 4 N HCl in dioxane. The solution is stirred for 4 h at 50° C., and after this time water is added and the pH is adjusted to 8 with NaHCO3. The suspension is extracted with n-butanol. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness to provide the title compound. Title compound: ES-MS: 226.2 (M+Hr; analytical HPLC: tret=3.09 minutes (Grad 2).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[CH3:16]>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(N2CCNCC2)n1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound can be obtained.
Reaction SMILES: [CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][CH2:12][C:13](O)=[O:14])[N:10]=2)[CH2:3][CH2:2]1.C[CH2:25][N:26]=[C:27]=NCCCN(C)C.Cl.C(N(CC)CC)C.CNC>C1COCC1>[CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][CH2:12][C:13]([N:26]([CH3:27])[CH3:25])=[O:14])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CN(c1nc(CCC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Reaction time: 0.25 h
Yield: 23.2 %

Procedure:
To a mixture of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid (0.2 g, 0.0006 mol) and EDC HCl (0.116 g, 0.0006 mol) in THF (10 ml) was added triethyl amine (0.122 g, 0.0012 mol), and the resulting mixture was stirred at R.T for 15 min. The dimethyl amine (0.0027 g, 0.0006 mol) in THF was added dropwise to the reaction mixture and stirring at R.T was continued for another 4 hrs. The solvent was removed; the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over Na2SO4, concentrated. The crude material was subjected to column purification on 60-120 silica using ethyl acetate (50%) in hexane to give 0.05 g (51%) of the desired product as off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm=0.43 (m, 2H), 0.69 (m, 2H), 1.75 (m, 2H), 1.89 (m, 2H), 2.85 (m, 7H), 2.94 (s, 3H), 3.0 (s, 3H), 3.05 (s, 3H), 3.20 (t, 2H). LC-MS: [M+H]=359.3.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH3:38])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:35]([O:34][CH:30]([O:31][CH2:32][CH3:33])[C@@H:29]([N:17]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:38])[CH3:37])[CH3:36]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 73 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:33]([NH2:35])[CH3:34].CCN(C(C)C)C(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([NH:35][CH2:33][CH3:34])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Reactant: CCN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 28.2 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (50 mg, 0.12 mmol), ethylamine hydrochloride (36 mg, 0.36 mmol), DIPEA (0.20 ml, 1.2 mmol) and diphenylphosphoryl azide (0.026 ml, 0.12 mmol) in 15 ml THF was stirred for 16 hours. The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. 2-(benzylamino)-N-ethyl-4-(4-benzoylpiperazin-1-yl)benzamide (15 mg, 33%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCL gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 1.10 (t, J=7.2 Hz, 3H), 3.19-3.47 (m, br, 10H), 4.40 (s, 2H), 6.43 (t, J=8.3 Hz, 2H), 7.27-7.59 (m, 13H), 8.26 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 14.8, 33.6, 47.5, 127.0, 127.2, 127.8, 128.4, 128.5, 129.4, 129.6, 135.7, 168.3, 169.0.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)O1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:29]1[C:30]2[C:26](=[C:25]([C:7]3[CH:16]=[N:15][C:10]4[O:11][CH2:12][CH2:13][NH:14][C:9]=4[CH:8]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1cnc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc(-c2cnc3c(c2)NCCO3)c2cc[nH]c2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 139.8 %

Procedure:
To 3 ml of tetrahydrofuran (THF)/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-indole (109 mg, 0.45 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (172 mg, 0.15 mmol) were added and stirred at 80° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain 7-(1H-indol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)Cc1ccccc1)CC2

Procedure:
First 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (60 g, 0.2 mol) is heated to 130° C. with N-methyl-benzylamine (65 g, 0.54 mol) for 1.5 hours. After cooling the mixture is distributed between water and methylene chloride. The organic phase is separated off, dried and evaporated. The residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol=10:1). M.p. of the hydrochloride: 205°-208° C.
Reaction SMILES: CO[C:3]([CH:5]([CH3:22])[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][CH2:9][C:10]([O:12][CH2:13]C)=[O:11])=[O:4].[H-].[Na+]>C1(C)C=CC=CC=1>[C:16]1([CH2:15][N:7]2[CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:3](=[O:4])[CH:5]([CH3:22])[CH2:6]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(Cc2ccccc2)CC(C)C1=O
Temperature: 90 °C
Yield: 94.3 %

Procedure:
N-[2-(Methoxycarbonyl)propyl]-N-[2-(ethoxycarbonyl)ethyl]phenylmethylamine (120.36g, 0.4 mole) from Example 2 in toluene (50 ml) was added slowly to a solution of 12 g (0.4 mole, 80% oil suspension) of sodium hydride in 300 ml of toluene. After the addition was complete, the temperature of the reaction solution was raised to 90° C. and maintained at this temperature overnight. After being cooled, the reaction solution was quenched with 200 ml of water, then extracted with ether to yield 98.54 g (70%) of the crude 1-phenylmethyl-3-methyl-5-methoxycarbonyl-4-piperidone.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][CH3:35])[CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: Clc1ncccn1
Reactant: CNCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ncccn1
Yield: 76.5 %

Procedure:
A mixture of 1.8 parts of 2-chloropyrimidine, 6 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N-methyl-1-piperidineethanamine, 1.7 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 1,1'-oxybisethane (50:50 by volume). The product was filtered off and dried, yielding 5.5 parts (76.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-N-methyl-2-pyrimidinamine; mp. 135.4° C. (514).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14]O>>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CO
Agent: Cl
Product: CCC(C(=O)OC)c1ccccc1
Temperature: 25 °C

Procedure:
2-Phenylbutyric acid (10 g, 61 mmole) was dissolved in methanol (30 ml) treated with concentrated HCl (1 ml) and heated at reflux for 20 hours. The heating was stopped and the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the oily residue was treated with ethyl acetate (100 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a clear oil. Yield 10.61 g (97%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.81 (t, J=7.35 Hz, 3 H) 1.69 m, 1 H) 1.98 (m, 1 H) 3.53 (d, J=7.35 Hz, 1 H) 3.58 (s, 3 H) 7.30 m, 5 H).