Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](SC)=[NH:21])=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.C(O)CC.[CH2:38]([NH2:40])[CH3:39]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]4[NH:40][CH:38]=[CH:39][N:21]=4)=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1
Reactant: CSC(=N)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2ncccn2)C3)cc1
Reactant: CCN
Solvent: CCCO
Product: c1cnc(N2CCc3c(nc(-c4ccc(Nc5ncc[nH]5)cc4)nc3N3CCOCC3)C2)nc1
Temperature: 97 °C
Reaction time: 1 h

Procedure:
Methyl 4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylcarbamimidothioate (0.070 g, 0.00015 mol) in 1-Propanol (5.00 mL, 0.0669 mol) was added Ethanamine, 2,2-diethoxy- (0.0664 mL, 0.000454 mol) heated at 97° C. for 2 hours. At this time, an additional portion of Ethanamine, 2,2-diethoxy- (0.0222 mL, 0.000152 mol) was added to the reaction mixture and stirred for 1 hour at 97° C. After this time, an additional portion of Ethanamine, 2,2-diethoxy- (0.0222 mL, 0.000152 mol) was added to the reaction mixture and heated at 97° C. for 6 hours. The reaction mixture was concentrated and dried in vacuo overnight. The crude product was cooled at 0° C. and then added 10.0 M of Hydrogen chloride in Water (2.00 mL), allowed to warm slowly to room temperature, stirred for 6 hours, then poured into ice, and to the ice solution was added saturated NaHCO3 until the pH was approximately 9. The aqueous solution was extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, and concentrated to provide the crude product which was chromatographed through silica gel (4 g, 0-10% MeOH in dichloromethane), and further purified by HPLC. 1-(4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-1H-imidazol-2-amine (tz) 1H NMR (400 MHz, DMSO) δ 8.44 (t, J=6.7, 3H), 8.23 (s, 1H), 7.58 (d, J=8.7, 2H), 6.93 (d, J=1.5, 1H), 6.71 (t, J=4.7, 1H), 6.59 (d, J=1.5, 1H), 5.52 (s, 2H), 4.86 (s, 2H), 4.00 (t, J=5.1, 2H), 3.74 (d, J=4.5, 4H), 3.52 (d, J=4.4, 4H), 2.79 (s, 2H). LC/MS-m/z+456.2 (M+H)+; and N-(4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-1H-imidazol-2-amine (ty) LC/MS-m/z+456.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:19][O:18][N:17]([CH3:16])[C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
To a solution of 3-(trifluoromethyl)phenylacetic acid (2.04 g, 10 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.07 g, 11 mmol) in DMF was added HATU (3.8 g, 10 mmol) and DIEA (6.99 ml, 40 mmol) and the resulting yellow solution was stirred at RT for overnight. The crude solution was then extracted with EtOAc and wash with NaHCO3 solution (5%), HCl solution (1:9 v/v) and brine, dried with sodium sulfate and concentrate to afford 2.66 gram of colorless oil as desired compound (4.1) used in the next step without further purification. Rf 0.5 (EtOAc/Hexane 1:1) MS (m/z): 248.1 (M+H), 1H NMR (CDCl3) δ 3.2 (s, 3H), 3.65 (s, 3H), 3.80 (s, 2H), 7.40-7.55 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][O:4][C:5]3[CH:6]=[C:7]([C:11]4[C:15]5[S:16][CH:17]=[CH:18][C:14]=5[O:13][N:12]=4)[CH:8]=[CH:9][CH:10]=3)[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(CCOc3cccc(-c4noc5ccsc45)c3)CC2)cc1
Yield: 66 %

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, and N-phenylpiperazine essentially as described in example 27 except that the freebase is dried to give the title compound (330 mg, 66%). Mp=91–93° C. Microanalysis (C, H, N) is consistent with the final compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH:20]=[C:21]2[O:25]C(=O)C)[C@H:17]2[C@H:8]1[C:9]1[CH:10]=[CH:11][C:12]([O:29][C:30](=[O:32])[CH3:31])=[CH:13][C:14]=1[CH2:15][CH2:16]2.C([O-])(=O)C.[Na+].[Br:38]N1C(=O)CCC1=O.O>CN(C)C=O>[C:30]([O:29][C:12]1[CH:11]=[CH:10][C:9]2[C@@H:8]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])([CH3:23])[C:21](=[O:25])[CH:20]([Br:38])[CH2:19]4)[CH2:16][CH2:15][C:14]=2[CH:13]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC1=CC[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3C(CCCCCCl)C[C@]12C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(CCCCCCl)C[C@]2(C)C(=O)C(Br)C[C@@H]12
Yield: 228.4 %

Procedure:
A solution of 6.2 g of 11-(5-chloropentyl)-3,17-diacetoxy-estra-1,3,5(10),16-tetraene in 95 ml of dimethylformamide is mixed at 0° C. first with 9.05 ml of sodium acetate solution (10%) and then with 2.6 g of N-bromosuccinimide, and it is stirred for one hour. Then, it is mixed with water, extracted with ethyl acetate, washed with sodium sulfate solution as well as common salt solution, dried on sodium sulfate and evaporated to the dry state in a vacuum. 15.3 g of crude 3-acetoxy-16-bromo-11-(5-chloropentyl)-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[N+:13]([O-])([OH:15])=[O:14].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 6.5 °C
Reaction time: 8 h

Procedure:
A solution of 2′-chloro-4′-fluoroacetanilide (85.5 g, 456 mmol) in concentrated sulfuric acid is cooled to 0° C., treated slowly with 70% nitric acid (32 mL, 502 mmol) while maintaining the temperature from 5-8° C., stirred at room temperature overnight and poured into water. The resultant aqueous mixture is filtered to obtain a solid which is recrystallized from ethanol to give the title product as pale, yellow plates (27.0 g, mp 158-160° C.).
Reaction SMILES: C(N[C:9](=[O:36])[CH:10]([N:17]1[C:21]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=2[N:19]=[C:18]1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH3:35])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.C(OC(=O)C)(=[O:39])C.C(O)(=O)C.N([O-])=O.[Na+]>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:18]2[N:17]([CH:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]([OH:39])=[O:36])[C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[N:19]=2)=[C:29]([CH3:35])[CH:30]=1
Reactant: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
N-benzyl-2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetamide (3.8 g, 6.508 mmol) were dissolved in 49.3 ml (521.9 mmol) acetic acid anhydride and 24.7 ml (431.5 mmol) acetic acid. The dark brown solution was cooled to 0-5° C. and 2.245 g (32.54 mmol) sodium nitrite were added in four portions within 10 min. After 30 min. the reaction mixture was allowed to warm to room temperature. The reaction mixture was then evaporated, taken up with toluene and evaporated again. The residue was extracted twice ethyl acetate, saturated aqueous sodium bicarbonate solution, water and brine. The organic layers were separated, dried over magnesium sulfate, filtered and evaporated. The crude intermediate was then dissolved in a mixture of tetrahydrofuran and water. To the dark brown solution slowly a solution of lithiumhydroxide monohydrate in 30% aqueous hydrogen peroxide was added dropwise over 20 min (gas evolution, exothermic). The mixture was stirred until all starting material had disappeared. The reaction mixture was then evaporated and the pH of the residue was adjusted to 4 with acetic acid. Ethyl acetate was added, the phases separated and the aqueous layer extracted another time with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated. The residue was taken up in toluene, stirred at 0-5° C. for 15′, the solid was filtered off, washed with cold toluene and dried in vacuum to give the desired compound as a beige solid (54%). MS (ESI): 418.87 (M+).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.F[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(F)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: Cc1ccc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-fluoro-5-methyl-pyridine following a procedure analogous to that described in Example 19. LC (method 5): tR=1.49 min; Mass spectrum (ESI+): m/z=403 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:33][CH:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)CC1
Temperature: 130 °C
Yield: 72 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (2.000 g, 6.672 mmol), tert-butyl-4-aminopiperidine-1-carboxylate (1.336 g, 6.672 mmol) and TEA (0.933 ml, 6.672 mmol) in MeCN (20 ml) was heated in a microwave reactor at 120° C. for 40 mins and 130° C. for 30 mins. tert-Butyl-4-aminopiperidine-1-carboxylate (0.267 mg, 1.334 mmol) and TEA (0.187 ml, 1.334 mmol) was added and the resulting mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) eluting with 10% petroleum ether 40-60° C. in DCM then 0-20% EtOAc in DCM to give the title compound (2.228 g, 72%) as a solid. 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.44 (m, 3H), 5.17 (d, 1H), 3.88 (bs, 2H), 3.08-3.00 (m, 1H), 2.32 (dt, 2H), 1.74 (s, 9H), 1.68-1.60 (m, 2H), 1.42 (s, 9H), 1.30-1.17 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 154.7, 134.1, 131.9, 130.2, 128.9, 125.3, 107.3, 80.1, 61.9, 50.4, 42.4, 32.4, 28.6, 27.9; Mass Spectrum M+H+ 464.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:17](=[O:18])[N:9]2[CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=[CH:13][C:8]2=[N:7]1.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.C(N)CCCCC>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:17](=[O:18])[N:9]2[CH:10]=[C:11]([C:14]([NH:29][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:28])=[O:15])[CH:12]=[CH:13][C:8]2=[N:7]1
Reactant: O=C(O)c1ccc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)n2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCCN
Product: CCCCCCNC(=O)c1ccc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)n2c1
Reaction time: 8 h

Procedure:
In a 15-mL round-bottom flask 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.065 mmol) was dissolved in dichloromethane (2.4 mL). HOBT (0.01 mmol), EDC hydrochloride (0.13 mmol), triethylamine (0.13 mmol), and n-hexylamine (0.13 mmol) were added sequentially to the reaction flask and stirred overnight. Extracted with 1N aqueous HCl and dichloromethane. Organic layer concentrated and residue chromatographed on silica gel using 2% MeOH in dichloromethane as eluent. Product 2-(3,4-dichlorobenzyl)-3-oxo-N-hexyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was obtained as white solid.
Reaction SMILES: C(OC(N1C[C@H](O)C[C@@H]1C(O)=O)=O)(C)(C)C.[CH2:17]([N:21]([CH3:34])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29]C)=[O:28])=[O:23])[CH2:18][CH2:19][CH3:20].COC(C1C=C(C=CC=1)C(O)=O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>ClCCl.CN(C=O)C>[CH2:17]([N:21]([CH3:34])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([OH:29])=[O:28])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(C)C(=O)c1cccc(C(=O)OC)c1
Agent: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: CCCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN(C)C(=O)c1cccc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
Step F (1): Methyl 3-(butyl(methyl)carbamoyl)benzoate. To a solution of 3-(methoxycarbonyl)benzoic acid (1.8 g, 10 mmol) in dichloromethane (40 mL) and DMF (20 mL) was added Hunig's base (2.58 g, 20 mmol) to make a clear solution and HATU (4.18 g, 11 mmol) was then added. After stirring for 10 min, the reaction mixture was added methylbutylamine (1.13 g, 13 mmol) and the reaction mixture was stirred at rt for 3 h. Dichloromethane was removed and ethyl acetate (300 mL) was added and the mixture was washed with 1N HCl, sodium carbonate solution, H2O, dried and concentrated to give the title compound ready for next step without purification: 1H NMR (CDCl3, 500 MHz) δ 0.79-0.98 (3H, m), 1.15 (1H, m), 1.41 (1H, brd s), 1.52 (1H, brd s), 1.64 (1H, m), 2.92-3.07 (2H, m), 3.21 (1H, brd s), 3.53 (1H, brd s), 3.91 (3H, s), 7.47 (1H, m), 7.58 (1H, d, J=10 Hz), 8.05-8.07 (2H, m).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:19]=[CH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[O:27]=[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][NH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CCCCCCC(N)C(=O)OCC
Reactant: C=CC(=O)CCCCC
Product: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Reaction time: 3 h

Procedure:
The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctyl amino)nonanedioate as a colourless oil, δ2.3 (4H, multiplet, --CH2 --CO2Et and NCH2CH2CH--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature, and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH 5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanediote as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.
Reaction SMILES: C([C:5]1[C:6]([NH2:45])=[C:7]([CH:11]=[CH:12][C:13]=1[C@H:14]([NH:17][C:18]([N:20]1[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[O:36][CH3:37])[CH2:24][NH:23][C:22](=[N:38][CH2:39][CH:40](OC)OC)[CH2:21]1)=[O:19])[CH2:15][CH3:16])[C:8]([OH:10])=[O:9])(C)(C)C.[C:46]1([CH3:56])[CH:51]=CC(S([O-])(=O)=O)=C[CH:47]=1.[NH+]1C=CC=CC=1>O1CCOCC1>[NH2:45][C:6]1[CH:5]=[C:13]([C@H:14]([NH:17][C:18]([N:20]2[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[O:36][CH3:37])[CH2:24][N:23]3[CH:40]=[CH:39][N:38]=[C:22]3[CH2:21]2)=[O:19])[CH2:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:46]([CH3:56])([CH3:51])[CH3:47])=[O:9]
Reactant: CC[C@@H](NC(=O)N1CC(=NCC(OC)OC)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Product: CC[C@@H](NC(=O)N1Cc2nccn2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The compound 89a crude product obtained at Step (1) (94.2 mg) was dissolved in 1,4-dioxane (4 ml), pyridinium p-toluenesulfonate (5 mg) was added, and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated, then the residue was purified by flash column chromatography (NH2 silica gel, ethyl acetate/hexane=7/3 to 1/0) to obtain tert-butyl 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-7-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl]carbonyl}amino)propyl]benzoate (compound 89b) (33.4 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:25]([CH3:27])[CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[F:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49](O)=[O:50].C(Cl)Cl>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:29][CH2:30][N:31]([C:49](=[O:50])[C:48]4[C:47]([F:46])=[CH:55][CH:54]=[CH:53][C:52]=4[F:56])[CH2:32][CH2:33]3)=[C:25]([CH3:27])[CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCNCC3)c(C)c2)cc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(5-methyl-6-piperazin-1-yl-pyridin-3-yl)-urea (300 mg, 0.670 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (154 mg, 0.804 mmol), 2,6-difluorobenzoic acid (127 mg, 0.804 mmol), and 4-N,N-dimethylaminopyridine (15 mg, 0.134 mmol) in acetonitrile (10 mL). Heat the reaction to 60° C. for 18 hours. Cool reaction to room temperature and add CH2Cl2 and water. Separate organic layer and extract aqueous layer with CH2Cl2 (2×20 mL). Combine organic layers, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 10-70% EtOAc:hexane to yield the title compound. MS(ES+): m/z=588.3 [M+H].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.O>[Cl:1][CH2:2][C:3]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: C1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)N1CCCCC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Add chloroacetyl chloride (1.242 g, 11.0 mmol) to a mixture of potassium carbonate (2.073 g, 15 mmol) and piperidine (852 mg, 10 mmol) in THF (50 mL) at 0° C. Stir the reaction for 12 h and gradually raise to room temperature. Dilute with water, extract with EtOAc three times. Combine the organic extracts and wash sequentially with saturated aqueous NaHCO3, 0.1N aqueous HCl and brine. Dry over Na2SO4, filter and concentrate to give the title compound (1.65 g, 100%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].NCCCNCC[CH2:20][N:21]([CH2:29][CH:30]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:31]1[C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][CH2:35][CH:30]1[CH2:29][N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:20][CH2:11][CH2:12][N:8]1[CH2:9][CH2:6][CH2:7][NH:3][C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCNCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Solvent: C1CCOC1
Product: O=C1NCCCN1CCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.9 %

Procedure:
1,1′-Carbonylbis-1H-imidazole (0.02 mol) was added to a solution of (±)-N-(3-aminopropyl)-N′-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-(phenylmethyl)-1,3-propanediamine (0.02 mol) in THF (100 ml). The reaction solution was stirred for 17 hours at room temperature. The solvent was evaporated. Water was added to the residue and the mixture was extracted with toluene. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from ethyl acetate (50 ml). The precipitate was filtered off and dried, yielding 3.3 g (42%) of (±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propyl]-tetrahydro-2(1H)-pyrimidinone (comp. 13); mp. 94.7° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=[O:10].[N+](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)([O-])=O.S(Cl)(Cl)=O.[N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O.C([N:59]1[CH2:63][CH2:62][N:61]=[C:60]1SC)(OC(C)(C)C)=O>CC#N>[NH:61]1[CH2:62][CH2:63][N:59]=[C:60]1[NH:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CSC1=NCCN1C(=O)OC(C)(C)C
Reactant: Nc1cc(C(=O)NCC(=O)O)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(O)CNC(=O)c1cc(NC2=NCCN2)cc(C(F)(F)F)c1
Temperature: 35 °C
Reaction time: 72 h

Procedure:
To 3-amino-5-trifluoromethylhippuric acid hydrochloride [prepared according to Example M, Steps A and B substituting 3-nitro-5-trifluoromethylbenzoyl chloride (prepared from 3-nitro-5-trifluoromethylbenzoic acid (Lancaster) and thionyl chloride for M-nitrobenzoyl chloride in Example M, Step A] (3 g, 0.01 mole) in CH3CN (5 mL) was added the product from Example 472, Step A (2.2 g, 0.01 mole). The reaction was stirred at 35° C. for 3 days then at reflux for 4 hours. After cooling, the CH3CN was decanted off, the residue slurried several times in ether (ether decanted off) and then dried to yield 3-(4,5-dihydro-1H-imidazol-2-yl)amino-5-trifluoromethylhippuric acid.HCl (2.5 g) as a white solid.