Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([NH2:17])=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[N:14]=[N:13]1.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[NH2:17][C:16]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[N:13]=[N:14][C:15]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3Cl)c2N)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1c(-c2ccc(O)cc2)nnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 3-(2-chloro-4-trifluoromethyl-phenyl)-5-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-ylamine (3) (1.000 g, 2.7119 mmol) in anhydrous dichloromethane (20 ml), cooled to −78° C. and under a nitrogen flow, a solution of boron tribromide (11.5497 g, ˜4.36 ml, 46.1023 mmol) in 10 ml of anhydrous dichloromethane is added drop-wise. The mixture is allowed to reach room temperature spontaneously overnight and it is then cooled again in an ice-salt bath and the excess of the reagent is decomposed upon drop-wise addition of 10 ml of methanol and 10 ml of water. After 10 min stirring, 10% sodium hydroxide solution (20 ml) is added and the aqueous layer, once separated, is acidified with 10% hydrochloric acid solution and extracted with chloroform (3×70 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to afford a solid grey residue (0.800 g, 83% yield, 99.47% pure at HPLC). M.p. 161-162.3° C. LC-ESI-HRMS of [M+H]+ shows 355.0579 Da. Calc. 355.057348 Da, dev. 1.6 ppm.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41]1>C1COCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:46][CH2:45][C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: NCc1ccsc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2ccsc2)c1F
Yield: 99.1 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.413 g, 2.85 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.48 mL, 3.4438 mmol), followed by commercially available (3-thienylmethyl)amine (0.322 g, 2.85 mmol) which was dissolved in THF (1 mL). After stirring, the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a white solid (1.6214 g, 99%). LCMS: (M+H−3Boc)+=374.1.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)C(=O)C1(CC1)O2)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (1.35 g.) in pyridine (13.5 ml.) was added carbobenzyloxy chloride (30% toluene solution, 7 g.) under ice-cooling, and the mixture stirred for one hour. The reaction mixture was poured into ice-hydrochloric acid (14 ml.) and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was recrystallized from ethanol. By the above procedure there was obtained 5-benzyloxycarbonylaminospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as pale yellow needles, m.p. 118°-119° C. Yield 1.57 g.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)C1C=CC=CC=1.[H][H]>[Pd]>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Yield: 35 %

Procedure:
A mixture of 400 mg. (0.988 mmole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-2-enone and 20 mg. of 5% palladium-on-carbon was stirred under one atmosphere of hydrogen pressure for 30 minutes. The reaction mixture was then filtered through diatomaceous earth with ether and the filtrate evaporated to a solid. The crude solid was recrystallized from petroleum ether to yield 110 mg. (35%) of the title compound, M.P. 122°-123° C.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C(I)=C(C=CC=1)C(O)=O.N1C=CN=N1>>[F:16][C:4]1[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=[CH:2][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(O)c1cccc(F)c1I
Agent: c1c[nH]nn1
Product: O=C(O)c1cccc(F)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 3-fluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(OCC)(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[N:8][N:7]4[C:2]([NH:31][CH:28]5[CH2:30][CH2:29]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: NC1CC1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccco3)nn12
Solvent: CCOC(C)=O
Product: c1coc(-c2nn3c(NC4CC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 100 °C
Yield: 32 %

Procedure:
4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (100 mg, 0.26 mmol) and cyclopropylamine (5 mL) were put in a steel bomb. After heating at 100° C. for 3 days, the reaction was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (3:7 ethyl acetate:hexanes) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine (34 mg, 32%) as a yellow foam. 1H NMR (CDCl3): δ 8.15 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.30 (t, 1H), 6.86 (d, 1H), 6.57 (d, 1H), 6.52 (m, 1H), 6.36 (d, 1H), 6.32 (s, 1H), 5.14 (d, 1H), 4.36 (m, 1H), 2.63 (m, 1H), 2.08 (m, 2H), 1.76–1.52 (m, 6H), 0.86 (m, 2H), 0.75 (m, 2H). MS m/401 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.C(Cl)(C)(C)C.[Cl-:14].[Al+3].[Cl-:16].[Cl-]>C(Cl)Cl>[Cl:14][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([Cl:16])([CH3:8])[CH2:4][CH2:3]1
Reactant: [Cl-]
Reactant: CC1CCC(C)CC1
Agent: [Al+3]
Solvent: CC(C)(C)Cl
Solvent: ClCCl
Product: CC1(Cl)CCC(C)(Cl)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,4-dimethylcyclohexane (10 g, 89.1 mmol) and tert-butyl chloride (32.6 g, 348 mmol) in 45 mL of anhydrous methylene chloride in a 3-neck round-bottom flask under argon at 0° C., was slowly added aluminum chloride (1.24 g, 8.91 mmol). The resulting mixture was stirred at 0° C. for 1.5 hours then quenched with ice, and the product was extracted with CH2Cl2. The organic layer was separated and washed with water, and brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by Kugelrohr distillation to yield the title compound as a pale yellow liquid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([C:31](O)=O)=[N:24]2)=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([C:31]3[NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:9][C:10]=4[N:15]=3)=[N:24]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])c(C(=O)O)n2)cc1
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc([N+](=O)[O-])c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
A mixture of 4-morpholin-4-ylmethyl-benzene-1,2-diamine (2.5 g, 12 mmol), 1-(4-methoxy-benzyl)-4-nitro-1H-pyrazole-3-carboxylic acid (2.91 g, 10 mmol), EDC (2.3 g, 12 mmol) and HOBt (1.62 g, 12 mmol) in dry DMF (40 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo, the residue partitioned between EtOAc (100 ml) and water (50 ml) and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was dissolved in AcOH (70 ml) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue purified by flash column chromatography [SiO2, MeOH:DCM (5:95)] to give 2-[1-(4-methoxy-benzyl)-4-nitro-1H-pyrazol-3-yl]-5-morpholin-4-ylmethyl-1H-benzimidazole (2 g, 37%) as a yellow foam. (LC/MS: Rt 1.91, [M+H]+ 449).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]2[C:23](=[O:24])[CH2:22][O:21][C:20]2=[O:25])[CH2:13][CH2:12]1.[NH3:26]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][C:23]([NH2:26])=[O:24])[CH2:13][CH2:12]1
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3ccccc3n2)CC1
Reactant: N
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 3 (step 3.4). Starting with 1.14 g (3.36 mmol) of 3{2-[1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, described in Example 8 (step 8.2), and 9.60 ml (67.20 mmol) of a solution (7M) of aqueous ammonia in methanol, and after chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by recrystallization from ethyl acetate, 0.360 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)[CH2:19][CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:18]([C:21]1[CH:26]=[CH:25][C:24]([O:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:23][CH:22]=1)[CH2:19][CH3:20]
Reactant: OCCCN1CCN(c2ccc(Cl)nn2)CC1
Reactant: CCOc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(OCCCN2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
3-[4-(6-chloropyridazin-3-yl)piperazin-1-yl]propan-1-ol (0.77 g, 3 mmol), p-ethoxylphenol (0.41 g, 3 mmol), triphenylphosphine (0.79 g, 3 mmol) and anhydrous THF (20 mL) were placed in a 100 mL three-necked bottle, and DEAD (0.52 g, 3 mmol) was added slowly in dropwise within 10 min under an ice-bath condition. The mixture was stirred at room temperature overnight, subjected to a column chromatography (eluting agent: petroleum/ethyl acetate, v/v 3: 2) to obtain a white solid, 0.27 g, yield 23.9%. mp: 125-127° C.; 1H-NMR (400 MHz, CDCl3, δppm) δ1.39(t, 3H, J=7.2 Hz), 2.00(m, 2H), 2.61(br, 6H), 3.67(br, 4H), 3.98 (m, 4H), 6.83(s, 4H), 6.90(d, 1H, J=9.6 Hz), 7.21(d, 1H, J=9.6 Hz); EI-MS(m/z): 376.2[M+H].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].O>CN(C)C=O>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:30])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (234 mg, 1.00 mmol) prepared in Process 3 of Example 12 in N,N-dimethylformamide (2 mL) was added with potassium carbonate (277 mg, 2.00 mmol) and ethylbromoacetate (167 mg, 1.00 mmol) at room temperature, and the resultant was stirred at 80° C. for 20 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=2:1), and ethyl [4,4-dimethyl-3-oxo-2-(adamantan-2-yl)-1,2-diazetidin-1-yl]acetate (190 mg, 59.4%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.C(O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(N2CC[C@@H](O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CC[C@@H](OS(C)(=O)=O)C2)n1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (3R)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (970 mg, 4.00 mmol) (obtained as described in Reference Example 18(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (1.24 ml, 16.0 mmol) and triethylamine (2.24 ml, 16.0 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, ethanol (0.81 ml) was added thereto and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (4:1→1:1) as the eluant to afford (3R)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (1.00 g, yield 78%) as a pale yellow solid.
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:27]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:28](C(ON1C(=O)CCC1=O)=O)[CH2:29][CH3:30]>>[NH:27]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C@H:28]([C:20]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:22])[CH2:29][CH3:30]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC)NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
Using 6.50 g of Boc-Asn-Leu-OEt and 5.48 g of Boc-Abu-OSu, the same procedure as in Reference Example 35 was repeated to obtain 7.20 g (yield: 90.2%) of the above objective compound having a melting point of 152°-155° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[OH-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:30]3[NH:31][CH:32]=[CH:33][CH:34]=3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([C:30]3[N:31]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:32]=[CH:33][CH:34]=3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Reactant: CCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOCCn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Yield: 44 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole obtained in the same manner as described in Reference Example 6 (1.81 g, 5 mmole), 2-bromoethyl ethyl ether (0.92 g, 6 mmole), and tetra-n-butylammonium bromide (0.16 g, 0.5 mmole) are refluxed in two phases of benzene (20 ml) and 50% aqueous sodium hydroxide (20 ml) for 4 hours. To the mixture are added water and benzene under ice-cooling, and the mixture is shaken. The benzene layer is taken, washed with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is subjected to silica gel column chromatography (solvent, ethyl acetate:cyclohexane=1:20) and is recrystallized from n-hexane to give 4,5-bis(4-methoxyphenyl)-2-[1-(2-ethoxyethyl)pyrrol-2-yl]thiazole (0.96 g, yield: 44%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[N:8][CH2:7]1)=[O:5].C1C2C(CCCC2)CCC1.Cl>[Pd].O>[CH3:2][O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCC2CCCCC2C1
Product: COC(=O)c1cnc(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Yield: 115.3 %

Procedure:
A mixture of 3.9 g of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline carboxylic acid methyl ester, hydrochloride, 100 ml of decalin and 2 g of 10% palladium on carbon was stirred and refluxed for 2 hours. The cooled mixture was diluted with water, acidified with 6N hydrochloric acid, and the catalyst was removed by filtration. The aqueous solution was washed with ether, made basic with excess ammonium hydroxide, and the product was extracted with ethyl acetate, dried, and evaporated to give 4.1 g of crude 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid methyl ester. Crystallization from ether provided the analytically pure material, mp 127°-128°.
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]([F:27])([F:26])[CH:7]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1>O>[F:5][C:6]([F:26])([F:27])[CH:7]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(CCOc1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 50 °C
Yield: 74.5 %

Procedure:
0.082 g of sodium hydroxide was dissolved in 1 ml of water, followed by addition of 3 ml of methanol and 0.22 g of ethyl p-(3-trifluoromethylheptyloxy)benzoate and 3 hours of stirring at 50° C. After the reaction, water was added, methanol was removed by distillation under a reduced pressure, and 6N-hydrochloric acid was added to precipitate a crystal. The crystal was recovered by filtration, washed with water and dried to obtain 0.15 g (yield: 76%) of p-(3trifluoromethylheptyloxy)benzoic acid, which showed: [α]D24 +4.2, [α]43525 +8.6 (c 1.00, CHCl3).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][N:2]([C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:33]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of (2R)-2-(N-Methylamino)-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one (free-base, 14 mg, 0.037 mmol) in 1,2-dichloroethane was added a solution of formaldehyde (37% w/w, 50 μL, 0.61 mmol) and then Na(OAc)3BH (0.12 mmol). The reaction mixture was stirred at room temperature for 3 hours, after which saturated NaHCO3 was added, and the reaction mixture was stirred 10 minutes. The suspension was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The residue was filtered through a Fluorosil plug with ETOAC, and the filtrate was concentrated by rotary evaporation. The resulting residue was dissolved in ether and excess 4M HCl/dioxane was added. The yellow solids were isolated by filtration with nitrogen pressure and dried under reduced pressure to afford the desired product (7 mg, 41%) as the dihydrochloride salt. Rt 2.20. MS (ESI+) [M+H]+ 390.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:5]([C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:17])[CH3:16])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].[Cl:30][C:31]1[N:36]=[C:35]([CH2:37]Cl)[CH:34]=[CH:33][N:32]=1>CN(C=O)C>[Cl:30][C:31]1[N:36]=[C:35]([CH2:37][N:12]2[C:7]([C:5](=[O:6])[C:4]3[CH:3]=[C:2]([CH3:1])[CH:20]=[C:19]([CH3:21])[CH:18]=3)=[C:8]([CH:15]([CH3:17])[CH3:16])[C:9](=[O:14])[NH:10][C:11]2=[O:13])[CH:34]=[CH:33][N:32]=1
Reactant: ClCc1ccnc(Cl)n1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccnc(Cl)n2)c1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a stirred solution of (20) (286 mg, 1 mmol), anhydrous powdered potassium carbonate (134 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 ml) at room temperature, was added 2-Chloro-4-chloromethyl-pyrimidine (164 mg, 1 mmol). After stirring for overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1)) to afford 210 mg (51%) of a white solid. m.p. 197-198° C.; 1H NMR (300 MHz, CDCl3) δ 1.17 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 2.29-2.39 (7H, m), 4.73 (1H, d, J=17.4 Hz), 4.95 (1H, d, J=17.4 Hz), 7.07 (1H, d, J=5.1 Hz), 7.28 (1H, s), 7.48 (2H, s), 8.46 (1H, d, J=5.1 Hz), 9.41 (1H, s); m/z (EI) 412 (M+).