Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[OH:26][C@@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: C1COCCN1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN1CCOCC1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 297, (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), was reacted with morpholine (73.2 mg, 0.84 mmol) to give (2S)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (82 mg, 63%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:27])[NH:12][C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Si:20]([O:19][CH2:18][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:3][CH:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:5]2)[S:7][CH:8]=1)=[O:27])[C@@H:14]([CH3:17])[CH2:15][CH3:16])([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.35 g, 3.26 mmol) (obtained as described in Reference Example 38(4)) in methylene chloride (68 ml) were added methanesulfonyl chloride (758 μl, 9.79 mmol) and triethylamine (1.37 ml, 9.79 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, 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 n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.55 g, yield 97%) as a pale yellow oil.
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5](=[O:23])[C@@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([O:29][CH2:4][C:5](=[O:23])[C@@H:6]([NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:28]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)COC(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium fluoride (0.326 g, 5.61 mmol) was added to a mixture of the tert-butyl (S)-3-bromo-2-oxo-1-phenethylpropylcarbamate (1.00 g, 2.81 mmol) and 2,5-dichlorobenzoic acid (1.07 g, 5.61 mmol) in DMF (10 mL). The mixture was stirred for 2 hours at room temperature and then ethyl acetate (75 mL) was added. The solution was washed with 1M hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (MgSO4), filtered, and evaporated to dryness to provide crude (S)-3-tert-butoxycarbonylamino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6]1.Cl.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][O:28][CH3:27])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:19])[CH3:20])=[CH:6]1
Reactant: CON
Reactant: CN(C)Cc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Agent: Cl
Product: CONC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-dimethylaminomethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) 6; 8.90 (s, 1H), 8.50 (s, 1H), 7.89 (s, 1H), 7.41 (m, 1H), 7.00-7.07 (m, 2H), 5.64 (s, 2H), 4.52 (s, 2H), 3.82 (s, 3H), 2.85 (s, 6H). LCMS (APCl, M+H+): 375.0. HRMS calcd for C19H21F2N4O2 (M+H) 375.1633, found 375.1644. HPLC: 100% purity.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:12][C:13]([C:15]4[N:16]=[CH:17][S:18][CH:19]=4)=[O:14])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(Nc1cccc2ccc(Cl)nc12)c1cscn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(Nc1cccc2ccc(-c3cccc(F)c3)nc12)c1cscn1
Temperature: 140 °C
Yield: 24.6 %

Procedure:
A solution of N-(2-chloroquinolin-8-yl)thiazole-4-carboxamide (29 mg, 0.100 mmol), 3-fluorophenylboronic acid (28 mg, 2 eq.), CsCO3 (65 mg, 2 eq.), Pd(dppf)Cl2.DCM (4 mg, 0.05 eq.) in DME (2 mL) was microwave heated (140° C.×15 min.). The reaction was filtered and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The product was purified by column chromatography (0 to 100% EtOAc in Pentane) to obtain 8.6 mg of N-(2-(3-fluorophenyl)quinolin-8-yl)thiazole-4-carboxamide. MS (ESI) calcd for C19H13FN3OS (m/z): 350.08. found: 350.1 [M+1].
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=2)=[O:8])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3,5-difluorophenyl)boronic acid. HPLC (Condition 4) tR=5.71 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=480.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.76 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=11.73 Hz, 1H) 3.16-3.28 (m, 2H) 3.42 (m, J=7.00 Hz, 1H) 4.20 (m, J=2.00 Hz, 1H) 4.85 (d, J=3.52 Hz, 1H) 7.15 (dd, J=8.21, 1.95 Hz, 2H) 7.21-7.29 (m, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.02 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH:8]([C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=1)[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([CH:8]([C:9]3[CH:17]=[CH:16][C:12]4[O:13][CH2:14][O:15][C:11]=4[CH:10]=3)[CH:2]([NH:1][C:34](=[O:35])[CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CCOC(=O)C(N)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)C(c1ccccc1)c1ccccc1)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 70 %

Procedure:
The amino ester of Example 19 (0.510 g, 1.43 mmol) is mixed with diphenylacetyl chloride (0.346 g, 1.5 mmol) in 20 mL of dry chloroform. Triethylamine (0.6 mL, 4.3 mmol) is added to the reaction mixture and it is stirred for 2 hours. The solvent is evaporated and the residue is taken up into 75 mL of ethyl acetate. The solution is washed with 1N hydrochloric acid and saturated sodium bicarbonate respectively. The organic phase is dried (magnesium sulfate), filtered and purified by a short column to afford 0.552 g (70%) of product as a white solid;
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCc2ccccc2N1
Product: CC(=O)N1c2ccccc2CCC1C
Reaction time: 8 h
Yield: 243.5 %

Procedure:
2-Methyl-1,2,3,4-tetrahydroquinoline (216 mg, 1.469 mmol, available from TCl), was measured into a reaction test tube and acetic anhydride (0.139 ml, 1.469 mmol) was added and left to stir overnight. LCMS analysis showed the reaction had gone to completion. The crude product was purified by MDAP to give the desired compound (677 mg)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:27]2[C:28]3[O:33][CH2:32][O:31][CH2:30][C:29]=3[CH:34]=[C:25]([F:24])[CH:26]=2)=[O:36])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)cc3c2OCOC3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=528.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:14]([CH3:22])([CH2:16][CH2:17][C:18](Cl)([CH3:20])[CH3:19])[CH3:15]>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]2[C:14]([CH3:22])([CH3:15])[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:6]=2[CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Reaction time: 10 h
Yield: 68 %

Procedure:
60 g (347 mmol) of 3-bromophenol are dissolved in 600 mL of dichloromethane. This solution is added to a solution of 46 g (347 mmol) of aluminum chloride in 200 mL of dichloromethane. 127 g (694 mmol) of 2,5-dichloro-2,5-dimethylhexane are added in 10 g portions every 40 minutes. The medium is then stirred for 10 hours, after which it is poured onto ice and extracted with dichloromethane. The residue obtained is dissolved in ethyl ether and this organic phase is then washed with 1N sodium hydroxide solution, and then with water. The residue obtained is purified by chromatography (eluent: heptane and then 1/1 heptane/dichloromethane). A thick oil is obtained (67 g; yield=68%).
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])C=CC=CC=1.[CH2:17]([OH:19])[CH3:18]>>[CH3:18][CH2:17][O:19][C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: CCO
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Product: CCOC(=O)Nc1ccccc1
Yield: 93 %

Procedure:
Following the same procedures as in Example 8, a total amount of N,N'-diphenyl urea crystal was reacted with 50.00 g of ethyl alcohol. After the reaction, the reaction mixture was analyzed to obtain a 93% yield for N-phenylethyl carbamate and a 95% yield for aniline.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.[CH3:23][C@H:24]([NH2:28])[CH2:25][O:26][CH3:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH3:23][C@H:24]([NH:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)[CH2:25][O:26][CH3:27]
Reactant: COC[C@H](C)N
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC[C@H](C)NCCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (610 mg) in methanol (8 ml) was added 1-(s)-methyl-2-methoxyethylamine (0.85 mL), acetic acid (0.5 mL), and followed by sodium triacetoxyborohydride (0.82 g). The mixture was stirred at room temperature for 4 hours, then diluted with sodium bicarbonate aqueous solution (5%, 50 ml). The mixture was extracted with ethyl acetate (50 ml plus 3×20 ml). Combined organic layer was dried over sodium sulphate, filtered, solvent removed under vacuum. Residue was columned on silica gel using DCM-MeOH (20:1) as eluant to give 4-[3-(1-(s)-methyl-2-methoxyethylamino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (250 mg). The above neutral product was dissolved in DCM and then HCl (1M in ether, 1 ml) added, 4-[3-(1-(s)-methyl-2-methoxyethylamino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile HCl salt was collected by filtration (180 mg). 1H NMR (MeOD): δ 8.50 (s, 1H), 8.48 (d, 1H), 8.27 (s, 1H), 7.90 (d, 1H), 7.79 (t, 1H), 3.68 (m, 1H), 3.48 (m, 2H), 3.43 (s, 3H), 3.17 (m, 2H), 3.10 (t, 2H), 2.25 (m, 2H), 1.36 (d, 3H). MS m/z 379.5 (M+1), 80%.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@:4]1([C:20]([F:23])([F:22])[F:21])[CH2:19][N:7]2[C:8](=[O:18])[CH:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:6]2[NH:5]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:3][C@@:4]1([C:20]([F:23])([F:21])[F:22])[CH2:19][N:7]2[C:8](=[O:18])[CH:9]=[C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:11]=[C:6]2[N:5]1[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1C(=O)c1ccccc1

Procedure:
14.2 mg of sodium hydride are added to a solution of 150 mg of (2S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]-pyrimidin-5-one (Example 1j), in 3 ml of tetrahydrofuran. After stirring for 25 minutes at a temperature in the region of 20° C., 0.092 ml of benzoyl chloride is added. The reaction medium is stirred for 1 hour at ambient temperature before the addition of 1.5 ml of a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase is successively separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered, and then concentrated under reduced pressure. After purification by silica column chromatography (eluent: dichloromethane/methanol: 98/02), 49 mg of (2S)-2-methyl-7-(morpholin-4-yl)-1-(phenylcarbonyl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:34]COC)[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O)C1C=CC=CC=1>[Pd].CO>[CH3:34][N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:13][CH2:12][NH:11][CH3:9]
Reactant: COCCN(CCNC(=O)OCc1ccccc1)CCOCCOCCOCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNCCN(C)CCOCCOCCOCCNC(=O)OC(C)(C)C
Yield: 105.8 %

Procedure:
tert-Butyl N-[2-[2-[2-[2-[2-(benzyloxycarbonylamino) ethyl-(2-methoxyethyl)amino]-ethoxy]ethoxy]ethoxy]ethyl]carbamate (2.99 g,) and palladium on carbon (10%, wet, 0.6 g) in methanol (30 mL) were stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered through celite and evaporated to give product as an oil (2.18 g, quantitative).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1
Yield: 94 %

Procedure:
160 Parts of p-nitrobenzotrifluoride is dissolved in 500 parts of ethanol and 1 part platinum oxide catalyst is added. The mixture is placed in a pressure vessel and hydrogen is added at a temperature of 30° C and a pressure of 13.6 atmospheres. The hydrogen pressure is increased to 34 atmospheres during the course of the reaction, which continues until the hydrogen uptake ceases. The excess hydrogen is removed from the reaction vessel under reduced pressure and the catalyst is removed from the mixture by filtration. The solvent is removed from the filtrate under reduced pressure to give 127 parts (94% yield) of p-aminobenzotrifluoride.
Reaction SMILES: [NH2:1][CH:2]([C:4]1([CH2:8][NH2:9])[CH2:7][CH2:6][CH2:5]1)C.CO.C(N(CC)CC)C.C[O:20][C:21](=O)[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]>N>[NH2:23][CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:9][CH2:8][C:4]1([CH2:2][NH2:1])[CH2:5][CH2:6][CH2:7]1)=[O:20]
Reactant: CC(N)C1(CN)CCC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Product: NCC1(CNC(=O)C(N)Cc2ccccc2)CCC1
Yield: 38.7 %

Procedure:
3.6 g (31.5 mmol) of 1 was mixed with 100 mL of methanol, followed by adding triethyl amine to adjust pH to 9-10 to obtain a first reaction solution. 5.1 g (28.7 mmol) of 2 was mixed with 100 mL of methanol to obtain a second reaction solution. The second reaction solution was added dropwisely into the first reaction solution to obtain a reaction mixture. The reaction mixture was subjected to reflux reaction at 60-70° C. for 19 hours, followed by evaporation to obtain a crude product. The crude product was dissolved in ammonia, followed by extracting with chloroform and water and evaporating to obtain a product of 2.9 g (11.1 mmol, 38.6%) of a light-yellow oil 3. The analytic data of the product are as follows: 1H-NMR (D2O, 400 MHz), δ(ppm): 7.29-7.15 (m, 5H, Ar), 3.57 (t, 1H, J=3, H2NCH), 3.20-2.95 (m, 2H, NHCH2), 2.89-2.76 (m, 2H, CH2Ar), 2.21-2.05 (m, CH2NH2), 1.69-1.66 (m, 2H, CH2CH2CH2), 1.52-1.45 (m, 4H, CH2CH2CH2); 13C-NMR (D2O, 100 MHz), δ(ppm): 176.88, 137.37, 129.38, 128.90, 127.11, 56.60, 45.82, 43.99, 42.36, 40.90, 26.59, 26.51, 14.27; ESI-MS (m/z): calcd. 261.36, found 262.18 [M+H]+; Anal. Calcd (Found) for C15H23N3O.HCl: C, 60.94 (60.49); H, 8.43 (8.12); N, 14.53 (14.11).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 61.8 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 232 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (122 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][OH:18].O>CN(C)C=O>[OH:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: OCCCCl
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ncn(CCCO)c2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.76 g of NaH, the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise 5 ml of 3-chloro-1-propanol, and the reaction was carried out by stirring at room temperature for 2 days, followed by an addition of water to stop the reaction. Subsequently, according to the same processes as in Example 1, crude 1-(3-hydroxypropyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 90%.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][CH:12]=2)[CH2:7][C@@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[O:28][C:24]=2[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([O:17][CH3:18])[CH:16]=4)[CH2:7][C@@H:6]3[CH3:20])=[O:4])[C:27](=[O:29])[O:28][C:24]=2[CH:23]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)[C@@H](C)C2)ccc1Cl

Procedure:
Compound 9 was prepared according to the procedure described in Example 2 using 2-chloro-1-[(S)-4-(4-chloro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (8), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.75 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 450.4, found, 450.4.