Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=1.N[C@H](C(O)=O)C.C([O-])([O-])=O.[Na+].[Na+].[CH:32](=O)[C:33]1[C:34](=[CH:36][CH:37]=[CH:38][CH:39]=1)[OH:35]>O>[OH:35][C:34]1[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=1[CH:32]=[C:5]1[C:4](=[O:7])[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:2](=[O:1])[NH:6]1
Reactant: O=Cc1ccccc1O
Reactant: N#Cc1ccc(N2C(=O)CNC2=O)c2ccccc12
Agent: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(N2C(=O)NC(=Cc3ccccc3O)C2=O)c2ccccc12
Yield: 35.1 %

Procedure:
A mixture of compound 1C (150 mg, 0.6 mmol), alanine (53.1 mg, 0.6 mmol), and Na2CO3 (31.7 mg, 0.3 mmol) in water (1.4 mL) was treated with salicylaldehyde (0.11 mL, 0.94 mmol) and refluxed for 3.0 h. (Ref: Eur. J. Org. Chem. 1999, 2609-2621). The mixture was diluted with water (1 mL) and filtered, washing the yellow precipitates with water (2×2 mL). The yellow solids were triturated with ether (2 mL) and dried to give the title compound as a yellow solid (74.9 mg, 35.4%), mp 251-252° C. LC/MS m/z 356 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(S(C)(=O)=O)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (22 mg, 0.049 mmol) and triethylamine (0.040 mL, 0.29 mmol) in acetonitrile (2 mL) at room temperature, methanesulfonyl chloride (0.020 mL, 0.26 mmol) was added. The solution was stirred at room temperature for 1 h. The mixture was then purified by HPLC to give the titled compound (14 mg). MS 531.36 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O>C(Cl)Cl>[CH3:13][C:14]([S@@:17]([N:19]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N=Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a mixture of 3-(trifluoromethyl)benzaldehyde (5 g, 28.7 mmol) and (S)-2-methylpropane-2-sulfinamide (4.17 g, 34.4 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (12 g, 43 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered off and the filtrate was extracted with DCM (2×150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (7 g, yield: 88%); m/z (ES+): 278 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH2:31][CH2:32][N:28]([CH3:27])[C:29]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2F)CC1
Yield: 47.6 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (209 mg) described in Preparation Example 121 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (104 mg) was obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(C(=O)CCOCCc1ccccc1)c1ccccc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCN(C(=O)CCOCCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-(2,2-Diethoxyethyl)-3-phenethyloxy-N-phenyl-propanamide (Example 6a), 0.11 g) was dissolved in anhydrous dioxane (5 mL) and cooled to 0° C. Concentrated hydrochloric acid (0.3 mL) was added dropwise to the stirred solution at 0° C. The resultant reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was then poured into dichloromethane (10 mL) and washed with water (2×10 mL) and brine (10 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.07 g) as a viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:10])=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH3:5].[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Cl)ccc1CN1CCOCC1
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Bromomethyl)-6-chloro-2-methylpyridine (500 mg, 2.27 mmol) was taken up in CH2Cl2 (5.0 mL) and morpholine (257 μL, 2.95 mmol) and DIEA (594 μL, 3.40 mmol) were added. After stirring at room temperature overnight, the reaction was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered, and evaporated. Flash chromatography (0-10% MeOH (w/2 M NH3)/CH2Cl2) provided the title compound as a colorless oil.
Reaction SMILES: CS(Cl)(=O)=O.[O:6]([CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]O)[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li+].[Cl-:34].CC1C=C(C)N=C(C)C=1>CN(C=O)C.O>[O:6]([CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Cl:34])[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Cl-]
Reactant: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CC(C)(C)[Si](OCc1cccc(CCl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
Methanesulfonyl chloride (3.96 g, 34.6 mmol) was added dropwise to a stirred solution of 23 (11.8 g, 31.4 mmol), LiCl (1.33 g, 31.4 mmol), and s-collidine (4.19 g, 34.6 mmol) in anhydrous DMF (120 mL) at 0° C. under argon. The reaction mixture was allowed to warm to room temperature over 2 h, and was then poured into water and extracted twice with diethyl ether. The organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 11.8 g (95%) of 24 as a clear, dark yellow liquid. The chloride was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ7.72-7.76 (m, 4H, ArH), 7.31-7.48 (m, 10H, ArH), 4.82 (s, 2H, CH2OSi), 4.62 (s, 2H, CH2C1), and 1.15 (s, 9H, SiC(CH3)3); 13C NMR (75 MHz, CDCl3) δ141.71, 137.35, 135.58, 135.51, 133.39, 129.74, 129.60, 128.64, 127.74, 127.08, 126.20, 126.06, 65.24 (CH2OSi), 46.34 (CH2C1), 26.84 (SiC(CH3)3), and 19.32 (SiC(CH3)3); MS (DCI) m/e 395 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCNCC
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Product: CCN(CC)CC(O)COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and diethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.[O:23](S(C)(=O)=O)[S:24]([CH3:27])(=O)=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([O:14][S:24]([CH3:27])(=[O:25])=[O:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(O)CCc1ccccc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of ethyl-2-hydroxy-4-phenylbutyrate (2.08 g, 10 mmol) in CH2Cl2 (20 mL) was added triethylamine (2.1 mL, 15 mmol) and Ms2O (1.92 g, 11 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 15 min. DMAP (50 mg) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (Na2SO4), filtered and CH2Cl2 was removed under reduced pressure. The residue was purified by flash chromatography (CH2Cl2), giving 2.7 g (94%) of the title compound. 13C NMR (CDCl3): 6169.3, 140.0, 128.9, 128.8, 126.7, 62.3, 52.8, 39.5, 33.9, 31.2, 14.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:9][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)nc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Product: Cc1cc(OCCC(C)(C)O)nc(C)c1Br
Yield: 70.1 %

Procedure:
According to a method described in [WO 2009/054423 pamphlet, (Production Example 37)], from 5-bromo-4,6-dimethyl-2-hydroxypyridine (1.50 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (2.11 g), the subject compound (1.50 g) was obtained as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[O:17][C:18](Br)=[CH:19][CH:20]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[O:17][C:18]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[CH:19][CH:20]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(Br)o1
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(-c2ccc(F)cc2)o1

Procedure:
The furyl bromide (84) (100 mg, 0.29 mmol) was coupled to 4-fluoro-phenylboronic acid (44 mg, 0.32 mmol) using Method E. The solvents were removed in vacuo as described, but the residue was dissolved in 2M NaOH (10 ml) and washed with EtOAc (2×10 ml). The aqueous layer was acidified to pH 1 with 2M HCl until a white precipitate formed and extracted with EtOAc (2×10 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])C>CC(C)=O.Cl>[CH:9]1([C:7](=[O:8])[CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:5][CH:4]=[O:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(CC(C(=O)C1CCCCC1)c1ccccc1)OCC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Reaction time: 8 h
Yield: 93.6 %

Procedure:
A solution of 1.17 g of Compound 5b in 10 ml of acetone and 22.1 ml of 2N HCl was stirred at r.t. for 5 h. After overnight resting, the aqueous layer was extracted with EtOAc. The collected organic layers were washed with water, dried (Na2SO4) and the solvent was evaporated under vacuum to give 0.84 g (100%) of the title compound used immediately without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[C:18]([OH:20])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>C(#N)C>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][C@H:36]([NH:35][C:18]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)=[O:11])=[O:20])[CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)C1CCCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C2CCCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 1-(4-nitrobenzyloxycarbonyl)-2-piperidinecarboxylic acid (1.54 g) in anhydrous acetonitrile (30 ml), N,N-carbonyldiimidazole (851 mg) was added at the room temperature, followed by stirring for one hour. The reaction mixture was allowed to react with a solution of (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (931 mg) in anhydrous acetonitrile (15 ml) under ice cooling in a similar manner to that described in Referential Example 1-(1), whereby 1.81 g of (3S)-1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)piperidin-2-ylcarbonylamino]pyrrolidine were obtained as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:18].[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:29]
Reactant: Cc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Intermediate 20 (0.0085 mol) was added at 5° C. to DCM (30 ml) under N2 flow. trichloro-acetyl chloride (0.01 mol) then triethylamine (0.01 mol) were added dropwise. The mixture was brought to room temperature, stirred at room temperature for 3 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 4.2 g (quantitative) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methylbenzoyl)phenyl]-acetamide (intermediate 21).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[CH:32]=[N:31][C:30]([NH:36][CH:37]([CH3:39])[CH3:38])=[N:29][C:28]=3[CH2:27]2)=[O:25])[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][C@@H:12]([NH:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[CH:32]=[N:31][C:30]([NH:36][CH:37]([CH3:39])[CH3:38])=[N:29][C:28]=2[CH2:27]1)=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCNC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCN)c1ccc(C(F)(F)F)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 292 (0.090 g, 0.16 mmol) and DCM (3 mL) at RT was added TFA (1 mL) and the reaction was stirred at RT for 1 h and then concentrated to dryness. The resulting product was next dissolved in minimal DCM (using MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to afford 0.060 g (75%) of I-72: MS m/z (APCI-pos) M+1=455.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH2:26][CH3:27])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH:26]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[CH3:27])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CCC(=O)Cc1ccc(/C=C/C(=O)OC)cc1
Product: COC(=O)/C=C/c1ccc(CCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 22.3 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.71 g) and 4-{(E)-2-carbomethoxyethenyl}phenylbutan-2-one (2.32 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound (0.86 g), m.p. 87°-89° C. (hexane) as a 50:50 mixture of diastereoisomers. τ(CDCl3), 8.9 (3H, d, J=6 Hz), 8.15-8.55 (2H, m), 6.9-7.7 (7H, m, 2H disappears with D2O), 6.3 (3H, s), 5.45 (1H, m), 3.65 (1H, d, J=16 Hz), 2.55-2.9 (8H, m), 2.4 (1H, d, J=16 Hz).
Reaction SMILES: [CH2:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][NH2:13])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])[CH3:24]>C(Cl)Cl>[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:15][CH:14]=1)=[O:29])[CH3:24]
Reactant: CCSc1ccccc1C(=O)Cl
Reactant: CCCCCc1ccc(C(=O)NN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)NNC(=O)c2ccccc2SCC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 4-pentylbenzohydrazide (1-C) (206 mg, 1.0 mmol) and triethylamine (153 μL, 1.1 mmol) in methylene chloride (5 mL) was added a solution of 2-(ethylthio)benzoyl chloride (1-B) (210 mg, 1.0 mmol) in methylene chloride (2.0 mL). After stirring at room temperature for 18 h, the mixture was diluted with methylene chloride and washed with water, 10% NaHCO3, brine, dried (MgSO4) and evaporated in vacuo to give 2-(ethylthio)-N′-(4-pentylbenzoyl)benzohydrazide (1-D). MS m/z 371 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Br[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([S:9][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[N:8][C:4]=2[CH:3]=1
Reactant: Cn1c(S)nc2cc(Cl)ccc21
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SC(C(=O)O)c2ccccc2)nc2cc(Cl)ccc21
Yield: 775.4 %

Procedure:
5.96 g (0.03M) of 5-Chloro-2-mercapto-1-methylbenzimidazole of C above, 0.5 g (0.03M) of α-bromophenylacetic acid and 6.0 g (0.06M) of triethylamine are dissolved in methylene chloride (200 ml) and the mixture heated to reflux overnight. The basic solution is washed with a diluted HCl solution and a white solid is collected. The crude material is recrystallized from 5 L of acetonitrile to give 6.0 g (60% yield) of the title compound, m.p. 203°-5° C. dec.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.[OH-].[K+].CS(C)=O>O>[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Reactant: C[C@H]1CN(CCO)CCN1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@@H](C)C5)ccn34)c12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A flask equipped with a condenser was charged with the 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (15.0 g, 32.68 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (10.34 g, 65.37 mmol, Example 23), crushed KOH (9.17 g, 163.4 mmol) and 100 mL of DMSO. The mixture was heated to 95° C. for 22 hours. The mixture was allowed to cool to ambient temperature, 350 mL of water were added and the mixture stirred vigorously for 30 minutes. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine and 10% aqueous potassium carbonate, dried and concentrated. The resulting material was purified by column chromatography (10% MeOH/DCM/0.5% NH4OH to 15% MeOH/DCM/0.5% NH4OH) and then triturated with ether. The resulting solid was collected to give 10 g (53%) of the title compound. MS (APCI), positive scan, m/z=581.1 (M+H). [α]D=+5.6° (c=1.0, CHCl3).
Reaction SMILES: [CH3:1][C:2]([NH2:17])([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15].O.CO[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH:29]=[O:30])=[O:28].[CH3:31]S(C)=O>>[CH3:16][C:2]([N:17]=[C:29]([O:30][CH3:31])[C:27]([C:22]1[CH:21]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15]
Reactant: COc1ccccc1C(=O)C=O
Reactant: CS(C)=O
Reactant: COc1ccc(CC(C)(C)N)c(OC)c1OC
Solvent: O
Product: COC(=NC(C)(C)Cc1ccc(OC)c(OC)c1OC)C(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 133 mg of α,α-dimethyl-2,3,4-trimethoxyphenethylamine in 1.5 ml of dimethylsulfoxide is added to 111 mg of 2-methoxyphenylglyoxal hydrate, and the mixture is stirred at 20° C. for one hour, whereby a solution of α-(α,α-dimethyl-2,3,4-trimethoxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(Cl)c2)C1=O
Product: COCCN1CCN(CC2CCN(c3cccc(Cl)c3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(3-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 1(8).