Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[C:9](=[O:42])[NH:10][C:11](=[O:41])[N:12]([CH:40]=1)[C@@H:13]1[O:39][C@H:17]([CH2:18][O:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:15]([OH:16])[CH2:14]1.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[OH-].[K+]>O1CCOCC1>[CH2:43]([O:16][C@@H:15]1[C@@H:17]([CH2:18][OH:19])[O:39][C@@H:13]([N:12]2[CH:40]=[C:8]([F:7])[C:9](=[O:42])[NH:10][C:11]2=[O:41])[CH2:14]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of 50 ml of benzene and 50 ml of dioxane were added 1.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine, 0.30 ml of benzyl bromide and 0.23 g of potassium hydroxide powder, and the mixture was refluxed for 25 hours. The insolubles were removed by filtration and the filtrate was concentrated and the concentrate was dissolved in 5 ml of 80% acetic acid. The solution was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was placed on a silica gel column to conduct a gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform. The fractions corresponding to 3'-O-benzyl-2'-deoxy-5-fluorouridine were collected and concentrated. The concentrate was recrystallized from ethanol, giving 0.14 g of the title compound in a yield of 20%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([CH3:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(C)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 150 mg (37%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.82˜8.73 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 8.03-802 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 8.00˜6.88 (m, 7H); 3.87 (s, 3H) 3.49˜2.57 (m, 12H), 2.5 (s, 3H).
Reaction SMILES: CN(C=O)C.[CH3:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:20]1[CH:25]=[CH:24][C:23]2=[N:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:42]([F:45])([F:44])[F:43])=[C:33]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=3)=[CH:28][N:22]2[N:21]=1>O>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36]([NH:35][C:33]1[CH:34]=[C:29]([C:27]2[N:26]=[C:23]3[N:22]([CH:28]=2)[N:21]=[C:20]([N:10]2[CH2:11][CH2:12][CH:7]([CH3:6])[CH2:8][CH2:9]2)[CH:25]=[CH:24]3)[CH:30]=[CH:31][C:32]=1[C:42]([F:44])([F:43])[F:45])=[O:41]
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCN(c2ccc3nc(-c4ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c4)cn3n2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
An 8 mL vial is charged with DMF (1 mL), 4-methylpiperidine (0.030 g), Cs2CO3 (0.130 g), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0396 g, 0.1 mmol). The mixture is stirred at 120° C. for 16 hr, then diluted with H2O (5 mL) and extracted with Et2O (3 mL×2). Organics are dried and concentrated onto celite, purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.020 g, 43% yield). LCMS m/z=460.6 [M+H]+, tR=3.14 min. (compound same as Example 233)
Reaction SMILES: Cl.Br[C:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH2:4][CH2:5][NH2:6].CC(C)=[O:23]>O.S(=O)(=O)(O)O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:3]([OH:23])([CH3:7])[CH2:4][CH2:5][NH2:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)=O
Reactant: CC(Br)(CCN)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
3.59 g of 3-bromo-3-(4'-fluoro-4-biphenylyl)butylamine hydrochloride [obtainable by reacting 3-hydroxy-3-(4'-fluoro-4-biphenylyl)-butyramide with PBr3 to give 3-bromo-3-(4'-fluoro-4-biphenylyl)-butyramide and reduction with LiAlH4 ] are dissolved in a mixture of 15 ml of acetone and 15 ml of water, 1 drop of sulfuric acid is added, and the mixture is warmed to 45° for 4 hours and worked up in the customary manner to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°. A little 3-(4'-fluoro-4-biphenylyl)-2-butenylamine, which can be removed by chromatography (over SiO2), is formed as a by-product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[C:6]2[CH3:16].[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[N:8]([CH3:20])[CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C)cn(C)c2cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
A solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (900 mg, 4 mmol) in 7 ml DMF was cooled to zero degrees C., and sodium hydride (104 mg, 4 mmol, 95% powder) was added. The reaction mixture was stirred 15 minutes at zero degrees C., and then iodomethane (270 ul, 4 mmol) was added. The reaction mixture was stirred for 1 hour and allowed to warm to room temperature. The reaction mixture was then cooled to 0° C., quenched by addition of 1 N N4Cl, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-Methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 75%) as a solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[C:31]([F:37])=[CH:30][C:29]=1[O:38][CH3:39]>C1COCC1>[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[C:31]([F:37])=[CH:30][C:29]=1[O:38][CH3:39])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A stirred suspension of sodium hydride (60% in oil, 37 mg, 0.926 mmol) in THF (1 mL) was treated at 0° C. with (S)-4-benzyl-2-oxazolidinone (33 mg, 0.185 mmol) dissolved in THF (1 mL), under an atmosphere of N2. The reaction was stirred for 20 min and a solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 50 mg, 0.124 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 60 h. The reaction was quenched with H2O (1 mL) and partitioned between EtOAc (25 mL) and H2O (10 mL). The aqueous phase was re-extracted with EtOAc (3×15 mL) and the combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash silica-gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass. LCMS=502.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.69-7.64 (m, 1H), 7.58 (s, 1H), 7.39-7.36 (m, 1H), 7.29-7.24 (m, 3H), 7.06 (d, J=8.5 Hz, 1H), 6.97-6.91 (m, 2H), 6.73 (d, J=11.7, 1H), 4.79 (d, J=15.8 Hz, 1H), 4.30 (d, J=15.8 Hz, 1H), 4.08-4.05 (m, 1H), 3.99-3.97 (m, 1H), 3.76 (s, 3H), 3.65-3.58 (m, 1H), 3.27-3.17 (m, 1H), 2.81 (dd, J=13.5, 4.1 Hz, 1H), 2.45-2.40 (m, 1H), 1.30-1.4 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[N:38]([CH3:39])[C:37]3[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=3[N:35]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-1-methyl-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([C@H:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH2:58][CH3:59])=[CH:55][CH:56]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of compound 81 (2.0 g, 2.46 mmol) and Pd/C (10% wt., 200 mg) in THF (12 mL) and MeOH (12 mL) was stirred at room temperature under an atmosphere of H2 for 16 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E024 (514 mg, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a cold (−20° C.) solution of Rac-(1S,3R)-3-Hydroxy-cyclopentanecarboxylic acid tert-butyl ester (0.905 g) in dichloromethane (12 mL) was added methanesulfonylchloride (0.664 g) and triethylamine (0.636 g). The reaction mixture was stirred 10 min at −20° C. then poured into ice-water. Organic layer was washed with brine and dried over sodium sulfate then concentrated in vacuo to afford the title compound (1.15 g, 89%) as light yellow oil, used without further purification in the next step. MS (EI): 282 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:28])[N:16]=[CH:15]2.[C:29](O)(=[O:32])[C:30]#[CH:31].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>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:28][C:29](=[O:32])[C:30]#[CH:31])[N:16]=[CH:15]2
Reactant: C#CC(=O)O
Reactant: CCOc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(F)ccc(OCC)c3Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.3 %

Procedure:
A mixture of (1R,2S)—N1-(6-(2-chloro-3-ethoxy-6-fluorophenyl)quinazolin-2-yl)cyclopentane-1,2-diamine (0.1 mmol), propiolic acid (0.007 mL, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (0.052 mL, 0.3 mmol) in dichloromethane (1 mL) was stirred at room temperature for 40 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2-chloro-3-ethoxy-6-fluorophenyl)quinazolin-2-yl)amino)cyclopentyl)propiolamide (Compound 6) (35 mg, 76%). MS (ES+) C24H22ClFN4O2 requires: 452, found: 453 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: OCc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(CO)cc1

Procedure:
4-(Chloromethyl)-benzylalcohol (5.01 g, 32 mmol) and NaN3 (2.50 g, 38.4 mmol) were stirred in DMF (25 mL) at 90° C. for 17 h. The solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (2×50 mL) and the combined org. layers were dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give (4-azidomethyl-phenyl)-methanol, pure enough for further reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24](Cl)=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17].O>CN1C(=O)CCC1>[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=3[N:7]=[CH:8]2)=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Reactant: COc1cc2nc[nH]c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
5,6-Dimethoxybenzimidazole (470 mg, 2.64 mmol) was added to a suspension of NaH (60% in mineral oil, 112 mg, 2.8 mmol) in NMP (5 ml) at <5° C. The mixture was stirred for 20 min, then a solution of 2-chloro-4-phenylthiazole-5-carboxylic acid ethyl ester (589 mg, 2.2 mmol) in NMP (1.5 ml) was added over 2-3 min. The mixture was stirred 2.5 hrs at RT. Water (15 ml) was added and stirred for 20 min. Solid was collected by filtration to provide the product 2-(5,6-dimethoxy-benzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (753 mg. Yield 84%). 1H-NMR (300 MHz, CDCl3) 8.44(s, 1H); 7.87-7.90(m, 2H); 7.72(2, 1H); 7.44-7.49(m, 3H); 7.30(s, 1H); 4.32(q, J=Hz, 2H); 3.98(s, 3H); 3.97(s, 3H); 1.33(t, J=Hz, 3H). MS M/z 410(M+1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:44])[CH2:39]1)([CH3:37])[CH3:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][C@@H:40]4[CH3:44])[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN[C@@H](C)C1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)C[C@@H]4C)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added (S)-1-isopropyl-3-methylpiperazine (33.1 mg, 0.232 mmol) in 1,4-dioxane (1 mL) and triethylamine (15.7 mg, 22 μL, 0.155 mmol). The reaction mixture was stirred at 60° C. for 4 d, after which the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[C:23]#[N:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(C#N)ccc1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-4-fluorobenzonitrile (ABCR), the title compound was obtained as a beige solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:23])#[N:2].[CH2:27](I)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:13]([C:16]2[S:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=2)(=[O:14])=[O:15])[C:8]1=[O:23])#[N:2]
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)c1
Reactant: ICc1ccccc1
Product: N#Cc1cccc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 4,5-dichlorothiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 80, part A, and benzyl iodide. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 40% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: C(N1C=C2C(C=C([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)C=C2)=N1)C1C=CC=CC=1.Br[C:27]1[CH:28]=[CH:29][C:30]2[C:34]([CH:35]=1)=[N:33][N:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]=2[NH2:42]>>[C:36]1([N:32]2[C:31]([NH2:42])=[C:30]3[C:34]([CH:35]=[C:27]([B:17]4[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]4)[CH:28]=[CH:29]3)=[N:33]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1c2ccc(Br)cc2nn1-c1ccccc1
Product: CC1(C)OB(c2ccc3c(N)n(-c4ccccc4)nc3c2)OC1(C)C

Procedure:
This compound was prepared in a manner similar to the procedure described for the preparation of 2-benzyl-6-(4,4,5,5-tetramethyl-{1,3,2]dioxaborolan-2-yl)-2H-indazole (Intermediate C, step 2), using 6-bromo-2-phenyl-2H-indazol-3-ylamine in place of 2-benzyl-6-bromo-2H-indazole. 1H-NMR (300 MHz, DMSO-d6) 7.72 to 7.69 (m, 3H), 7.64 (s, 1H), 7.56 (t, 2H), 7.44 (t, 1H), 6.93 (d, 1H), 6.25 (s, 2H), 1.30 (s, 12H); ES-MS m/z 336.2 [M+H]+, RT (min) 2.51.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:3]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]4[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:16][CH2:17]3)=[O:11])=[N:6][CH:5]=2)=[O:28])[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: NC1CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CC3)cn2)CC1
Yield: 69 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using cyclopropylamine. And then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:24][CH2:23][CH2:22][O:6]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(C2OCCO2)c1

Procedure:
4.66 g of 3,5-dichlorobenzaldehyde is mixed with 0.23 g of paratoluenesulphonic acid, 3 ml of ethylene glycol and 40 ml of toluene. The reaction medium is heated under reflux for 2 hours, poured into a saturated solution of sodium bicarbonate and the aqueous phase is decanted. The organic phase is dried and evaporated under reduced pressure. 5.756 g of expected product is isolated in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH2:15]Br)=[CH:4][N:3]=1.ClC1C=CC([Mg]Br)=CC=1.ClC1C=CC(C=[O:34])=CN=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH2:15][OH:34])=[CH:4][N:3]=1
Reactant: Clc1ccc(CBr)c(-c2ccc(Cl)nc2)c1
Reactant: O=Cc1ccc(Cl)nc1
Agent: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1-c1ccc(Cl)nc1

Procedure:
2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromomethane may be prepared in the following manner: 0.153 cm3 of thionyl bromide is added to a solution of 100 mg of (2-chloropyrid-5-yl)-(4-chlorophenyl)methanol in 2 cm3 of carbontetrachloride, under an inert argon atmosphere, at a temperature in the region of 0° C. After 3.5 hours at a temperature in the region of 0° C., the reaction medium is concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 1.3 g of a brown liquid are thus obtained, which liquid is taken up in dichloromethane and supplemented with water and sodium dithionite. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.33 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)bromomethane is thus obtained in the form of a brown oil. 2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromomethane may be prepared by carrying out the procedure in a manner similar to Example 84, starting with 22.5 cm3 of 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 30 cm3 of tetrahydrofuran, under an inert argon atmosphere, and 2.9 g of 2-chloropyridine-5-carboxaldehyde in 30 cm3 of tetrahydrofuran. 3.42 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)methanol are thus obtained in the form of a pale green powder.