Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]Br)=[CH:6][CH:5]=1.CN.CC(O)C.Br>CC(O)C>[CH3:1][NH:2][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CN
Agent: Br
Solvent: CC(C)O
Product: CNCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 11 h
Yield: 90 %

Procedure:
1000 mL of IPA was placed in a 3 L flask and cooled to 0° C. A steady stream of methylamine gas from a cylinder was slowly passed through the IPA until the total volume reached 1750 ml. 100 g of (2-[4-hydroxyphenyl]ethyl) bromide (A11) was added to the cooled methylamine IPA solution in several portions. The cooling bath was removed after all A11 was added. The reaction mixture was allow to warm to room temperature and continue to stir for another 10-12 h. The excess methylamine was distilled into another 1000 mL of pre-cooled to 0° C. IPA by heating the reaction mixture at 50° C. When most of the methylamine was distilled off, the bath temperature was raised to 100° C. and the IPA was distilled out. After most of the IPA had been distilled out, about 300 mL of IPA was added to the reaction mixture and distillation was continued to aid removal of the methylamine. After the volume was reduced to 250 mL, the reaction mixture was allowed to cool down to room temperature. The precipitate was collected by filtration and washed by toluene to give 104 g (90% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine as an HBr salt (A12 HBr). 1H NMR (CDCl3) δ 2.69 (3H, s, CH3), 2.90 (2H, t, J=7.2 Hz), 3.18 (2H, t, J=6.3 Hz), 6.76 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.7 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:37])([F:25])[F:38]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1C(F)(F)F)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), [2-(trifluoromethyl)phenyl]acetic acid (120 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solid was washed with ethyl acetate/heptane to give the title compound (120 mg, 79%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([O:20]CC)=[O:19])=[C:4]([Cl:23])[CH:3]=1.[OH-].[Na+].C(O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([OH:20])=[O:19])=[C:4]([Cl:23])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C2CCOC2)c1-c1ccc(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn(C2CCOC2)c1-c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 102.4 %

Procedure:
A mixture of (±)-ethyl 5-(4-bromo-2-chlorophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (1.05 g) and a 5 M aqueous sodium hydroxide solution (1.58 mL) was stirred in a mixed solvent of ethanol (20 mL) and water (5 mL) at 60° C. for three hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. 5 M hydrochloric acid was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)=[O:17].Br[CH2:27]C(C1C=C(CC)C=CN=1)=O>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([C:18]1[CH:23]=[C:22]([CH2:24][CH3:27])[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: CCc1ccc2[nH]c(C(=O)c3cc(C)ccn3)c(CC(=O)OC)c2c1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(CC)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate (Example 133, step 2) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([CH3:38])[CH2:10][C@H:11]([O:36][CH3:37])[C@@H:12]([O:28]CC1C=CC=CC=1)[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[OH-].[OH-].[Pd+2]>[C:1]([O:7][CH2:8][C@H:9]([CH3:38])[CH2:10][C@H:11]([O:36][CH3:37])[C@@H:12]([OH:28])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](OCc1ccccc1)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Agent: [Pd+2]
Agent: [OH-]
Product: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Yield: 99.4 %

Procedure:
Benzyl ether 23 (3.58 g, 6.48 mmol) was dissolved in 50 ml of ethyl acetateand treated with 950 mg of 20% palladium hydroxide on carbon. Hydrogen gas was bubbled into the solution at 25° C. for 1 hr. The mixture was filtered through celite and concentrated in vacuo to give 2.98 g of the alcohol 24 as an oil. This material was used directly in the subsequent transformation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1SC(C)=NN=1)=[O:17])(=[O:10])=[O:9].[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31](N)=[C:30](C)[CH:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:25])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][C:30]=1[CH3:31])=[O:17])(=[O:9])=[O:10]
Reactant: Cc1nnc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)s1
Reactant: COc1ccc(N)c(C)c1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)-aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide (EXAMPLE 150), except that 4-methoxy-2-methylaniline was used instead of 2-amino-5-methyl-1,3,4-thiadiazole and that pyridine was not used. The title compound was obtained via HPLC purification as a dull yellow powder (66% yield, m.p. 58-62° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[N+:21]([O-])([OH:23])=[O:22]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:20])=[C:15]([N+:21]([O-:23])=[O:22])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCOCC1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (7.7 g) was dissolved in ethyl acetate (500 ml) and a solution of nitric acid in dichloromethane (2M, 13.6 ml) was gradually added at 20° C. into. The solution was stirred 30 min at room temperature and then it was poured into ice-cold water and the resultant solid was filtered and dried in vacuum. The product was recrystallized from acetic acid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10](=[O:20])[C:11]1[CH:16]=[C:15]([I:17])[C:14]([OH:18])=[C:13]([I:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].C([O:33][C:34](=[O:36])[CH3:35])C>CC(C)=O>[CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10](=[O:20])[C:11]1[CH:12]=[C:13]([I:19])[C:14]([O:18][CH2:35][C:34]([OH:36])=[O:33])=[C:15]([I:17])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCC(=O)O)c(I)c1
Temperature: 50 °C
Yield: 49.7 %

Procedure:
A mixture of 2-n-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran 1.0 g (1.83 mmol) and potassiumcarbonate 0.56 g (4 mmol) in aceton (dry) 100 ml, α-brom ethylacetate 1.0 g (12 mmol was added, and the solution was extracted with 100 ml water. The organic layer was evaporated to dryness and the yellow rest was dissolved in methanol 50 ml+1M NaOH 50 ml. The solution was heated to 50° C. for 15 h, extracted with 3×75 ml dichloromethane, and dried (MgSO4). Evaporating the solution and purification on silica gave 0.55 g (005).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[C:12]1([C@@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[C:12]1([C@H:18]([NH:20][C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]2[C:2]([F:11])([F:10])[F:1])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1CCCCC1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H](N[C@@H]1CCCC[C@@H]1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a 1,2-dichloroethane solution of 2-(trifluoromethyl)cyclohexanone (10.0 g) and [(1S)-1-phenylethyl]amine (7.29 g) was added NaBH(OAc)3(25.51 g) at ambient temperature. After stirring for 2 days at ambient temperature, 150 mL of saturated aqueous sodium hydrogencarbonate was added. After extraction with EtOAc, combined organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel column chromatography (n-hexane:EtOAc=8:1 to 2:1) to give (1R,2S)—N-[(1R)-1-phenylethyl]-2-(trifluoromethyl)cyclohexanamine (7.83 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=2)=[N:10]1
Reactant: ClCC1CO1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg, 0.69 mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL) was added cesium carbonate (450 mg, 1.38 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc, and washed with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 5% acetone/CH2Cl2) to afford 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (141 mg, 59%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.38. MS (electrospray) m/z 347.1 (347.1, calculated for C17H13F3N4O, M++H). 1H NMR (400 MHz, CDCl3): 8.51 (dd, J=2.8, 1.8 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7, 6.1 Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0, 2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:37][C:38]1[N:43]=[C:42]([N:44]([CH3:46])[CH3:45])[CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([N:44]([CH3:46])[CH3:45])[N:43]=2)[CH:27]=1)[C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(CCl)n1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: COc1ccc(N(Cc2cnn(Cc3cccc(N(C)C)n3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 25.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and 6-chloromethyl-2-(dimethylamino)pyridine (0.68 g) as starting materials, 5-benzyloxy-N-({1-[(6-(dimethylamino)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. 1H-NMR (CDCl3) δ: 1.38-1.67(1H,m), 1.73-2.07(3H,m), 2.61-2.82(2H,m), 3.04(6H,s), 3.59-3.72(1H,m), 3.93(3H,s), 4.64(1H,d,J=14.4 Hz), 4.83(1H,d,J=14.4 Hz), 5.03(2H,s), 5.21(2H,s), 6.18(1H,d,J=7.2 Hz), 6.40(1H,d,J=8.4 Hz), 6.54(1H,d,J=7.5 Hz), 6.62-6.76(2H,m), 7.01(1H,t,J=8.0 Hz), 7.21-7.52(9H,m), 7.99(1H,d,J=2.4 Hz).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.Br[C:17]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O>>[N+:25]([C:23]1[CH:24]=[C:17]2[C:18](=[CH:21][CH:22]=1)[CH:19]=[C:2]1[C:1]([O:14][C:5](=[O:7])[C:4]3[C:3]1=[C:12]2[CH:11]=[CH:10][CH:9]=3)=[O:13])([O-:27])=[O:26]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1Br
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2cc3ccc([N+](=O)[O-])cc3c3cccc1c23

Procedure:
As described in example 50, the following compounds were prepared from dimethyl homophthalate and 2-bromo-4-nitrobenzaldehyde (Dandegaonker, S. H. J. Ind. Chem. Soc. 1969, 46, 148):
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2nc(Sc3ccccn3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.90 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyridylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to dryness. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.42 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyridylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [C:1]([C:4]1[C:9](/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([F:19])[C:7]([Cl:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:4]1[C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[C:8]([F:19])[C:7]([Cl:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)O
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of Intermediate 12D (25 g, 84 mmol) in DCM (330 mL) and TFA (330 mL) was stirred at rt. After 1.5 h, the solvent was concentrated to give Intermediate 12 (19.5 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.69 (bs, 1H), 7.80-7.76 (m, 2H), 7.62 (d, J=12.1 Hz, 1H), 6.30 (dd, J=2.4, 2.0 Hz, 1H), 2.6 (s, 3H) ppm. MS (ESI) m/z: 241 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([Cl:29])[CH3:28]>>[Cl:29][CH:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: CC(Cl)CCCCBr
Product: COc1ccc(C(C#N)(CCCCC(C)Cl)Sc2ccc(C)cc2)cc1OC
Yield: 82 %

Procedure:
The procedure of Example 15 is repeated using 3.8 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.66 g of 1-bromo-5-chlorohexane. This affords 4.35 g of the desired product as a colorless oil.
Reaction SMILES: C(C[C:7]1[N:11](C)[C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:9][C:8]=1C)(OCC)=O.N>CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C:10]2[NH:11][CH:7]=[CH:8][N:9]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cc1c(C)nc(SCc2ccc(OC)cc2)n1C
Agent: N
Solvent: CO
Product: COc1ccc(CSc2ncc[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 5-carbethoxymethyl-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (2 g, 6 mmoles) in methanol (15 ml) was cooled in an acetone/dry ice bath and treated with liquid ammonia (15 ml). The mixture was warmed to 25° C. and concentrated in vacuo to afford 5-(aminocarbonylmethyl)-1,4-dimethyl(-2-(4-methoxybenzylthio)imidazole.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>>[CH2:3]([C:2]1[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:1]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CCCCCCCCC
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCCCCCCCC1=CC1C(=O)OCC

Procedure:
Ethyl 2-octylcycloprop-2-ene-1-carboxylate was prepared from 1-decyne and ethyl diazoacetate by the method of Mueller, P.; Pautex, N.; Helv. Chim Acta 1990, 73,1233.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:16](=[O:31])[CH:15]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:15]1[C:16](=[O:31])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:29])([F:28])[F:30])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:10]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-bromosuccinimide (0.24 g, 1.36 mmol) was added into 4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one (0.54 g, 1.36 mmol) in 20 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (150 ml) was added into the reaction mixture and the combine solution was transferred to a separatory funnel. The product was extracted with ethyl acetate (250 ml). The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=7.25 Hz, 1H), 7.7 (app t, J=7.66 Hz, 1H), 7.60 (m, 2H), 7.26 (s, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 6.09 (s, 1H), 5.25 (app d, J=3.35 Hz, 2H), 1.94 (s, 3H); LC/MS, tr=2.84 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-HRMS m/z 474.0113 (M+H calcd for C20H14BrF5NO2 requires 474.0123).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:14]2[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CCCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nccn1Cc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-n-butylimidazole (3.75 g, 0.03 mol) in dry dimethylformamide (4 mL) was added to sodium hydride (0.95 g) in dimethylformamide (18 mL). After the gas evolution subsided, the mixture was stirred one hour under argon and 2-chloro-6-fluorobenzylchloride (5.5. g, 0.031 mol) in dimethylformamide (7 mL) was added to produce an exotherm. The mixture was stirred for 17 hours at ambient temperature, diluted with ice water and extracted with ethyl acetate. The washed, dried, concentrated organic layer provided 7.63 (94%) of the title compound whose NMR was consistent with the structure. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:39]([Cl:38])=[O:41])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC[C@@H](Nc2nccc(-c3c(-c4ccc(F)cc4)nc4occn34)n2)C1
Yield: 95.8 %

Procedure:
To a solution of 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine (200 mg, 0.45 mmol) and Hunig's base (145 μL, 0.90 mmol) in 10 mL DCM was added a solution of triphosgene (660 mg; 2.25 mmol) in 10 mL DCM dropwise over 10 min with stirring. The mixture was allowed to stir at ambient temperature for 1.5 hr. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with 20 mL ether and concentrated under reduced pressure yielding (3R)-3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carbonyl chloride as an off-white solid (190 mg). The solid was diluted in 10 mL DCM. To the resulting solution was added morpholine (60 μL, 0.67 mmol) and triethylamine (70 μL, 0.50 mmol). The mixture was allowed to stir at ambient temperature for 20 hr. The reaction mixture was then concentrated under reduced pressure and the residue purified by flash chromatography on silica gel (1:4, ethyl acetate:hexanes) to yield 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine as an off-white solid (50.2 mg, 23%). 400 MHz 1H NMR (DMSO-d6) δ: 8.75 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.62-7.66 (m, 2H), 7.30-7.34 (m, 2H), 6.37 (s, 1H), 3.76 (m, 2H), 3.53 (m, 4H), 3.15 (m, 2H), 3.09 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 1.99 (s, 1H), 1.78 (br.s, 1H), 1.50-1.54 (m, 2H). LCMS: 492 [M+H].