Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:28][C:29]([F:32])([F:31])[F:30])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].Cl.C[N:35](C)CCCN=C=NCC.CN(C)C=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:28][C:29]([F:32])([F:31])[F:30])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:35])=[O:27])[CH2:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.5 %

Procedure:
A mixture of {2-[7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (410 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (240 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (310 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio), and the obtained solid was washed with hexane to give the title compound (260 mg, yield 63%) as brown crystals. The crystals were recrystallized from acetone-hexane to give pale-yellow prism crystals. melting point 239-240° C.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1COCC1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:19][CH:18]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To tributyltin chloride (652 mg, 2.00 mmol, 1.00 equiv) in THF (2 mL) at 23° C. was added 4-methoxyphenylmagnesium bromide (0.50 M in THF, 8.0 mL, 4.0 mmol, 2.0 equiv). After stirring for 1.0 hr at 60° C., the reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl (10 mL), and Et2O (10 mL) was added. The phases were separated and the aqueous phase was extracted with Et2O (2×10 mL). The combined organic phases were washed with brine (10 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by fractional distillation to afford 637 mg of the title compound as a colorless oil (80% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27]OS(C)(=O)=O)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH2:27][C:12]1[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)[CH3:35]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 61.8 %

Procedure:
Following the procedure of Example 7, 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a pale yellow crystalline powder (yield: 61.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNS(=O)(=O)c1cccc(C2=Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Yield: 84.2 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (175 mg, 0.438 mmol) in methanol/tetrahydrofuran (9.5 mL/9.5 mL) was treated with H2 at room temperature overnight. LC-MS showed the reaction was complete. The mixture was separated by filtration and the filtrate was concentrate in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give 143.2 mg of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate, yield: 81.2%.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[F:30])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C=O.[CH3:35]C(C)(C)[C@H](NC(N1C2CCN(C)CC=2C(C2C=C(F)C(F)=CC=2F)=N1)=O)C(NC)=O>>[CH3:1][C:2]([CH3:32])([CH3:31])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:35])[CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:21]=2[F:30])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(C(F)(F)F)ccc2F)c2c1CCNC2)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: C=O
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(C(F)(F)F)ccc2F)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 59 was prepared reductive amination of compound 58 with formaldehyde following the procedure as described for the synthesis of compound 37. LCMS (+ESI) m/z=456.2 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][OH:46])[CH2:39][CH2:38]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][OH:46])[CH2:41][CH2:42]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(CCCO)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(CCCO)CC2)ccc1O
Temperature: 25 °C
Reaction time: 30 h
Yield: 35.7 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.036 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.018 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 hours. To the reaction mixture, 10% palladium-carbon (0.018 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.011 g of methyl 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:26])[C:21]([Cl:25])=[CH:22][C:23]=1[F:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([Cl:25])=[C:20]([CH:19]=1)[O:26][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Yield: 56.2 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (600 mg, 1.83 mmol) in N,N-dimethylformamide (12 mL) were added 3-amino-6-chloro-4-fluorophenol (443 mg, 2.74 mmol) and potassium carbonate (505 mg, 3.66 mmol). In the same manner as in Example 232, the title compound (372 mg, 56%) was obtained as a brown powder.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].OS(O)(=O)=O.[CH2:16](O)[CH2:17][CH2:18][CH3:19]>>[C:6]([C@H:4]([C@@H:2]([C:1]([O:10][CH2:1][CH2:2][CH2:4][CH3:6])=[O:9])[OH:3])[OH:5])([O:8][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CCCCO
Agent: O=S(=O)(O)O
Product: CCCCOC(=O)[C@@H](O)[C@H](O)C(=O)OCCCC
Temperature: 25 °C

Procedure:
d-Tartaric acid (25 g, 167 mmol), n-butanol (200 mL) and concentrated H2SO4 (59 mL) were heated under reflux overnight. The solution was cooled to room temperature then partitioned between H2O and CH2Cl2. The organic layer was washed with aqueous saturated NaHCO3 then filtered through Celite. The organic solution was then washed with brine, dried (MgSO4), filtered, and the solvent removed in vacuo. The resulting oil was purified by Kugelrohr distillation (bp=100-105° C., 0.06 mm Hg) to yield 38 as a clear light yellow oil: 1H NMR (300 MHz, CDCl3) δ0.9 (t, 6H), 1.4 (m, 4H), 1.65 (m, 4H), 3.2 (m, 2H), 4.35 (m, 4H), 4.5 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:24](=[O:25])[C:23]3[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2cccc(C(F)(F)F)c2)CCNC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccc(C(F)(F)F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][N:2]([S:18]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[CH:23][C:22]=1[Cl:29])(=[O:20])=[O:19])[CH2:3][CH2:4]OS(C1C=C(Cl)C(Cl)=CC=1Cl)(=O)=O.[F:30][C:31]1[CH:45]=[CH:44][C:34]2[NH:35][C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[N:37][C:33]=2[CH:32]=1>>[Cl:29][C:22]1[CH:23]=[C:24]([Cl:28])[C:25]([Cl:27])=[CH:26][C:21]=1[S:18]([N:2]([CH2:3][CH2:4][N:41]1[CH2:42][CH2:43][N:38]([C:36]2[NH:35][C:34]3[CH:44]=[CH:45][C:31]([F:30])=[CH:32][C:33]=3[N:37]=2)[CH2:39][CH2:40]1)[CH3:1])(=[O:19])=[O:20]
Reactant: Fc1ccc2[nH]c(N3CCNCC3)nc2c1
Reactant: CN(CCOS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Product: CN(CCN1CCN(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using 2,4,5-Trichlorobenzenesulfonic acid 2-(methyl-(2,4,5-trichlorobenzenesulfonyl)-amino)-ethyl ester (D4) and 1-(5-fluoro-1H benzimidazol-2-yl) piperazine. MH+ 520/522/524/526.
Reaction SMILES: CCCCC.C(NC(C1C=C2C=C(C([C:26]3[CH:31]=[CH:30][C:29](S(C)(=O)=O)=[CH:28][CH:27]=3)CC(C)C)NC2=NC=1)=O)(C)C.C([Li])(C)(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH:45]=[O:46]>C(OCC)C>[CH:28]1([CH2:27][C:45]([C:44]2[CH:47]=[CH:48][C:49]([Cl:50])=[C:42]([Cl:41])[CH:43]=2)=[O:46])[CH2:29][CH2:30][CH2:31][CH2:26]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)NC(C)C)cnc2[nH]1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: O=C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
A solution of pentane (50 mL), diethyl ether (50 mL) and iodomethylcyclopentane (prepared as in PCT WO2004/052869 A1 Example 1, 3.9 g, 18.6 mmol) was cooled to −78° C. and a solution of t-butyl lithium in pentane (1.7 M, 18.5 mL, 31.5 mmol) was added dropwise. The mixture was then stirred at −78° C. for 30 min and then warmed to room temperature and stirred for 30 min and finally recooled to −78° C. To this mixture was then added a solution of 3,4-dichlorobenzaldehyde (5.0 g, 28.6 mmol) in diethyl ether (20 mL) dropwise. The mixture was then stirred at −78° C. for 1 h and then warmed up to room temperature and stirred overnight. The mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (50 mL). The organic layer was then separated and washed with a saturated brine solution (50 mL), dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10% ethyl acetate/hexanes) afforded 2-cyclopentyl-1-(3,4-dichloro-phenyl)-ethanone (2.36 g, 50%) as a yellow solid.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[K+].[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:17](/[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=2)=[CH:18]/[C@@H:19]2[NH:23][C:22](=[O:24])[CH2:21][CH2:20]2)=[N:13][C:14]=1[O:15]C.O>C(#N)C>[Cl:8][C:9]1[C:14](=[O:15])[NH:13][C:12](/[C:17](/[C:25]2[CH:26]=[CH:27][C:28]([CH2:31][OH:32])=[CH:29][CH:30]=2)=[CH:18]/[C@H:19]2[CH2:20][CH2:21][C:22](=[O:24])[NH:23]2)=[CH:11][CH:10]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(CO)cc2)ccc1Cl
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@H](/C=C(\c2ccc(CO)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
Chlorotrimethylsilane (0.123 mL) and potassium iodide (263 mg) were sequentially added to a solution of (5R)-5-{(E)-2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(hydroxymethyl)phenyl]ethenyl}pyrrolidin-2-one (142 mg) in acetonitrile (1.5 mL) at room temperature, after which the mixture was stirred at 60° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (methanol:ethyl acetate=1:10) to give the title compound as a colorless solid (19 mg, 14%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[NH:4][CH:5]=[C:6]([C:12](=[O:24])[C:13]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+]>C1COCC1>[F:20][C:17]1[C:18]([CH3:19])=[C:13]2[C:14](=[C:15]([F:22])[C:16]=1[F:21])[N:4]([C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1])[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]2=[O:24]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(C)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a cold (5° C.) solution of 2.77 g (6.64 mmol) of ethyl 3-(2,4-difluoroanilino)-2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)acrylate in 60 ml of dry THF was added 0.32 g of 60% sodium hydride. The solution was stirred overnight at room temperature, then concentrated to an orange foam. The residue was partitioned between methylene chloride and 1N HCl. The organic phase was washed with water, dried over magnesium sulfate, and concentrated to an orange solid which was recrystallized (ethyl acetate:hexane) to give 1.55 g of the title compound, mp 152°-154° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([N:7]([CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:6])[CH3:2].[C:26](ON1C(=O)CCC1=O)([O:28][CH2:29][CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([N:7]([CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:26]([O:28][CH2:29][CH:30]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:27])[CH2:11][CH2:10]1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCNCC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 1.25 h
Yield: 39.8 %

Procedure:
To a solution of 4-{[[ethoxy(oxo)acetyl](piperidin-4-ylmethyl)amino]methyl}benzoic acid (7.650 g, 16.54 mmol) in dioxane/H2O (1/1) (120 mL) was added Fmoc-OSu (6.697 g, 19.85 mmol) and a 1 M aqueous solution of NaHCO3 (10 mL). The resulting reaction mixture was stirred for 1.25 h, then concentrated under vacuum. The oily residue dissolved in DCM (120 mL) was washed with a 1 N aqueous solution until pH 1, dried over MgSO4, filtered and the solvents were evaporated under vacuum. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/1 in about 1 h) to give the title compound as a white powder (3.755 g, 40%). 1H NMR (CDCl3, 300 MHz) δ 8.1 (m, 2H), 7.75 (d, 2H, J=7.6 Hz), 7.55 (d, 2H, J=7.2 Hz), 7.38 (m, 4H), 7.29 (t, 2H, J=7.3 Hz), 4.70 (s, 1H), 4.56 (s, 1H), 4.45-4.07 (m, 7H), 3.0 (m, 2H), 2.45 (m, 2H), 1.7-1.5 (m, 1H), 1.40 (m, 2H), 1.38 (t, 1H, J=7.0 Hz), 1.31-1.21 (m, 3H), 1.0-0.8 (m, 2H). M−(LC/MS (ESI)): 569.4; M+(LC/MS (ESI)): 571.8. HPLC (Condition A), Rt: 4.83 min (HPLC purity: 99.3%).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][O:10][C:11](=[O:29])[CH:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.N1C=CN=C1>ClCCl>[CH3:9][O:10][C:11]([C@@H:12]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([O:20][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[CH2:16][CH2:15]1)=[O:29]
Reactant: COC(=O)C(CC1CCC(O)CC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a solution of TBSCl (12.7 g, 85 mmol) in dichloromethane (20 mL) was added dropwise a mixture of 2-tert-butoxycarbonylamino-3-(4-hydroxy-cyclohexyl)-propionic acid methyl ester (17 g, 56 mmol) and imidazole (7.68 g, 113 mmol) in dichloromethane (200 mL) at 0° C. After stirring at rt for 5 h, the reaction mixture was washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to give tert-butyl (S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)cyclohexyl)ethylcarbamate (21 g, 91%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 0.08 (d, 6H), 0.89 (d, 9H), 1.45 (s, 9H), 1.51 (m, 4H), 1.58 (m, 1H), 1.68 (t, 4H), 1.85 (d, 1H), 3.71 (d, 3H), 3.91 (m, 1H), 4.34 (m, 1H), 4.86 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[N:10][C:11](Cl)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[C:9]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[N:10][CH:11]=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCCNc1nc(Cl)ncc1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCOCCNc1ncncc1Cc1ccccc1
Yield: 4.5 %

Procedure:
A mixture of 5-benzyl-2-chloro-4-[2-(2-hydroxyethoxy)ethylamino]pyrimidine (3.50 g, 12.08 mmoles), ethanol (190 mL) and 10% Pd on carbon (Aldrich) (0.84 g) was shaken in to presence of hydrogen at 2-3 atm for 17 hours. The reaction mixture was filtered through a pad of CELITE®, and the filtrates were spin evaporated in vacuo. The residual syrup was dissolved in dichloromethane (40 mL) and washed with water (20 mL) brine (20 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give a residue that was triturated under hexanes to give 0.15 g (5% yield) of 5-benzyl-4-[2-(2-hydroxyethoxy)ethylamino]pyrimidine as a white solid, mp 86-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH2:18])[N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>CN(C)C(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[N:17]=3)[CH:14]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(COc2ccc3nc(N)cn3c2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a solution of 6-[(4-methoxybenzyl)oxy]imidazo[1,2-a]pyridin-2-amine (8.5 g, 31.6 mmol) in N,N-dimethylacetamide (80 mL) was added a solution of cyclopropanecarbonyl chloride (3.43 mL, 37.9 mmol) in N,N-dimethylacetamide (20 mL) at 0° C., and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was diluted with water, and the precipitate was collected by filtration and washed with water and ethyl acetate to give the title compound (8.9 g, 83%) as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.FC(F)(F)[C:16](O)=[O:17].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(OC(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(OC(F)(F)F)cc1C=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Combine 2-methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2 mmol) and trifluoroacetic acid (200 mL). Add slowly portionwise hexamethylenetetraamine (26 g, 185.7 mmol). Heat at 60° C. After 24 hours, cool to ambient temperature and pour the reaction mixture into a 2M aqueous solution of sulfuric acid (500 mL). Cool and extract ten times with diethyl ether. Dry the combined organic layers over Na2SO4, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give 2-methoxy-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[I:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[I:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1I
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)c1c(I)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (b) Example I from 5-bromo-3-iodoindole-2-carboxylic acid ethyl ester (see step (a) above) and 4-isopropoxyphenylboronic acid.