Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH3:19])[C:9]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of tert-butyl(2-oxopiperidin-3-yl)carbamate (1714 mg) in DMF (20 mL) was added 60% sodium hydride (480 mg, containing mineral oil) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and iodomethane (1703 mg) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (530 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24]C)=O)[C:13]=3[C:12](=O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>>[CH2:1]([N:8]1[CH2:9][C:10]2[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:22](=[O:24])[NH:28][N:29]=[C:12]([C:13]=34)[C:11]=2[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2CCN(Cc2ccccc2)C1

Procedure:
Example 18 was prepared from methyl 2-benzyl-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and hydrazine hydrate according to the same procedures described as those in Example 15. 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 7.21-7.56 (m, 8H), 3.81 (s, 2H), 3.39 (s, 2H), 2.91 (t, 2H, J=8.4 Hz), and 2.25 (t, 2H, J=8.4 Hz). MS (ESI) m/e [M+1]+ 331.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:9]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=O>O1CCOCC1>[NH2:7][C:8]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:9]=1[CH2:10][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1
Reactant: Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a refluxing suspension of lithium aluminum hydride (16.1 g, 424 mmol, 3.50 equiv) in dioxane (800 mL) was added a solution of 2-amino-N-(1-benzylpiperidin-4-yl)-3-fluorobenzamide (39.7 g, 121 mmol) in dioxane (250 mL) at such a rate that gas evolution was limited to a safe flow. Upon completion of the addition, the resulting suspension was heated at reflux for 4 h. The reaction was cooled to 0° C., and quenched by the cautious addition of 20% potassium hydroxide. Upon formation of a white, filterable precipitate, the solid was filtered through a course glass sintered funnel, and the eluent concentrated to give 36.3 g (96%) as a light yellow oil which was used without purification. Mass spec.: 314.29 (MH)+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]1)[CH2:11][CH3:12]
Reactant: CCCOCCn1c(Cl)nc2ccccc21
Reactant: CN1CCCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: CCCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Yield: 59.3 %

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(n-propoxy)ethyl]benzimidazole (2.83 g), N-methylhomopiperazine (3.00 g) and fumaric acid (2.04 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(n-propoxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (2.86 g) as colorless needles, m.p. 159.5°-160.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24]O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][O:34][C:35]([N:37]1[CH2:41][CH2:40][NH:39][S:38]1(=[O:43])=[O:42])=[O:36]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24][N:39]5[S:38](=[O:43])(=[O:42])[N:37]([C:35]([O:34][CH3:33])=[O:36])[CH2:41][CH2:40]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCO
Reactant: COC(=O)N1CCNS1(=O)=O
Product: COC(=O)N1CCN(CCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)S1(=O)=O

Procedure:
Methyl 5-{2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylene)-3-(2-hydroxyethyl)thiazolidine-2,4-dione (from Example 340) and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid methyl ester following General Procedure C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(C)cc(Sc2ccccc2)c1
Yield: 91.4 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-Xylene (144 μL, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3,5-dimethylphenyl phenyl sulfide (196 mg, 92% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.19-7.29 (m, 5 H), 6.97 (s, 2 H), 6.87 (s, 1 H). MS (EI) m/z (relative intensity) 214 (100), 137 (30).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[CH2:7]([N:9]([CH2:30][CH3:31])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[S:29])[NH2:28])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8].S>C(O)C>[CH2:30]([N:9]([CH2:7][CH3:8])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[S:29])[NH:28][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:31]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Agent: S
Solvent: CCO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Reaction time: 16 h

Procedure:
3-Methylbutylamine (10.7 cc) is added to a solution of 10-(1-diethylamino-2-propyl)-2-phenothiazinecarbothioamide acid fumarate, L series (3 g), in absolute ethanol (45 cc) and this solution is saturated with hydrogen sulphide. The mixture is then brought to a temperature in the region of 105° C. for 16 hours and concentrated to dryness under reduced pressure (30 mm Hg; 4 pKa). The residual orange-colored oil is purified by chromatography on a column (height: 35 cm; diameter: 3 cm) of silica gel (0.2-0.063 mm), eluting with mixture (400 cc) of ethyl acetate and cyclohexane (70:30 by volume) and collecting 30-cc fractions. Fractions 7 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 pKa) at 50° C. to give 10-(1-diethylamino-2-propyl)-N-(3-methyl-1-butyl)-2-phenothiazinecarbothioamide, L series (3.1 g), in the form of an orange-colored oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH2:5][CH3:6].[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1.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>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:11]([NH:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1)=[O:13])[CH2:5][CH3:6]
Reactant: Cn1ccc(N)n1
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 77.5 %

Procedure:
To a solution of 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoic acid (4.75 g, 14.4 mmol) and 3-amino-1-methyl-1H-pyrazole (2.04 g, 21 mmol) in DMF (25 mL) was added HATU (8.53 g, 22.4 mmol) then DIPEA (7.0 mL, 40 mmol) and the resulting mixture was stirred for 16 hours. The mixture was partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with 1N citric acid (30 mL), water (30 mL), saturated sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL) then dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with 50% ethyl acetate in isohexane, to give the title compound as a colourless oil (4.57 g).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:17][C:18]1[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH2:27]([O:26][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)C(C)(C)c1ccc(O)cc1
Product: CCOC(=O)c1ccccc1COc1ccc(C(C)(C)C(=O)OCC)cc1

Procedure:
Reaction of ethyl α,α-dimethyl-p-hydroxyphenylacetate with ethyl α-bromo-o-toluate as described in Example 1b provides ethyl 4-(2-ethoxycarbonylbenzyloxy)-α,α-dimethylphenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:6]=2[CH:16]=1
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
Acylation of 5-chloro-2-phenylbenzofuran with anisoyl chloride was accomplished as described in the procedure of Example 10 to give 5-chloro-2-phenyl-3-(4'-methoxybenzoyl)benzofuran which was then demethylated and the product treated with epichlorohydrin as described above. Opening of the epoxide ring with isopropylamine as previously described gave the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:22][CH2:23][C:24]1[C:25]([CH2:30]Cl)=[CH:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][Cl:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccccc1CCl
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a cooled solution of 4-tert-butyl-2-(5-hydroxybenzofuran-2-yl)thiazole (0.8 g) in tetrahydrofuran (16 ml), sodium hydride ((60% in mineral oil) 0.152 g) was added below 10° C. After being stirred for 30 minutes, α,α'-dichloroxylene (2.05 g) was added to the mixture. After subsequently being stirred at ambient temperature for 30 minutes, the mixture was refluxed for 9.5 hours. After the solvent was removed under reduced pressure, the residue was subjected to column chromatography on silica gel (25 g) and eluted with a mixture of n-hexane and toluene (1:1). The fractions containing object compound were combined and concentrated under reduced pressure to give an oil of 4-tert-butyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (0.9 g).
Reaction SMILES: BrCC(N1C[CH2:9][N:8]([C:11](=O)[C:12]2[CH:17]=[C:16](C)[CH:15]=[C:14](C)[CH:13]=2)[CH2:7][CH:6]1[C:21]1[CH:26]=[CH:25]C(Cl)=C(Cl)C=1)=O.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C([O-])(O)=[O:44].[Na+]>C1COCC1>[CH2:11]([N:8]1[CH2:7][CH2:6][C:21](=[O:44])[CH:26]([CH3:25])[CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: O=C([O-])O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: -23 °C
Reaction time: 2 h

Procedure:
To a cooled solution of compound 3 from step 1 (8.65 g, 34.8 mmol) in THF (100 mL) at -23° C. was added 27.8mL of 1M L-selectride (27.8 mmol). The mixture was stirred at -23° C. for 2 h. After warming to RT, the reaction mixture was added to sat. NaHCO3 and partitioned. The aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine (50 mL), dried with MgSO4 and concentrated. The product was purified by silica gel chromatography eluting with 6:1 to 3:1 hexane-EtOAc to give 2.47 g of compound 4 and 2.75 g of recovered starting material.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=CC=1)([O-])=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:36]=1>O1CCCC1>[N+:22]([C:18]1[CH:17]=[C:16]([C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)NCCCCc1cccnc1
Yield: 84.3 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.950 g) and 3-pyridinebutanamine (0.34 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was crystallized from ethyl acetate-hexane to yield 0.82 g of (E)-5,5-bis(3-nitrophenyl)-N-[4-(3-pyridinyl)butyl)-2,4-pentadienamide mp 158°-159° C. Anal. Calculated for : C26H24N4O5 : C, 66.09; H, 5.12; N, 11.86 Found: C, 65.91; H, 5.34; N, 11.82.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-:33][Si](C)(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([NH2:33])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Product: Cn1c(-c2ccccn2)nc(-c2ccc(N)cc2)c1Sc1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
2-{4-(4-Bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 300 mg, 0.57 mmol), Pd(dba)2 (19 mg, 0.03 mmol), and biphenyl-PCy2 (11.5 mg, 0.03 mmol) were charged into a flask that was flushed with nitrogen. Toluene (2.2 mL) was added, followed by LiHMDS (1M in PhMe, 2 mL, 2 mmol). After heating at 75° C. overnight, the reaction was quenched with aqueous NH4Cl and diluted with EtOAc. The organic layer was washed with water and brine. The volatiles were evaporated and the residue was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CD3OD): 8.58 (broads, 1H), 8.18 (broad s, 1H), 7.98 (t, 1H), 8.27 (d, 2H), 7.68 (d, 2H), 7.46 (broad s, 7.07 (d, 2H), 6.78 (d, 2H), 3.98 (s, 3H). LCMS: m/z 393 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1
Reaction time: 0.03 h

Procedure:
The phenyl bromide (139)(100 mg, 0.25 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification. For the ester: LC/MS tr 1.62 min; MS(ES+) m/z 412 (M+H)
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.[Br:28]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:28][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[N:16]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[N:5]=3)[O:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CO)cc4)no3)cc2C)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CBr)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mechanically stirred solution of (4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanol (Example 110, 1.50 g, 4.16 mmol) in dichloromethane (60 mL) was added tetrabromomethane (1.66 g, 5.00 mmol) and triphenyl-phosphane (1.64 g, 6.24 mmol). The mixture was stirred at rt for 5 h and then partly concentrated under reduced pressure. The solid formed was filtered off and dried under reduced pressure to yield the title compound. The filtrate was concentrated and purified by MPLC (silica, cyclohexane/ethyl acetate 9:1) to afford another batch of the title compound (combined 1.55 g, 88%): 1H-NMR (400 MHz, DMSO-d6) δ 8.07 (d, 2H), 7.66 (d, 2H), 7.17 (d, 2H), 7.12 (d, 2H), 6.90 (s, 1H), 5.42 (s, 2H), 4.70 (s, 2H), 2.32 (s, 3H). 2.28 (s, 3H); ES-MS m/z 423 (MH)+; HPLC RT (Method D) 3.05 min.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[C:23]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2cccc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 6.5 mL of 3-chlorobenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 122°-124° C.). 1H NMR (CDCl3) δ 2.83 (dd, 1 H), 2.96 (dd, 1 H), 3.60 (dd, 2 H), 5.68 .(dd, 1 H), 7.25-7.42 (m, 4 H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:16]([CH:17]([NH:21][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:13])[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:14]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OCCO2

Procedure:
Prepared in a similar manner to example 4 using 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid and heptan-4-amine. MS (M+H, 278.2).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)[S:6][C:7]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1)=[O:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1.CCOCC>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:1]([OH:2])[C:3]2[N:4]=[C:5]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=3)[S:6][C:7]=2[C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)=[CH:34][CH:33]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(=O)Nc1cc(-c2nc(C=O)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(C(O)c3ccc(Cl)cc3)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
N-{4-[4-formyl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.250 g, 0.564 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled at 0° C. 1.0 M 4-Chlorophenylmagnesium bromide in ether (1.41 mL, 1.41 mmol) was added and the solution was stirred at 0° C. for 30 minutes. The reaction was quenched by the addition of MeOH (10 mL), and was evaporated under reduced pressure. The residue was purified using column chromatography (20 to 100% ethyl acetate in hexane) to give the title compound (0.150 g, 48%). LCMS: (FA) ES+, 556, 558. 1H NMR (400 MHz, CDCl3) δ: 8.69 (s, 1H), 8.34 (d, J=5.23 Hz, 1H), 8.21 (s, 1H), 7.65 (dd, J=5.23, 1.55 Hz, 1H), 7.31 (d, J=8.28 Hz, 2H), 7.21-7.16 (m, 3H), 7.07 (d, J=1.31 Hz, 1H), 6.26-6.15 (m, 1H), 5.30 (s, 1H), 3.46-3.36 (m, 2H), 2.24 (s, 3H), 0.94-0.84 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][NH2:22]>[Pd].CO>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][NH:22][CH:2]1[CH2:5][CH:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)CC1CC(=O)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CC(NCc2ccc(OC)cc2OC)C1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To methyl 2-(3-oxocyclobutyl)acetate (426 mg) and (2,4-dimethoxyphenyl)methanamine (501 mg) in a flask was added MeOH (20 mL) and Pd/C (10%, 100 mg). The reaction mixture was stirred under hydrogen atmosphere for overnight. Catalyst was removed by filtration through the Celite pad. Removal of the solvent afforded the crude product (850 mg) which was used directly to the next step without further purification.