Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([NH:40][C:41](=[O:46])[CH2:42][CH2:43][CH2:44]Cl)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2].[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:46])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC(=O)CCCCl)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCCC3=O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(4-chlorobutyrylamino)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (283 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto is added sodium hydride (18 mg) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution and the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→1:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-oxopyrrolidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 667 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[NH:8][C:9](=[O:11])[CH3:10])=O.[OH-].[Na+]>>[Cl:16][C:14]1[CH:15]=[C:6]2[C:7](=[CH:12][CH:13]=1)[NH:8][C:9](=[O:11])[CH:10]=[C:4]2[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(-c2ccccc2Cl)c2cc(Cl)ccc2[nH]1

Procedure:
In the manner given in Preparation 2, 2'-(o-chlorobenzoyl)-4'-chloroacetanilide was reacted with sodium hydroxide to give 6-chloro-4-(o-chlorophenyl)-2(1H)-quinolone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Ba+2:10].[OH-].[CH3:12][C:13]([CH3:24])([C:15](=[O:23])[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:12][C:13]([CH3:24])([CH3:14])/[C:15](/[O-:23])=[CH:16]/[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22].[CH3:12][C:13]([CH3:24])([CH3:14])/[C:15](/[O-:23])=[CH:16]/[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22].[Ba+2:10]
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Ba+2]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)C(=O)/C=C(\[O-])C(C)(C)C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
37.8 g of barium hydroxide octahydrate (0.12 mole) were placed in a 250 ml round-bottomed flask. 50 ml of 2,2,6,6-tetramethyl-3,5-heptane dione (0.24 mole) were added in drops via a dropping funnel. Then 70 ml of xylene were added. The reaction mixture was then heated to 50° C. by means of an oil bath and stirred at this temperature for 10 hours. Then the oil bath temperature was adjusted to 60° C. and volatile constituents were distilled off under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH3:14]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-3-[2,6-dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COC(=O)CCCCN
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Yield: 69.8 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (500 mg, 2.00 mmol) and 1,1'-carbonyldiimidazole (421 mg, 2.60 mmol) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. After cooling to 0° C., the HCl salt of methyl 5-aminovalerate (787 mg, 4.7 mmol) is added followed by triethylamine (836 μL, 6.0 mmol). The mixture is heated at reflux overnight. The mixture is partitioned between ethyl acetate and 1N HCl. The organic layer is washed with in HCl, saturated NaHCO3, then brine. The organic layer is next dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 1:9 ethyl acetate:hexane to provide 530 mg (70%) of product; mp 82°-84° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1I.[N:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[N:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: OB(O)c1cncnc1
Reactant: N#Cc1nccc(I)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1nccc(-c2cncnc2)c1F
Temperature: 85 °C
Yield: 68.3 %

Procedure:
A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (1.25 g, 5.04 mmol), pyrimidin-5-ylboronic acid (1.249 g, 10.08 mmol), and cesium carbonate (3.45 g, 10.58 mmol) in dioxane (Ratio: 2.0, Volume: 10.18 ml) and water (Ratio: 1.000, Volume: 5.09 ml) was degassed with N2 for 5 min, then PdCl2(dppf)-CH2Cl2Adduct (0.218 g, 0.267 mmol) was added. The solution was heated at 85° C. for 17 hr, and then allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was purified by MPLC (80 g column, 60 mL/min, 30-100% EtOAc in hexanes) to give the title compound (695 mg, 3.44 mmol, 68.2% yield) as a pink solid. ESI MS (M+H)+=201.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=2)=[CH:29][CH:28]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.10 g, 0.39 mmol), potassium carbonate (0.08 g, 0.58 mmol) and 4-chlorophenacyl bromide (0.11 g, 0.47 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 191-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Na].O[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:14]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(C=CO)c1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1

Procedure:
A mixture of 0.83 g. of 3-aminopyrazole and 2.38 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone sodium salt is 25 ml. of glacial acetic acid is refluxed for 15 hours and then concentrated to dryness. The residue is treated as described in Example 1, giving the desired product, m.p. 104°-106° C.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[CH:3]1.[Br:34]N1C(=O)CCC1=O>O1CCOCC1>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[C:3]1[Br:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Solvent: C1COCCO1
Product: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1c(Br)n(C)c3cccc2c13
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g of 1,6-dimethyl-8β-methyl-[3-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-10α-methoxy-ergoline in 75 ml of dioxane were added portionwise 0.9 g of N-bromo-succinimide. After stirring at 40° C. for 2 hours, the solvent was removed and the residue was chromatographed on silica gel eluting with ethylacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[N:20][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 85.8 %

Procedure:
To a solution of [1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methanol (1.39 g, 6.9 mmol, 1.5 equiv.), 5-bromo-3-pyridinol (796 mg, 4.6 mmol) and Ph3P (1.80 g, 6.9 mmol, 1.5 equiv.) in anhydrous THF (35 mL) was added diethyl azodicarboxylate (1.09 mL, 6.9 mmol, 1.5 equiv.) dropwise at 0° C. under Ar protection. After stirring at rt for 120 h, the solvent was removed under reduced pressure. The mixture was diluted with hexane/EtOAc 4:1, and the solution was washed with brine and dried over Na2SO4. After evaporation, the residue was purified by CC (SiO2, hexane/EtOAc 4:1, then 1:1) to afford 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (1.41 g, 86%) as a pale yellow oil, which solidified upon storage at room temperature.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: OCc1ccccc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C

Procedure:
Using the procedure of Example 3, 12.5 ml of 1 M/l of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 1.35 ml of benzyl alcohol were reacted to obtain 1.77 g of benzyl (1R,trans) 2,2-dimethyl-3[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+47.5°±1.5° (c=1% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][N:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=3[C:7](=[O:20])[C:8]1=2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2n1C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of methyl 8-chloro-4,10-dihydro-4,10dioxo-1H-1-benzopyrano-[3,2-b]pyridine-2-carboxylate (7.0 g, 0.023 mole), methyl iodide (14 g, 0.099 mole) and potassium carbonate (3.22 g, 0.023 mole) in dimethyl formamide (100 ml) was stirred at 100° under nitrogen for 3 hrs. The reaction mixture was cooled. The product, which precipitated, was filtered, washed with water and dried. Recrystallization from DMF gave white crystals (6.3 g, 86%), m.p. 276°-278°.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=O)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41]>O1CCCC1>[S:41]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:16]1[C:14]1[CH:13]=[CH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([CH2:19][O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)nc(COCc1ccccc1)n2-c1ccccc1
Reactant: Nc1ccccc1S
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: c1ccc(COCc2nc3cc(-c4nc5ccccc5s4)ccc3n2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 4-neck flask (500 mL) equipped with a reflux condenser was charged with 1-pheny-2-(phenylmethoxy)methylbenzimidazole-5-carboxylic acid (see Working Example 1-1) (4.00 g, 11.16 mmol) and anhydrous tetrahydrofuran (63 mL), and after the addition of oxalyl chloride (1.65 g, 13.0 mmol), this was warmed to 50° C. and stirred for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Anhydrous THF (30 mL) was again added to the greenish-milky white semisolid residue, and after gradual addition of 2-aminobenzenethiol (1.40 g, 11.22 mmol), this was warmed to 50° C. and stirred for 16 hours. After cooling to room temperature, the precipitated crystals were filtered off and washed with saturated aqueous sodium hydrogen carbonate solution (approx. 20 mL), and the precipitated solid was filtered off to yield a mixture of starting material and the title compound (2.43 g, an approx. 1:1 mixture of starting material/title compound, based on 1H-NMR). The filtrate was allowed to stand for a further 16 hours at room temperature and the precipitated crystals were filtered off, washed with saturated aqueous potassium carbonate solution, washed with distilled water, and then dried under reduced pressure with heating to yield the title compound (0.82 g, 16% yield) as a white powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH:13]=[O:14])[CH:2]=1
Reactant: OCC#Cc1cnc2ccccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC#Cc1cnc2ccccc2c1
Yield: 72.6 %

Procedure:
A mixture of 3-(3-quinolinyl)-2-propyn-1-ol (prepared as described in J. Med Chem. 1996, 39, 3179) (360 mg, 1.96 mmol) and the Dess-Martin reagent (1.00 g, 2.36 mmol) in dichloromethane (10 mL) was stirred at RT for 1.5 h. The solution was washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:4 hexane/ethyl acetate) yielded 258 mg (72%) of the title compound. MS 182 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][O:33]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:29]([F:53])[C@H:8]2[O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][OH:33])[C@H:29]([F:53])[C@H:8]2[OH:9])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1
Reactant: F[C@@H]1[C@@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@H]1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
Compound 5 (0.28 g, 0.32 mmol) was dissolved in 10% CF3COOH in CHCl3 (20 mL) and stirred at room temperature in a stoppered flask for 45 min. The reaction mixture was evaporated to dryness in vacuo, the oily residue was purified by flash chromatography (EtOAc/hexane 5:1, 2 cm×15 cm), appropriate fractions pooled, evaporated to dryness and crystallized from MeOH/H2O to give 85 mg (74%) of compound 7 as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([Sn](CCCC)CCCC)[CH2:13][CH2:14]C.O>CN(C=O)C>[CH2:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:13]=[CH2:12]
Reactant: CCCC[Sn](CCCC)CCCC
Reactant: COC(=O)c1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cccc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-bromobenzoate (10.0 g, 46.5 mmol) in DMF (50 mL) was added ally tributyltin (23.1 g, 69.8 mmol) followed by tetrakis(triphenylphoshine) palladium(0) (1.08 g, 0.93 mmol). After stirring 80° C. overnight the reaction mixture was poured into H2O (500 mL), extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired product.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[Cl:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[N:12]=[C:11](NN)[C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>S([O-])([O-])(=O)=O.[Cu+2].C(O)CC>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[Cl:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)[N:12]=[CH:11][C:10]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nc(NN)c(-c2ccccc2)c1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)ncc(-c2ccccc2)c1Cl
Temperature: 100 °C
Yield: 26.1 %

Procedure:
A mixture of 4-chloro-6-hydrazinyl-2-(4-phenoxyphenyl)-5-phenylnicotinonitrile TFA salt (72.6 mg, 0.138 mmol), 1.0 M aqueous copper(II) sulfate (0.276 mL, 0.276 mmol) and 1-propanol (1 mL) was heated to 100° C. in a sealed tube for 2 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated and purified by reverse phase HPLC (isocratic 100% solvent B for 25 min, 40 mL/min, Sunfire 30×250 mm to give 4-chloro-2-(4-phenoxyphenyl)-5-phenylnicotinonitrile TFA salt as white solid (17.9 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (1H, s), 7.87-7.96 (2H, m), 7.46-7.56 (5H, m), 7.37-7.45 (2H, m), 7.20 (1H, t, J=7.40 Hz), 7.09-7.17 (4H, m); MS (ES+) m/z: 383 (M+H); LC retention time: 4.790 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH3:23])=[C:17]([CH:20]=1)[CH:18]=[O:19]>>[CH2:22]([O:21][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:20][C:17]=1[CH:18]=[O:19])[CH3:23]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOc1ccc(Br)cc1C=O
Product: CCOc1ccc(-c2ccc(C#N)cc2)cc1C=O

Procedure:
4-cyanophenylboronic acid (500 mg, 3.40 mmol) is coupled to 5-bromo-2-ethoxybenzaldehyde (780 mg, 3.40 mmol) using Method A to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=O)[CH3:4].[Cl:12][C:13]1[N:18]=C(Cl)C=[C:15]([CH2:20][O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:14]=1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:13]1[N:18]=[C:8]([CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:11])[CH:10]=[C:15]([CH2:20][O:21][CH2:22][C:23]([F:24])([F:26])[F:25])[N:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) suspension of NaH (400 mg, 9.96 mmol, 60% in oil) in THF (8 mL) was slowly added ethylacetoacetate (1.45 mL, 11.5 mmol). The solution was allowed to stir at rt for 10 min then concentrated in vacuo. The residue was rapidly put under N2. A solution of 2,4-dichloro-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine (2.0 g, 7.66 mmol) in toluene (38 mL) was added to the residue. The reaction mixture was stirred under reflux for 16 h. Ammonium chloride (aq, 1 mL) was added and stirred vigorously for 10 min. Silica was added and the mixture was concentrated. The residue was purified on a silica gel cartridge eluting with 0% to 40% EtOAc/heptanes to give ethyl the title compound, 600 mg (28%).