Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1[CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[CH2:23][CH2:24][C:25]#[CH:26]>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:18]2[CH2:17][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:19]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCCN1CCNCC1c1ccccn1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C#CCCN2CCN(c3ccccn3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-bromo-5-nitropyridine (3.11 g, 0.015 mol) and the alkyne prepared in Step (a) (3.0 g, 0.014 mol) in 5.8 mL of triethylamine and 60 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.2 g (0.0003 mol) of bis(triphenylphosphine)palladium chloride and 0.05 g (0.0003 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 30 mL of dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/ 99% dichloromethane) to give the title compound as a brown solid; mp 126°-126.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(=O)N2
Yield: 62.9 %

Procedure:
6-Hydroxy-3,4-dihydroquinolin-2(1H)-one (18.38 mmol, 3.00 g) was treated in the presence of K2CO3 (22.98 mmol, 3.18 g) with methyl iodide (22.98 mmol, 3.26 g) in N,N-dimethylformamide (30 ml) at room temperature for 24 hours, resulting in 2.05 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[I:21]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[C:18]([I:21])[CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: Nc1nnc(-c2ccc(O)cc2)c(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1nnc(-c2ccc(O)c(I)c2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (vide supra; 140 mg, 0.530 mmol) was reacted with AcOH (2 mL) and 1-iodopyrrolidine-2,5-dione (119 mg, 0.530 mmol). The mixture was stirred at room temperature for 1 hour then concentrated in vacuo and purified by column chromatography (35 mg, 32%).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH2:15][N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:8]=1>O1CCCC1>[C:29]([O:28][C:26](=[O:27])[N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[CH2:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][OH:4])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)Cc1ccc(OC)c(CN(CCc2ccccc2F)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCO)cc1CN(CCc1ccccc1F)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 106.9 %

Procedure:
2M Lithium borohydride in tetrahydrofuran (1.5 mL) was added to a solution of [3-({tert-butoxycarbonyl-[2-(2-fluoro-phenyl)-ethyl]-amino}-methyl)-4-methoxy-phenyl]-acetic acid methyl ester (0.25 g) in tetrahydrofuran (5 mL), at 0° C. under nitrogen. After 4 hours, the reaction was quenched by the addition of ethyl acetate. The reaction was diluted with ethyl acetate and extracted sequentially twice with saturated aqueous sodium bicarbonate solution, brine, dried (magnesium sulfate) and evaporated. Purification on silica, eluting with a gradient of methanol (0% to 1%) in dichloromethane, to give the subtitle compound as an oil (0.25 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][N:5]1[C@H:9]2[C@H:10]3[N:15]4[C@H:16]([O:17][CH2:18][C@H:14]4[C:13]4[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:12]=4[CH2:11]3)[C@@H:6]1[CH2:7][C@H:8]2[C:25]([O-:27])=[O:26]>P([O-])([O-])([O-])=O>[CH3:4][N:5]1[CH:9]2[CH:10]3[N:15]([CH:16]([C:1]#[N:2])[CH:6]1[CH2:7][CH:8]2[C:25]([OH:27])=[O:26])[CH:14]([CH2:18][OH:17])[C:13]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:12]=1[CH2:11]3
Reactant: COc1cccc2c1[C@@H]1CO[C@@H]3[C@@H]4C[C@@H](C(=O)[O-])[C@H]([C@H](C2)N31)N4C
Reactant: [C-]#N
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COc1cccc2c1C(CO)N1C(C#N)C3CC(C(=O)O)C(C1C2)N3C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At first, 2.0 g of sodium cyanide is dissolved in 30 ml of 0.1M phosphate buffer (pH 7.4) and 1 g of crude DC-52-(containing 0.6 g of DC-52) is added thereto. The mixture is stirred at room temperature for 1.5 hours. The reaction mixture is passed through a column containing 200 ml of Diaion HP-20SS (made by Mitsubishi Chemical Industries Co., Ltd.), and the column is developed and eluted with 1 l of water (fraction Nos. 1-160; 6 ml each), and then with 1% acetone-99% water (by volume; fraction Nos. 161-224, 6 ml each). Fraction Nos. 125-165 and fraction Nos. 166-199 are joined together separately, and concentrated under reduced pressure, followed by freeze-drying to obtain 161 mg of fraction A and 179 mg of fraction B.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([CH2:29][CH3:30])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:7]=1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:5])[CH3:2].[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:42]3[CH:43]=[CH:44][C:39]([C:38]([F:49])([F:48])[F:37])=[CH:40][CH:41]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([CH2:29][CH3:30])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:7]=1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc2c(c1)c1ccccc1n2CC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc2c(c1)c1ccccc1n2CC

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-1-(9-ethylcarbazol-3-yl)-5-hydroxyindole-3-carboxylic acid ethyl ester (170 mg, 0.35 mmol, see step (b) Example 14) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol. Yield 130 mg (60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=O.[N:12]#[C:13][NH2:14]>C(O)(=O)C.Cl>[NH2:14][C:13]1[N:12]=[N+:9]([O-:11])[C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CN
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc2ccc(O)cc2[n+]([O-])n1
Temperature: 100 °C
Reaction time: 0.12 h
Yield: 51.6 %

Procedure:
7.7 g (0.05 mol) of 4-amino-3-nitrophenol was dissolved in 20 mL of glacial acetic acid and the resulting bright-red solution was heated to approximately 100° C. in 500 mL round-bottom flask equipped with a long condenser. To this solution was added a solution of 16.81 g (8.0 equivalent, 0.4 mol) of cyanamide in 20 mL of concentrated hydrochloric acid. In approximately 5-10 min the reaction mixture started to boil vigorously, so the heating was removed and it was stirred without heating until boiling subsided. Then the heating was reapplied and the reaction mixture was refluxed for 48 hrs. Then 150 mL of 30% NaOH was added and the resulting dark-reddish solution was refluxed for additional 3 hrs. Then it was cooled down to room temperature and dark-red slurry was formed. The red precipitate was filtered, re-dissolved in 200 mL of water and 1N HCl was added in portions with stirring until pH reached 5-4. The solution changed color from dark-red into light-yellow and a light-yellow fine precipitate was formed. The precipitate was filtered, washed twice with 50 mL of water, twice with 50 mL of acetonitrile and finally twice with 50 mL of diethyl ether and dried in vacuum to give 4.6 g of a bright-yellow solid. Yield: 51.7%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Cl:10])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].[O-]CC.[Na+]>C(O)C>[Cl:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Cl:10])=[CH:6][CH:7]=1
Reactant: ClCCCCCBr
Reactant: Oc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: ClCCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1

Procedure:
Combine (E and Z)-1-[(4-hydroxy)phenyl]-1,2-diphenyl-2-chloro-ethylene (2.3 g, 7.5 mmol) and 5-bromo-1-chloropentane (2.78 g, 15.0 mmol) in ethanol (40 mL). Add a solution of sodium ethoxide in ethanol (11.12 mL, 0.67M, 7.5 mmol). Heat to reflux under an inert atmosphere. After 24 hours concentrate in vacuo. Chromatograph on silica gel eluting with 1/7 ethyl acetate/hexane. Concentration of the product containing fractions to give the title compound which is taken on to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20](I)[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:34]3[CH:35]=[CH:36][C:37]([O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:32]([O:31][CH3:30])[CH:33]=3)[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nc([C@H]3CC[C@H](CNC(=O)OCc4ccccc4)CC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-[4-(8-amino-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (80.0 mg, 0.0002 mol), 2-(3-methoxy-4-phenoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (67.0 mg, 0.0002 mol), potassium carbonate (0.076 g, 0.00055 mol) in DME (3.00 mL) and H2O (0.50 mL) was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride DCM (9.0 mg, 0.00001 mol). The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. Solvent was removed under reduced pressure and the product was purified by flash chromatography (2% MeOH in DCM). MS (ES+): m/z: 577.95 [MH+]. HPLC: tR=2.72 min (OpenLynx: polar—5 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16](Br)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:16]3[CH:15]=[C:14]([CH:10]4[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9]4)[N:22]4[C:17]=3[C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A stirred, degassed mixture of 7-(4-benzylmorpholin-2-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (701 mg, 1.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (350 mg, 0.30 mmol) in DMF (2 mL) was stirred under N2 for 30 min at 80 C, then treated with 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (754 mg, 2.26 mmol), K3PO4 (765 mg, 3.61 mmol) and H2O (165 mg, 9 mmol). The reaction was heated (100° C.) for 1 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and MeOH (2.5 mL) and the mixture filtered through a long silica plug. After removal of the volatiles in vacuo, the residue was purified by ISCO® chromatography using a gradient of 1% to 10% MeOH in CH2Cl2 to afford 401 mg (43%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H, J=9 Hz), 7.57 (s, 1 H), 7.21-7.38 (m, 5 H), 7:12 (d, 1 H, J=9 Hz), 6.73 (s, 1 H), 5.65 (s, 2 H), 5.10 (dd, 1H, J=10, 2Hz), 3.88 (d, 1H, J=12 Hz), 3.69 (dd, 1H, J=10, 9 Hz), 3.57 (d, 1H, J=13 Hz), 3.51 (d, 1H, J=13 Hz), 2.97 (d, 1H, J=12 Hz), 2.17-2.28 (m, 1H), 2.67 (d, 1H, J=11 Hz), 2.36 (t, 1H, J=11 Hz); ES-MS m/z 516.3 [M+H]+, HPLC RT (min) 2.80.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:3]=1.[NH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[N:27]1([NH:26][C:8]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:5]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH:6]=2)=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NN1CCCCC1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a portion of the methylene chloride (1 mL) solution of 2-(chloro)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonyl chloride (0.068 mmol) from Step B was added a solution of 1-aminopiperidine (0.010 mL, 0.088 mmol) and TEA (0.014 mL, 0.10 mmol) in methylene chloride (1 mL). The reaction was stirred at rt for 16 h and was then evaporated. The residue was purified by preparative TLC (40% ethyl acetate in hexanes) to yield N-(piperidin-1-yl)-2-(chloro)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxamide. HPLC/MS: 494 (M+1), 496 (M+3); Rt=3.97 min
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[F:9][CH:10]([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>>[F:9][CH:10]([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: Cc1ccccc1I
Product: Cc1ccccc1C#Cc1ccc(OC(F)F)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 12, step 3 starting from 1-Iodo-2-methyl-benzene (0.15 g, 0.69 mmol), and 1-Difluoromethoxy-4-ethynyl-benzene (0.116 g, 0.69 mmol), and was obtained as a light brown oil, (0.141 g, 79%), identified by NMR and mass spectral analyses. MS (EI+): 258 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:4]1[CH:3]=[C:2]([C:30]2[O:29][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (150 mg, 0.31 mmol) and 2-furanylboronic acid (69 mg, 0.62 mmol) in DME (3 ml) was added potassium tert-butoxide (312 mg, 2.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then purified using an SCX cartridge followed by mass directed autoprep HPLC to afford the title compound (E308). MS (ES+) m/e 476/478 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(I)cn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
Under an N2 atmosphere 21.7 mL 2 M Na2CO3 solution and 250 mg (0.22 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 8.0 g (21.7 mmol) 5-iodo-pyridin-2-ol and 3.81 g (23.9 mmol) 4-chlorophenyl-boric acid in 120 mL 1,4-dioxane and 30 mL dry MeOH and the reaction mixture is stirred for 19 h at 110° C. The mixture is evaporated down i. vac., the residue is combined with water, the precipitate is filtered off, washed with water and dried at 40° C. in the circulating air dryer until a constant weight is obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1[N:28]([CH3:29])[N:27]=[C:26]([C:30]#[N:31])[CH:25]=1>ClCCCl.ClC(Cl)C>[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[C:26]([C:30]#[N:31])=[N:27][N:28]([CH3:29])[C:24]=1[C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:9]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Cn1nc(C#N)cc1-c1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: Cn1nc(C#N)c(C(=O)c2ccc(F)cc2Cl)c1-c1c(F)cccc1F
Temperature: 180 °C

Procedure:
To a mixture of aluminum chloride (0.18 g, 1.36 mmol) in 1,2-dichloroethane (2 mL) was added a mixture of 2-chloro-4-fluorobenzoyl chloride (0.26 g, 1.36 mmol) and 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carbonitrile (i.e. the product of Step B) (0.15 g, 0.68 mmol) in dichloroethane (1 mL). The reaction mixture was heated at 180° C. in a Biotage Initiator™ microwave apparatus for 30 minutes. The resulting mixture was poured directly onto a Varian Bond Elute SIC) column and eluted with methylene chloride followed by 30% ethyl acetate in hexanes to provide the title compound, a compound of the present invention, as a solid (0.07 g).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])=[CH:5][N:4]=1.[CH3:18][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:29][CH2:30][NH2:31])=[CH:24][CH:23]=1)[CH3:20]>N1C=CC=CC=1>[CH3:20][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:29][CH2:30][NH:31][C:3]2[NH:8][C:7](=[O:9])[C:6]([CH:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])=[CH:5][N:4]=2)=[CH:24][CH:23]=1)[CH3:18]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSc1ncc(C(C)c2cccnc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(c1cccnc1)c1cnc(NCCSCc2ccc(CN(C)C)o2)[nH]c1=O

Procedure:
Equimolar amounts of 2-methylthio-5-[1-(3-pyridyl)ethyl]-4-pyrimidone and 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine in pyridine are boiled under reflux for 48 hours and evaporated to dryness. The residue is purified to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(1-(3-pyridyl)ethyl)-4-pyrimidone.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[N:16]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:12]([C:9]3[CH:8]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:11][CH:10]=3)[S:13][CH:14]=2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
Methyl 2-bromo-5-(4-(3,4-dichlorophenyl)thiazol-2-yl)benzoate (177 mg, 0.4 mmol) was taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was dried (MgSO4), filtered, and evaporated. Dioxane (2 mL) was added, along with tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol), 3 M aqueous K2CO3 (267 μL, 0.8 mmol) and phenylboronic acid (available from ASDI Incorporated; 97.5 mg, 0.8 mmol). The vial was evacuated and filled with nitrogen, and then the mixture was heated at 100° C. for 20 h. The mixture was purified on an ISCO Combiflash system, using 0-15% ethyl acetate/hexanes as eluent. Fractions homogeneous for the product were evaporated, and the resulting material was dissolved in THF (2 mL). 1 M aqueous NaOH (2 mL) was added and the mixture was heated at 60° C. overnight. 1 M aqueous HCl was added to bring the pH to approximately 2, and the mixture was extracted 4 times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, evaporated, and purified by preparative HPLC, using the conditions outlined in General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (33 mg, 20%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 8.32 (d, J=1.6 Hz, 2H), 8.20 (dd, J=8.2, 2.0 Hz, 1H), 8.07 (dd, J=8.2, 2.0 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.35-7.48 (m, 5H).