Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=[C:15]([Cl:29])[N:14]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39](Cl)(Cl)=[O:40].C1(C)C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:13]3=[N:14][C:15]([Cl:29])=[N:16][CH:17]=[C:18]3[CH2:19][N:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[C:39]2=[O:40])[CH2:8]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1ccc(NCc2cnc(Cl)nc2N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (±)-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-{2-chloro-5-[(4-ethyl-phenylamino)-methyl]-pyrimidin-4-yl}-amine (270 mg, 0.58 mmol) (from Example 39a supra) and triethylamine (0.25 mL, 1.76 mmol) (Allied Signal) in dichloromethane (6 mL) was cooled to 0° C. A 20% phosgene in toluene solution (0.32 mL, 0.61 mmol) (Fluka) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The mixture was allowed to warm up to room temperature and 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) (Aldrich) was added. The reaction was stirred at room temperature overnight, heated at reflux for 4 hours, and then concentrated to dryness. The yellow residue was purified by flash chromatography (20% ethyl acetate in hexanes) to give (±)-1-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 213 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([CH3:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:24][CH2:23][C@@H:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:21][CH:20]=1)[CH3:32]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: C[C@@H](CN)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 54.6 %

Procedure:
Following General Procedure F, (R)-tert-butyl 2-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (100 mg, 0.20 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 5 mL, 5 mmol) to afford the desired product as a white solid (23 mg, 30%): 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=5.4 Hz, 1H), 7.56 (dd, J=7.9, 1.9 Hz, 1H), 7.47 (dd, J=7.8, 1.9 Hz, 1H), 7.39-7.28 (m, 3H), 6.12 (d, J=5.4 Hz, 1H), 3.36-3.13 (m, 3H), 1.49 (d, J=6.5 Hz, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC 98.4% (AUC), tR=9.19 min.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([Br:18])[C:14]([NH2:15])=[N:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](Cl)=[O:29]>O.ClCCl>[Br:18][C:16]1[C:14]([NH2:15])=[N:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Br:20])[C@@H:6]([OH:19])[CH2:7]1
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: NC[C@H]1O[C@@H](n2cc(Br)c(N)nc2=O)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3Br)O2)cc1Br
Reaction time: 0.17 h

Procedure:
0.84 ml of a 1M sodium hydroxide solution was added to a solution of 256 mg of 5'-amino-5-bromo-2',5'-dideoxycytidine in 3.3 ml of water. A solution of (2-bromophenyl)acetyl chloride (prepared from 185 mg of the acid) in 5 ml of dichloromethane was added, the mixture was shaken vigorously for 10 minutes and then filtered. The solid was recrystallized from 30 ml of ethanol to give 44 mg of 5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxycytidine in the form of a white solid of melting point 164°-167° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.O1CCC[CH2:22]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21

Procedure:
In 100 ml of tetrahydrofuran is suspended 25 g of methyltriphenylphosphonium bromide and 40 ml of 1.6 N-n-butyl lithium helium hexane solution is dropwise added thereto under a nitrogen atmosphere and ice-cooling. After stirring the mixture under ice-cooling for 30 minutes, a solution obtained by dissolving 15 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 250 ml of tetrahydrofuran is dropwise added thereto and the mixture is stirred at room temperature for two hours. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=3:1) to obtain 3.7 g of the desired product as a colorless oily matter.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.O>[F:26][C:12]([F:11])([F:25])[C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:17]1
Reactant: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Reactant: COC(=O)c1cnc(Br)s1
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (2.101 g, 9.46 mmol), (3S)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine (2 g, 8.7 mmol) and DBU (2.7 mL, 17.9 mmol) in dioxane (30 mL) was heated at 80° C. for 24 h. After cooling, the mixture was diluted with water and extracted twice with EtOAc. The combined EtOAc extracts were washed with water, dried and concentrated. Combi-Flash chromatography (120 g, 40-80% EtOAc in hexanes in 20 min, 70 mL/min, 25 mL/fraction) gave the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 7.84 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.51 (s, 1 H), 3.95 (m, 1 H), 3.80-3.65 (m, 6 H), 2.60-2.46 (m, 2 H).
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[OH-:14].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][N:18]=1>C(OC(C)C)(=O)C>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([C:21]([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([CH:3]3[CH2:6][CH2:5][CH2:4]3)[CH2:8][CH2:9]2)=[O:14])=[CH:23][CH:24]=1
Reactant: [OH-]
Reactant: C1CC(N2CCCNCC2)C1
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Product: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A 5-L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and a thermocouple and charged with 1-cyclobutyl-[1,4]diazepane dihydrochloride (110.0 g, 484.6 mmol), 1 N NaOH (1400 mL) and isopropyl acetate (600 mL). A pre-cooled (0° C.). solution of 6-chloronicotinyl chloride (82.7 g, 470.0 mmol) in isopropyl acetate (800 mL) was added via an addition funnel at a rate such that the reaction temperature was maintained between 5-10° C. After the addition was complete, the reaction mixture was warmed to rt and stirred for 2 h (pH of reaction mixture ca. 5.6). The reaction mixture was basified with 2 N NaOH(aq) (to pH ca. 13). The phases were separated and the aqueous layer was extracted with isopropyl acetate (2×300 mL). Some reddish-brown flocculent material was observed during the extractions. The organic layers were pooled and filtered through a pad of diatomaceous earth. The filtrate was washed with satd. aq. NaCl (1×300 mL) and dried over anhydrous Na2SO4. Filtration and removal of the solvent by rotary evaporation under reduced pressure afforded the crude product as a reddish brown oil (126.0 g, 91%). 1H-NMR (400 MHz, CDCl3) δ ppm: 8.45 (m, 1H), 7.74 (m, 1H), 7.39 (m, 1H), 3.86-3.76 (m, 2H), 3.53-3.45 (m, 2H), 3.05-2.80 (m, 1H), 2.70 (br s, 1H), 2.62-2.45 (m 3H), 2.10-1.56 (m, 8H). MS m/z (ESI+): 294.1 (M+H+). HPLC (Method B): Rt=6.06 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:18]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[CH:23][CH:22]=2)=[O:19])[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1>CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[CH:16][CH:17]=2)([OH:19])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(Br)cc1
Solvent: CCOCC
Product: COc1ccc(CC(O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
To the Grignard reagent prepared from 20 g 4-bromoanisole (107 mmol) and 2.43 g Mg turnings (107 mg-atom) in 20 mL Et2O was added 19.25 g dry (P2O5) desoxyanisoin (76 mmol) as a solid in four portions, each followed by a 50 mL wash of Et2O. The mixture was stirred at reflux 17 h, cooled to room temperature, poured onto 200 g ice and 40 mL 1N H2SO4, and filtered into a separatory funnel. 100 mL Et2O was added and the organic layer was washed with 100 mL H2O and saturated NaHCO3 (2×100 mL). The organic layer was dried (MgSO4), filtered, and the Et2O was removed under reduced pressure to give crude 1,1,2-Tris(4-methoxyphenyl)ethanol as an orange oil which crystallized (25 mL EtOH with a trace of NH4OH) as an orange solid, 18.6 g (67% crude yield), mp: 109°-127° C.; NMR δ7.47 to 6.63 (m, 12H, ArH), 3.73 (3 overlapping s, 9H, OCH3), 3.48 (s, 2H, CH2), 2.27 (s, 1H, OH). p-TsOH.H2O (2 g; 10.5 mmol) and 18.5 g of the crude carbinol (50.8 mmol) were dissolved in 50 mL C6H6, heated to reflux 2 h, cooled to room temperature, and poured onto 75 mL 5% NaHCO3. The organic layer was washed with 75 mL 5% NaHCO3. The combined aqueous layers were extracted with 25 mL C6H6. The combined organic layers were washed with 100 mL H2O, dried (Na2SO4), filtered, and the solvent removed to give a dark oil. The oil was purified on 80 g flash SiO2 (gradient elution with petroleum ether-CH2Cl 2) yielding an amber oil which solidified at room temperature to yield 1,1,2-Tris(4-methoxyphenyl)ethene as white cubes (11.3 g, 64%), mp: 100°-101° C. (lit. 100°-101° C.). NMR δ7.29 to 6.55 (m, 13H, ArH and C=CH), 3.78 (s, 3H, geminal ring OCH3), 3.75 (s, 3H, vicinal ring OCH3), 3.69 (s, 3H, central ring OCH3).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CC[CH2:22][CH2:21]1.[C:25]([Li])(C)(C)[CH3:26].[B-](F)(F)(F)F.CC[O+](CC)CC>O>[CH2:21]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH3:26])[CH3:22]
Reactant: C1CCOC1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)OC(C)(C)C

Procedure:
To a mixture of 2.65 g (10 mmole) of Boc-Phe in 50 ml of cold (ca. -78°), dry tetrahydrofuran was added 12 ml (ca. 22 mmole) of 1.9M t-butyllithium. After thirty minutes, the mixture was allowed to warm to -20° and then to react with 4.2 g (22 mmole) of triethyloxonium fluoborate. After thirty minutes, the mixture was allowed to warm to 0° and then poured into water and extracted with dichloromethane. The organic extract was washed sequentially with portions of 5% aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered, and concentrated to dryness. Distillation (ca. 130°-200°) afforded an oil that was further purified by column chromatography on silica gel to give the title compound (4.7 g) as an analytically pure solid, m.p. 58°-61.5°.
Reaction SMILES: [CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide (102 mg, 0.194 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.6 ml, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 52 mg (64%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light yellow powder. MS: (M+H)+=395; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.38 (br. s., 1H), 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (dd, J=9.1, 5.3 Hz, 1H), 8.03 (d, J=9.8 Hz, 1H), 7.69 (dd, J=9.8, 1.9 Hz, 1H), 7.20 (td, J=9.1, 2.3 Hz, 1H), 4.15 (s, 3H), 4.09-4.19 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 0.93 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[CH3:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH3:12][N:13]([CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: OB(O)c1cccc(CBr)c1
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN(Cc1cccc(B(O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
175 a) A suspension of [3-(bromomethyl)phenyl]boronic acid (1.0 g, 4.6 mmol), N-methyl-methanesulfonamide (0.56 g, 5.1 mmol) and potassium carbonate (1.9 g, 14 mmol) in acetone (10 mL) was stirred for 6 hours at room temperature. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. Crude (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid was isolated as a yellow viscous oil (1.08 g, 88%). MS=266 (M+Na)+. 175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+. 175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Cl.N1C=CC=CC=1.Cl>C(OCC)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Oc1cc(O)cc(C=Cc2ccccc2)c1
Temperature: 165 °C

Procedure:
For demethylation, a homogeneous mixture of 54.0 g (0.22 mol) of 3,5-dimethoxystilbene and 40.0 g (0.35 mol) of pyridine hydrochloride is heated at about 165° C. for 3 hours. The cooled, oily reaction mass is then introduced into 1.2 liters of 2N hydrochloric acid and the crude product is isolated by extraction with diethyl ether. Recrystallisation from toluene yields 3,5-dlihydroxystilbene in the form of a pale-yellow powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][C:13]3[N:17]4[N:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][C:13]3[N:17]4[N:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile (0.7 g, 2.1 mmol) in DCM (30 mL) at 0° C. was slowly added m-CPBA (0.4 g, 2.1 mmol). The reaction mixture was stirred at 0° C. for 2 h, then aq Na2SO3 (25 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a yellow solid (0.7 g, 96%). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=9.3 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (d, J=9.3 Hz, 1H), 4.54 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17](Br)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[C:39](F)(F)F.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[C:25]([CH3:39])[CH:26]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(F)c(C(F)(F)F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cn(CCO)c(C3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-Bromo-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (2000.00 mg; 5.34 mmol; 1.00 eq.), 2-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1233.97 mg; 8.02 mmol; 1.50 eq.), mg; 0.53 mmol; 0.10 eq.) and Cs2CO3 (3483 mg, 10.69 mmol) in dioxane 15 ml and water 1.5 ml was purged with argon, added Pd(0)(tBu3)2 (273 mg, 0.53 mmol), stirred at 50° C. for overnight. LC-MS showed desired as major product. Diluted reaction solution with EA 70 ml, washed with brine 30mIX2, separated out organic layer, dried, removed off solvent, got crude product, which was subjected to biotage NASP column (100 g), elated with 40-100% EA in hexane and contained 0.5% TEA in EA, collected title compound 1650 mg, 76%
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:7]([Cl:16])[C:8]2[N:9]([C:11]([CH:14]=O)=[CH:12][N:13]=2)[CH:10]=1)=[O:4].C(O)(=O)C.[CH3:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:7]([Cl:16])[C:8]2[N:9]([C:11]([CH2:14][NH:31][CH3:30])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cn2c(C=O)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)OC)cn12
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A suspension of 7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (58) (25 mg, 0.056 mmol), acetic acid (7 μL, 0.11 mmol), and methylamine (2.0 M solution in THF, 56 μL, 0.11 mmol) was stirred for 0.5 hours. Sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added and the solution allowed to stir overnight. The reaction mixture was concentrated to dryness and flashed (dichloromethane followed by 10:1 dichloromethane/methanol) to provide the desired product as a yellow solid (12 mg, 46%). MS (APCI+) m/z 455, 457, 459 (M+; Cl, Br pattern) detected.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][N+]([O-])=O)=[CH:26][CH:25]=1>CCO.C1(C)C=CC=CC=1>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1

Procedure:
The title compound (1.19 g) was prepared from 1.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 850 μL of benzylamine, and 1.43 g of 1-chloro-4-(2-nitro-vinyl)-benzene, using a 1:1 mixture of EtOH/toluene as the solvent. MS (ESI): exact mass calculated for C20H20Cl2N2, 322.12; m/z found, 323.2 [M+H]+, 325.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.37-7.26 (m, 7H), 7.18-7.16 (m, 3H), 5.15 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([NH:14][O:15][CH3:16])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>CN(C=O)C>[CH3:16][O:15][N:14]([S:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)(=[O:12])=[O:13])[C:23]1[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:18]=1[Cl:17]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CONS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, 3,4-dichloro-N-methoxybenzenesulfonamide (0.56 g (2.19 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3-chloro-4-fluoronitrobenzene (0.35 ml (1.99 mmol)) was added and the mixture was stirred for one hour under cooling with ice and 3 hours at room temperature. Then, water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed twice with water and the ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.56 g (68%) of the title compound as pale yellow-white crystals.