Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[N:24]=[C:23]2[N:25]([CH3:39])[C:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][C:27]=3[C:22]2=[CH:21][CH:20]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].[ClH:57]>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:57].[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[N:24]=[C:23]3[N:25]([CH3:39])[C:26]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[C:22]3=[CH:21][CH:20]=2)[C:8](=[O:12])[CH:7]=1
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5F)cc4=O)nc31)CNCC2
Temperature: 135 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (116 mg, 0.487 mmol), tert-butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (196 mg, 0.536 mmol), CuI (111 mg, 0.584 mmol), 8-hydroxyquinoline (14 mg, 0.097 mmol) and Cs2CO3 (175 mg, 0.536 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 20 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH)) afforded a clear wax. 2 N HCl in Et2O (100 mL) was added to a solution of the clear wax in CH2Cl2 (10 mL) under N2, and the resulting suspension was stirred at 25° C. overnight. The suspension was filtered under N2, and the solid was washed with Et2O. The solid was put in a vacuum oven at 40° C. for 16 h to afford 119 mg (58%) of the title compound as a white solid: mp 206-210° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 2H), 8.07 (d, J=8.5 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.67 (dd, J=15.0, 8.5 Hz, 1H), 7.40-7.33 (m, 2H), 7.18 (ddd, J=8.5, 8.5, 2.0 Hz, 1H), 6.15 (dd, J=8.5, 2.5 Hz, 1H), 6.07 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.37 (br s, 2H), 3.72 (s, 3H), 3.58-3.52 (m, 2H), 3.14 (t, J=5.5 Hz, 2H); ESI MS m/z 423 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[CH:8][CH:7]=1.[CH3:28][C:29](C)([O-])C.[K+].ICC>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH2:28][CH3:29])[C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(NCc1cccc(-c2ccc(C3OCCO3)cc2)c1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCN(Cc1cccc(-c2ccc(C3OCCO3)cc2)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
600 mg (1.7 mmol) of N-(4′-[1,3]dioxolan-2-ylbiphenyl-3-ylmethyl)benzamide, 5 ml of THF and 206 mg (1.85 mmol) of potassium tert-butoxide are introduced into a three-necked flask under nitrogen. 300 μl 15 (3.7 mmol) of iodoethane are added dropwise. The reaction mixture is stirred at room temperature for 3 hours, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). 400 mg (64%) of the desired product are obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[CH:19][C:20]2[CH:24]=[C:23]([F:25])[S:22][C:21]=2[CH:26]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[CH:19][C:20]4[CH:24]=[C:23]([F:25])[S:22][C:21]=4[CH:26]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Fc1cc2ccc(Br)cc2s1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3cc(F)sc3c2)CCN1c1cnccc1C1CC1
Yield: 4.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 150 mg, 0.738 mmol) was reacted with 6-Bromo-2-fluoro-benzo[b]thiophene (I-25d: 170.6 mg, 0.738 mmol), copper iodide (14.2, 0.071 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (10.2 mg, 0.071 mmol), potassium phosphate (469.9 mg, 2.21 mmol) and 1,4-dioxane (5 mL) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3), followed by preparative HPLC afforded 11.6 mg of the product (4% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N:20]([O-])=O.[Na+].[ClH:24]>O>[ClH:24].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)[NH2:20]
Reactant: Nc1ccc(CS(=O)(=O)NCc2ccccc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(CS(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A thick suspension of the product of stage (b) (3.68 g) in conc. hydrochloric acid (50 ml) was stirred at -5° whilst a solution of sodium nitrite (0.9 g) in water (10 ml) was added dropwise so that temperature did not exceed 0°. Stirring was continued for 30 min. The resulting suspension was filtered to remove starting material and the filtrate added in a few portions to a solution of stannous chloride dihydrate (13.5 g) in hydrochloric acid (15 ml) at -20° and warmed to ambient temperature. The solid that separated was filtered off and recrystallised from hot methanol (100 ml) to give the title compound as white plates (0.39 g) m.p. 192°-193°. The mother liquors afforded a second crop (0.52 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][N:1]2[CH3:16])=[CH:5][CH:6]=1)=[O:11]
Reactant: CI
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2ccn(C)c2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 6-indolecarboxylate (5 g) in dry dimethylformamide (30 ml) cooled to 5° C., sodium hydride (60% dispersion in oil, 1.49 g) was added portionwise. The reaction mixture was stirred at 5° C. for 0.5 hour, then a solution of methyliodide (12.18 g) in dry dimethylformamide (10 ml) was added dropwise. After 2 hours, the reaction mixture was diluted with water and the product obtained, after cooling and filtration.
Reaction SMILES: C[N:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:5]=[N:4][CH:3]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.O(C1C=CN=C(C2C=CC(C(F)(F)F)=CC=2)N=1)C1C=CC=CC=1>>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:2]=1
Reactant: CN1C(Oc2cccc(C(F)(F)F)c2)=CC=NC1c1ccc(C(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(-c2nccc(Oc3ccccc3)n2)cc1
Product: FC(F)(F)c1ccc(-c2nccc(Oc3cccc(C(F)(F)F)c3)n2)cc1

Procedure:
Analogously are prepared 3-methyl-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine, 5-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine, 4-phenoxy-2-(4-trifluoromethylphenyl)pyrimidine
Reaction SMILES: CO.[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH:28]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.C=O.[BH3-][C:38]#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]4)[CH:28]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: [BH3-]C#N
Reactant: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(C6CCNCC6)c5)nn34)c(F)cc21
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cnn(C)c6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To abs. MeOH (2 mL) stirred at rt were added 3-(6-fluoro-1-methyl-1H-indazol-5-ylmethyl)-6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 282, 79 mg, 0.184 mmol), formaldehyde (0.068 mL, 0.918 mmol) and NaBH3CN (58 mg, 0.918 mmol). The RM was then brought to pH 5-6 with addition of acetic acid and stirred at rt for 2 h. It was then taken into EtOAc and washed with saturated NaHCO3 sol. The organic layer was then washed with brine, dried on Na2SO4, filtered and evaporated. The residue was then purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound (tR 0.85 min (conditions 2), MH+=445).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Cc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccnc(OC2CCCCC(NC(=O)N3CCN(c4ccnc5cc(Cl)ccc45)CC3)C2)c1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-bromo-4-picoline are reacted to give the product. LC-MS 494 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.98 (d, 1H), 7.85 (d, 1H), 7.45 (d, 1H), 6.85 (d, 1H), 6.68 (d, 1H), 6.56 (s, 1H), 6.20 (d, 1H), 5.16 (m, 1H), 4.10 (m, 1H), 3.78 (m, 4H), 3.25 (m, 4H), 2.25 (s, 3H), 2.10 (m, 3H), 1.85 (m, 2H), 1.30–1.73 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C@H:10]([OH:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C@H:10]([O:28][CH2:34][CH2:33][O:32][CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)[C@H](O)C1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-trans-N-tert-butoxycarbonyl-3-hydroxy-4-(4-phenoxyphenoxy)-piperidine (1.47 g, 3.8 mmol) in dry DMF (30 ml) was added sodium hydride (300 mg 60% suspension in mineral oil, 4.2 mmol). After 1 h, 2-bromoethyl methyl ether (1.7 g, 7.6 mmol) was added. After 6 days water was added and the product was extracted with ethyl acetate (2×30 ml). After drying and evaporation the crude product was obtained as an oil.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH:3]=[O:4].P([O-])(O)(O)=[O:23].[Na+].CC(CC)=C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][C@@H:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[C:3]([OH:23])=[O:4]
Reactant: O=P([O-])(O)O
Reactant: C[C@H](C=O)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C=C(C)CC
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)O

Procedure:
(S)-2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionaldehyde (1.99 g; 6.6 mmol, prepared in accordance with Example 66) is suspended in a mixture of tert-butanol (48 mL) and water (12 mL); sodium dihydrogenphosphate (1.59 g; 13.3 mmol) and 2-methyl-butene (13.94 g; 199 mmol) are added and the resulting mixture is stirred until a solution is obtained. Sodium chlorite (1.12 g; 9.9 mmol) is added and the reaction is stirred at room temperature for one hour. The precipitate formed is filtered, is washed with water and is dried at 40° C. under 3 mbar. Aqueous sat ammonium chloride (50 mL) is added to the filtrate which is then extracted with dichloromethane (2×50 mL). The combined organic layers are washed with brine (50 mL) and concentrated under reduced pressure. The residue obtained is dried at 40° C. under 3 mbar. The enantiopure product is obtained as colourless solid (1.3 g; 4.1 mmol).
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[C:23]([O:27][C:28](=[O:34])[NH:29][C:30](=[O:33])[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[C:23]([O:27][C:28](=[O:34])[N:29]([C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)[C:30](=[O:33])[CH2:31][CH3:32])([CH3:25])([CH3:24])[CH3:26]
Reactant: CCC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reaction time: 1 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (1.00 g, 2.92 mmol), propionyl-carbamic acid tert-butyl ester (Intermediate W) (0.55 g, 3.21 mmol) and triphenylphosphine (0.115 g, 0.44 mmol) are placed under an inert atmosphere of Argon. THF (10 ml) is added followed by tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.15 mmol). The reaction mixture is stirred at 50° for 1 hour. The solvent is removed in vacuo and purification by chromatography on silica eluting with EtOAc/hexane (1:4) affords the title product. 1H nmr (CDCl3, 400 MHz); 8.70 (s, 1H), 6.15 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 5.60 (m, 1H), 3.15 (m, 1H), 2.75 (q, 2H), 2.10 (m, 1H), 1.55 (s, 9H), 1.15 (t, 3H), MS (ES+) m/e 426 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C>ClCCl>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]2[CH:25]=[CH:11][CH:12]=[C:13]([C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:23]=2)=[CH:4][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Into a 500 mL, 3-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 24.00 g (200.0 mMol) of 1-ethynyl-4-fluorobenzene (see examples A1 or A2), 55.82 g (200.0 mMol) of 3-bromo-4′-fluorobenzophenone (Rieke Metals, Inc.), 3.0 g of tetrakis(triphenylphosphine)palladium[0], and 300 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 3 hr and then cooled to ambient; stirring was continued overnight (approximately 16 hr). The reaction mixture was filtered to remove a white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solids obtained dissolved in dichloromethane. The resulting solution was washed with water (2×100 mL), 2% HCl (2×100 mL), brine, and then dried over sodium sulfate. After removal of the solvent, the product was purified by silica gel column chromatography using hexanes as the elutant. After removal of the solvent, white crystals with a melting point of 127-128° C. were obtained in a yield of 85%.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][C@@H:5]1[CH2:14][C:15]1[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.Cl[CH2:30][C:31]1[S:32][C:33]2[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=2[N:35]=1.O>CN(C=O)C>[F:41][C:37]1[C:38]([F:40])=[CH:39][C:33]2[S:32][C:31]([CH2:30][O:13][C:10]3[CH:11]=[C:12]4[C:7]([CH2:6][CH:5]([CH2:14][C:15]5[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=5)[CH:4]4[OH:3])=[CH:8][CH:9]=3)=[N:35][C:34]=2[CH:36]=1
Reactant: O=S(=O)(Nc1cccc(C[C@H]2Cc3ccc(O)cc3[C@H]2O)c1)C(F)(F)F
Reactant: Fc1cc2nc(CCl)sc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cccc(CC2Cc3ccc(OCc4nc5cc(F)c(F)cc5s4)cc3C2O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 127.4 %

Procedure:
382 mg (9.54 mmol) of sodium hydride, 60% oil dispersion, were added in one portion to a room temperature solution of 1.76 g (4.54 mmol) of the product of Example 56 in 30 mL of anhydrous DMF. After 20 minutes, a room temperature solution of 1.40 g (6.36 mmol) of 2-chloromethyl-5,6-difluorobenzothiazole in 10 mL of anhydrous DMF was added over 15-20 minutes. After stirring 18 hours at room temperature, the reaction mixture was poured into 500 mL H2O, acidified to pH 1, and extracted two times with 300 mL ethyl acetate. The ethyl acetate extracts were combined, washed three times with 150 mL H2O, one time with 100 mL brine, and dried over Na2SO4. Filtration, concentration and drying gave 3.3 g of a brown oil, which was purified by silica gel chromatography (15% to 25% ethyl acetate in CH2Cl2) to afford 1.52 g of the title product as an off-white solid. 59% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.Cl>CC(O)CCC.C(O)(C)C>[ClH:1].[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: N#Cc1cc2c(Nc3ccc4[nH]ccc4c3)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 120 °C
Yield: 96.7 %

Procedure:
A solution of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (80 mg, 0.21 mmol) and 5-aminoindole (33 mg, 0.25 mmol) in 2-pentanol (2.5 ml) containing 6.2N HCl in isopropanol (40 μl) was heated at 120° C. for 3 hours. After cooling, the solid was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-ylamino)quinoline hydrochloride (104 mg, 90%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.C(O)C>C(N(CC)CC)C>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][O:5][CH2:4]2)[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: NCC1(CO)COC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2(CO)COC2)n1
Yield: 32.7 %

Procedure:
A mixture of 3-aminomethyl-3-hydroxymethyloxetane (1.17 g, 0.01 mol), 2-amino-4,6-dichloropyrimidine (1.64 g, 0.01 mol), ethanol (40 ml) and triethylamine (4 ml) was refluxed for one day. The solvent was distilled away under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1, later 10:1) to give colorless prism crystals (0.8 g, 32.8%), m.p. 185-186° C. (acetone).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.[C:23]1([NH:29][C:30]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][N:35]3[CH:49]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([C:37]2[CH:38]=[CH:39][C:34]3[N:35]([CH:49]=[C:32]([C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:31])[N:33]=3)[CH:36]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)n1
Reactant: CC1(C)OB(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cccc(OCc4ccccc4)n3)ccc2n1
Temperature: 110 °C
Yield: 75.4 %

Procedure:
To a solution of 250 mg of 2-benzyloxy-6-bromopyridine in 12 mL of dioxane are added a solution of 1.234 g of caesium carbonate in 3 mL of water, 34.6 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and then 546 mg of N-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide hydrobromide (1:1). The mixture is heated at 110° C. for 2 hours 45 minutes, and then cooled and filtered. The solid is washed with a small amount of methanol and then with dichloromethane and is then taken up in 250 mL of boiling methanol containing 5 mL of trifluoroacetic acid. The insoluble matter is filtered off and washed with methanol and then with dichloromethane and the filtrate is concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a gradient of from 0 to 5% of methanol in dichloromethane. The fractions containing the pure expected product are combined and concentrated to dryness under reduced pressure to give 0.3 g of 6-(6-benzyloxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.