Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[Li+].C[Si]([N-:37][Si](C)(C)C)(C)C>C1COCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Pd]>[CH3:31][O:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH2:37])=[CH:3][C:4]=2[N:10]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Under inert atmosphere, to a solution of 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (0.4 g, 0.94 mmol, see Example 40/Step 1) in anhydrous THF (10 mL) was added SPHOS Pd precatalyst (0.07 g, 0.094 mmol) and LiHMDS (1.0 M solution in Toluene, 1.9 mL, 1.9 mmol) and the contents were heated at 70° C. After 5 h, the reaction mixture was brought back to ambient temperature and quenched with NH4Cl (5 mL). The organic contents were then extracted with EtOAc and the volatiles were then removed under reduced pressure. The residue thus obtained was purified by a flash column chromatography to afford the title compound. H1NMR (CDCl3, 400 MHz): δ 8.38 (s, 1H), 7.29-7.26 (m, 15H), 5.03 (s, 1H), 4.50 (bs, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[C:21]([CH2:32][O:33][CH2:34][CH3:35])[N:22]([CH2:23][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:40]=C=O)=O>ClCCl>[NH2:40][C:14]1[C:13]2[N:20]=[C:21]([CH2:32][O:33][CH2:34][CH3:35])[N:22]([CH2:23][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])([CH3:26])[CH3:25])[C:12]=2[C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 1 h
Yield: 82.3 %

Procedure:
N-[2-(8-Benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (2.29 g, 4.59 mmol) was suspended in dichloromethane (75 mL) and trichloroacetyl isocyanate (0.71 mL, 5.97 mmol) was added dropwise. After stirring for 1 hour, the volatiles were removed under reduced pressure. The resulting orange residue was dissolved in methanol (75 mL) and 6 mL of sodium methoxide (21% in methanol) was added. The reaction was stirred for two additional hours and then the methanol was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water followed by brine. The organic fraction was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange foam. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 10-30% CMA in chloroform to provide 1.88 g of N-[2-(4-amino-8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, mp 90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=O.C([OH:24])C.O1CCCC1>Cl.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]=1[CH:14]=[O:24]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1F)c1c[nH]c2ncccc12
Reactant: CCO
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(F)c(-c2[nH]c3ncccc3c2C=O)c1

Procedure:
Compound 295 (130 mg, 0.46 mmol) was suspended in 6 M hydrochloric acid (10.0 mL) and ethanol (5.0 mL) unser an atmosphere of nitrogen. Tetrahydrofuran (5.0 mL) was added to completely dissolve the compound. Iron (229 mg) was added to the mixture and the reaction was heated to reflux for 2.5 hours. The reaction was cooled and concentrated under reduced pressure. The solid was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic portions were dried with anhydrous magnesium sulfate and adsorbed onto silica and purified by silica gel flash chromatography using 3% methanol:dichloromethane. The appropriate fractions were combined and concentrated to provide compound 296 as a pure white solid characterized by MS and 1H-NMR (33.9 mg, LRMS (ESI) [M+H+]+=256.1, [M−H+]−=254.1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Si]([O:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)(C(C)(C)C)(C)C.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>COCCOC.CCOC(C)=O>[OH:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1CCO
Reaction time: 0.25 h

Procedure:
To the solution of N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (150 mg, 316 μmol, example 36, intermediate a) in DME (3 mL) was added 2-(2-(tert-butyldimethylsilyloxy)ethyl)phenylboronic acid (88.7 mg, 316 μmol, CAS RN 913835-62-8) and 2M aqueous Na2CO3 solution (1 mL). The reaction mixture was stirred under argon atmosphere for 15 minutes. Pd(II)acetate (3.55 mg, 15.8 μmol) and triphenylphosphine (8.3 mg, 31.6 μmol) were added. The reaction mixture stirred at 90° C. for 18 hours and then poured on 30 mL 1M aqueous HCl and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 60:40). Colorless solid (95 mg, 52%). MS (ESI): m/z=469.134 [M+H]+.
Reaction SMILES: [Cl:1][CH:2]([F:24])[C:3]([F:23])([F:22])[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]=NC2C=CC([N+]([O-])=O)=CC=2)=[N:9][CH:10]=1.C.[H][H]>C(O)(=O)C.[Pd]>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]([F:23])([F:22])[CH:2]([Cl:1])[F:24])=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(OC(F)(F)C(F)Cl)cn2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(OC(F)(F)C(F)Cl)cn1

Procedure:
In a 1 liter VA stainless steel autoclave, 85.1 g (0.24 mol) of 5-(2-chloro-1,1,2-trifluoroethoxy)-2-(4-nitrophenylazo)pyridine were hydrogenated in 600 ml of acetic acid, with addition of 10 g of palladium (10%) on activated charcoal, using 61 bar (take-up) of hydrogen at 20°-25° C. The mixture was filtered and the solvent removed by distillation on a rotary evaporator. The residue was taken up in 500 ml of dichloromethane, washed with 100 ml of 20% strength aqueous sodium carbonate and four times with 100 ml of water in each case, and dried over sodium sulfate. The solvent was subsequently removed by evaporation on a rotary evaporator and the residue was distilled in a high vacuum.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A solution/suspension of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (1.22 g, 4.18 mmol), 4-(benzyloxy)phenol (1.01 g, 5.04 mmol, 1.20 equiv.), K2CO3 (830 mg, 6.01 mmol, 1.40 equiv.) and KI (75 mg, 0.45 mmol, 0.11 equiv.) in acetone was heated to reflux under N2 overnight. After cooling to room temperature, the mixture was diluted with 100 mL of EtOAc, and the solids were filtered off. The filtrate was concentrated under vacuum, and the residue was applied onto a silica gel column, which was eluted with ethyl acetate/petroleum ether (1:5) to afford the product (1.25 g, 73%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.43-7.29 (m, 5H), 6.90 (d, 2H, J=6.6 Hz), 5.01 (s, 2H), 4.08 (d, 2H, J=7.2 Hz), 3.95 (t, 1H, J=4.2 Hz), 2.70 (t, 2H, J=9.6 Hz), 1.71-1.69 (m, 5H), 1.45 (s, 9H), 1.20-1.15 (m, 2H). LC-MS (ESI) m/z 434 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([N:34]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[N:28]=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:52][O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][N:34]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[C:29]2[N:30]=[C:31]([CH3:33])[N:32]=[C:27]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[N:28]=2)=[CH:50][CH:49]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 79.1 %

Procedure:
(R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (9.27 g, 26.2 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51) (11.47 g, 29.8 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (1.820 g, 2.57 mmol), and potassium acetate (8.17 g, 83.0 mmol) were suspended in a mixture of 1,4-dioxane (150 mL) and water (30 mL). The resulting mixture was sparged with nitrogen (for about 30 sec) and then stirred at 100° C. for 3.5 h. The reaction mixture was then allowed to cool to 25° C., water (150 mL) was added, and the resulting mixture was extracted with EtOAc (3×300 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 3% MeOH/DCM) furnished (R)-tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (13.63 g, 79% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=9.0, 2.3 Hz, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.24 (d, J=5.7 Hz, 2H), 7.22 (d, J=5.5 Hz, 2H), 6.86 (t, J=8.9 Hz, 4H), 4.83 (s, 2H), 4.80 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.54-3.61 (m, 1H), 3.40 (d, J=3.7 Hz, 4H), 2.55 (s, 3H), 2.44 (d, J=2.7 Hz, 2H), 2.27-2.39 (m, 2H), 1.44 (s, 9H), 1.40 (d, J=6.7 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −67.83 (d, J=9.2 Hz, 0.7F), −70.47 (d, J=5.7 Hz, 0.3F). m/z (ESI, +ve) 658.4 (M+H)+.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH:5]1([C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH:5]1([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3([CH3:20])[O:18][C:2](=[NH:3])[NH:1][CH2:19]3)=[CH:21][CH:22]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: N#CN
Reactant: CC1(COc2ccc(C3CCCCC3)cc2)CO1
Agent: [Na]
Solvent: CO
Product: CC1(COc2ccc(C3CCCCC3)cc2)CNC(=N)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Methanol (250 ml) and sodium hydrogen cyanamide (1.92 g, 30 mmol) were added to a flask containing 2-(4-cyclohexyl-phenoxymethyl)-2-methyl-oxirane (6.15 g, 25 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride and washed with water, then saturated potassium carbonate. The methylene chloride layer was dried over 4 A molecular sieves, filtered and concentrated in vacuo to yield 5.46 g of a white solid. The white solid was recrystallized from ether to yield 1.11 g of the title compound as white crystals. A second crop yielded 0.64 g of white crystals.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:13]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[OH-].[Na+]>O>[OH:19][C:15]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[CH:4]=[O:5]
Reactant: CCc1cccc(O)c1NCCNC(C)=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCc1ccc(C=O)c(O)c1NCCNC(C)=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A scrupulously dry flask was charged with anhydrous DMF (15 ml) and cooled in ice under argon. Phosphorus oxychloride, POCl3, 1.5 ml (1.15 eq) was added slowly dropwise to the stirred solution. After the addition was complete, the flask was removed from the ice bath and allowed to reach ambient temperature. This was accompanied by a color change to yellow. The flask was heated in a 40° C. bath for one hour. It was removed from the heat, and once at ambient temperature, a DMF solution of 3-(ethyl)(2-acetylaminoethyl)aminophenol (8; 3.2 g, 14 mmol) was added via addition funnel. After the addition was complete, the flask was returned to the 40° C. bath and stirred overnight. The reaction was cooled to 0° C. and 25 ml 10% NaOH was added, the mixture was allowed to warm to ambient temperature and was then placed in a 40° C. bath. Additional NaOH was added to achieve pH >10. Water (50 ml) was added. After 15 minutes the flask was removed from the bath and the pH adjusted to 5-5.5 with 1N HCl. The mixture was transferred to a separatory funnel and extracted with 4×100 ml ethyl acetate. The pooled organic fractions were washed with water (1×75 ml), predried with Na2SO4, and then dried with MgSO4 overnight. The solution was collected by filtration and the volatiles removed by rotary evaporation to yield the crude product (2.9 g). The material was purified by flash chromatography on silica, 45×150 mm column, eluting with 200 ml each of 2.5%, 5%, and 10% methanol/chloroform purified yield of(2-hydroxy-4-(ethyl)(2-acetylaminoethyl)aminobenzaldehyde) (9) was 1.52 g (45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([I:8])[CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)cc(I)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
A mixture of 3-Bromo-5-iodonitrobenzene (4.21 g, 0.0128 mol) and iron powder (3.6 g, 0.0642 mol) in glacial acetic acid (50 ml) was stirred at ambient temperature for 16 h. The reaction mixture was then filtered through a pad of celite and washed through with ethyl acetate. The filtrate was evaporated in vacuo to give a brown oil. This was re-dissolved in ethyl acetate, loaded onto a large pad of silica and eluted with ethyl acetate. The filtrate was evaporated in vacuo to afford 3-Bromo-5-iodoaniline as a brown solid (3.67 g, 96%) which was used without further purification.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl.[Cl:14][CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH:20]=1>>[ClH:14].[C:21]1([C:18]2[S:19][CH:20]=[C:16]([CH2:15][O:1][NH2:2])[N:17]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Product: NOCc1csc(-c2ccccc2)n1

Procedure:
Prepared by a similar procedure as described for preparation 12, starting from N-hydroxyphthalimide and 4-chloromethyl-2-phenyl-thiazole hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH2:17][CH2:18]3)=[O:12])[N:8]2[CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:4][C:3]=1[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]1
Reactant: CCS(=O)(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3[nH]2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3n2CC(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 144 mg (0.26 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone (example 10) in 3 mL N,N-dimethylformamide, were added 13 mg (0.29 mmol; 55% dispersion in mineral oil) sodium hydride. The reaction mixture was stirred 15 min at 70° C. 68 mg (0.29 mmol) 2,2,2-Trifluoroethyl methanesulfonate were added and the solution was stirred another 2 h at 70° C. After cooling to room temperature, the reaction was poured into water and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant, to afford 86 mg (52%) of the title compound as a light-yellow oil.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:2][CH2:3][CH3:4].[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27].C(N(CC)CC)C>CN(C=O)C.O.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.[Cu]I>[CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(I)ccc1OC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C#C[Si](C)(C)C)ccc1OC
Temperature: 50 °C
Yield: 96.8 %

Procedure:
A mixture of the product from Example 61 (330 mg, 0.7 mmol), ethynyltrimethylsilane (206 mg, 2.1 mmol), PdCl2(PPh3)2 (49 mg, 0.07 mmol), triethylamine (201 mg, 2.1 mmol) and CuI (33 mg, 0.18 mmol) in DMF (5 mL) was heated at 50° C. for 16 hrs, diluted with H2O and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 300 mg (97%) of the title compound. MS (DCI/NH4+) m/z 443 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][Si](C(C)(C)C)(C)C)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[C:29]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=5)[N:12]=4)=[N:9][N:10]=3)[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
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: [Na+]
Solvent: C1COCCO1
Product: Oc1cccc2ccc(-c3nnc4ccc(-c5ccccc5)cn34)nc12
Temperature: 110 °C
Yield: 37.1 %

Procedure:
2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline (0.500 g, 1.10 mmol), phenylboronic acid (0.167 g, 1.37 mmol), Pd(PPh3)4 (0.0634 g, 0.0549 mmol), and 2M aqueous Na2CO3 (2.74 mL, 5.49 mmol) (degassed with nitrogen 30 minutes prior to use) were combined with 7 mL dioxane (degassed with nitrogen 30 minutes prior to use), sonicated, and heated to 110° C. in a reaction block for 18 hours, during which the reaction went dry. The reaction mixture was cooled to ambient temperature, diluted with DMF, and the suspension was vacuum filtered through compressed Celite, rinsed with DMF, and the filtrate was concentrated. The crude material was purified on silica gel (1-20% methanol in dichloromethane gradient) to give the title compound (0.138 g, 0.408 mmol, 37.1% yield) as a brown solid.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=3[CH:29]=2)=[O:18])=[C:12]([Cl:31])[CH:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=3[CH:29]=2)([OH:18])[C:2]([F:4])([F:3])[F:1])=[C:12]([Cl:31])[CH:11]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1ccc2oc(=O)n(C)c2c1)c1ccc(Br)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 1.13 mL) was added at 0° C. to a solution of 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (404 mg) in THF (8 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (65 mg). Stirring was continued for 2 hours at 0° C. More tetrabutylammonium fluoride (1M in THF, 0.82 mL) was added to the reaction mixture and stirring was continued for 1 hour at 0° C. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=100:0 to 96:4) to give the title compound as a colorless foam (320 mg, 67%). MS (m/e)=466.1 [M+H+].