Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[C:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])(O)=[O:6]>C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:5][OH:6])=[CH:17][C:13]=1[CH2:14][OH:15]
Reactant: O=C(O)Cc1ccc(Cl)c(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of borane-methyl sulfide complex (2M in THF, 6.50 mL) was added portionwise over 5 minutes to a solution of 5-(carboxymethyl)-2-chlorobenzoic acid (example 61, step a) (1.37 g) in dry THF (20 mL) at room temperature. The resulting effervescing solution was stirred at room temperature for 1.5 hours, then heated to reflux for 1 hour. The cooled mixture was quenched by the portionwise addition of methanol (5 mL) over 5 minutes. The solution was stirred at room temperature for 2 hours and then purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a colourless oil. Yield 0.933 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1.C(=O)(O)[O-].[K+]>O1CCCC1>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:15]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCCc2c[nH]cn2)nc1

Procedure:
0.5 g (4.5 mmol) of histamine and 0.77 g (4.5 mmol) of 6-chloro-3-carbomethoxypyridine are stirred with potassium bicarbonate in 20 ml of tetrahydrofuran at 21° C. for 24 h and then heated at reflux for 24 h. The mixture is evaporated and the white solid residue is chromatographed through silica gel, using a chloroform/methanol (4/1) mixture as eluent. The fractions containing the pure product are combined and evaporated and the resulting oily residue is treated with a methanol solution of oxalic acid. Addition of ether provides the title compound in the form of the oxalate salt, M.p.: 209°-210° C. C12H14N4O2.1.7C2H2O4
Reaction SMILES: BrCC1C=CC2C(=CC=CC=2)C=1.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH:36]([CH2:37][O:38]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:35][N:34]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:33][CH:32]2[O:65][CH2:66][C:67]2[CH:76]=[CH:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:68]=2)=[CH:27][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]2[CH:32]([O:65][CH2:66][C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[CH:68]=3)[CH2:33][N:34]([C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[CH2:35][CH:36]2[CH2:37][OH:38])=[CH:29][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: BrCc1ccc2ccccc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22 (h), by reacting tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate with triphenylchloromethane in pyridine there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 731 (M+NH4)+ ], as a colourless foam, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 62 (h) gave tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 871 (M+NH4)+ ], as a colourless foam. Subsequent selective cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) yielded tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 612 (M+H)+. Subsequent alkylation with methyl iodide analogously to Example 62 (h) gave tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 626 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](Cl)[N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Reactant: Cc1ccccc1N
Solvent: CCO
Product: COc1cccc2c(Nc3ccccc3C)nc(Nc3ccccc3C)nc12

Procedure:
8-methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (1.00 g, 0.0033 mol) was dissolved in ethanol (15 ml) with o-toluidine (1.06 g, 0.0099 mol) and heated in a sealed vessel at 150° for 5 hours. After cooling and removal of excess solvent in vacuo the solid was chromatographed (silica gel, chloroform). 8-Methoxy-2,4-bis(2-methylphenylamino)quinazoline was isolated as crystals (0.93 g, from ethanol/water, m.p. 185°-187°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 29 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.56 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.056 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.157 g, 0.56 mmol) and 2.0 M aqueous sodium carbonate (0.8 mL, 1.6 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-fluoro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.070 g, 29%) as a solid. MS calcd. for C22H21FNO5S [(M−H)−] 430, obsd. 430.3.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Al]>C(Cl)Cl>[CH2:8]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCO
Agent: [Al]
Solvent: ClCCl
Product: OCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,5-pentanediol (2.10 mL, 20.0 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (100 mL). Ag2O (6.95 g, 30.0 mmol, 1.5 equiv.) and benzyl bromide (2.62 mL, 22.0 mmol, 1.1 equiv.) were added to the solution sequentially. The flask was wrapped with aluminium foil, and the solution was stirred at room temperature for 18 h. The solution was filtered through a pad of celite, eluting with CH2Cl2, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, Ethyl Acetate (EtOAc): petroleum ether (pet ether)=3:17 to 1:1) to give the alcohol as a colorless oil. 1H NMR (500 MHz, CDCl3) δ=7.37-7.26 (m, 5H), 4.50 (s, 2H), 3.64 (t, J=6.5 Hz, 2H), 3.49 (t, J=6.5 Hz, 2H), 1.70-1.63 (m, 2H), 1.62-1.55 (m, 2H), 1.50-1.42 (m, 2H), 1.34 (br s, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ=138.8, 128.6, 127.8, 127.7, 73.2, 70.5, 63.1, 32.8, 29.7, 22.7 ppm; Low Resolution Mass Spectrometry (LRMS) (ESI+ve) m/z: 217 (M+Na+).
Reaction SMILES: [NH:1]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:2]([C:18]([NH:20][C@H:21]([C:34]([NH:36][C@H:37]([C:53]([O:55][CH3:56])=[O:54])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42]C(OCC1C=CC=CC=1)=O)=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O>CO.C(Cl)Cl.[Pd]>[NH:1]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:2]([C:18]([NH:20][C@H:21]([C:34]([NH:36][C@H:37]([C:53]([O:55][CH3:56])=[O:54])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of 12 (0.88 g, 0.99 mmol) in MeOH (25 mL) and DCM (25 mL), was added Pd/C (0.20 g). This solution was flushed with H2 for 30 min. and then fitted with an H2 balloon. The reaction was allowed to proceed for 8 h at which time the mixture was filtered through celite, and conc. in vacuo to yield pure clear product 13 (0.622 g, quantitative): 1H NMR (500 MHz, d6 DMSO) δ 8.42 (br s, 1H), 8.16 (br s, 4H), 7.92 (br s, 1H), 6.92 (br s, 1H), 6.74 (br s, 1H), 4.27 (br s, 1H), 4.20 (br s, 1H), 3.89 (br s, 1H), 3.62 (s, 3H), 3.46 (br s, 3H), 2.87-2.73 (m, 5H), 2.52 (s, 1H), 1.80-1.45 (br s, 10H), 1.45-1.15 (m, 22H); 13C NMR (125 MHz, d6 DMSO) δ 173.2, 172.8, 156.4, 156.2, 78.94, 78.19, 54.91, 53.1, 52.7, 52.6, 39.3, 39.2, 32.8, 32.0, 30.9, 29.1, 29.1, 27.3, 27.2, 23.2, 23.1. HRMS (FAB) m/z calcd for C29H56N6O8 (M+H)+ 617.4238, found 617.4236.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.C1COCC1>C(Cl)Cl>[Br:26][C:17]1[CH:16]=[N:15][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH:18]=1
Reactant: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(-n3cc(Br)cn3)cc2)cc1
Yield: 87.1 %

Procedure:
Prepared from INT-85: To a stirring solution of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole (309 mg, 1.319 mmol) INT-85 in DCM (4 mL) was added NBS (258 mg, 1.45 mmol). After stirring at room temperature for 1 h additional THF (4 mL) was added and stirring continued. After 18 h the reaction mixture was concentrated in vacuo and slurried in MeCN (4 mL). The solid was collected by filtration and washed with MeCN (2×2 mL) to provide 360 mg (87%) of 4-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-86. LCMS-ESI (m/z) calculated for C16H13BrN2: 312; found 313 [M+H]+, tR=3.07 min (Method 5).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>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].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=4)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(-c2ccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)cc2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 1, step 2) was reacted with (3-methylsulfonylaminophenyl)boronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give N-[4′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-3-yl]-methanesulfonamide as a colorless solid. MS: 548.2 ([M+H]+)
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][CH:4]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([N:35]=[C:36]=[O:37])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>C(Cl)Cl>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([NH:35][C:36]([N:20]2[CH2:21][CH2:22][N:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:18][CH2:19]2)=[O:37])[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1
Reactant: c1ccc(N2CCNCC2)c(OCc2ccncc2)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazine dihydrochloride (0.3 mmol, 100 mg), DCM (5 ml), TEA (1 mmol, 139 ul), and 3,5-bis(trifluoromethyl)phenyl isocyanate (0.6 mmol, 104 ul) was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified on silica column using 80% EtOAc/hexanes to give N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-ylmethyl)oxy]phenyl}piperazine-1-carboxamide. 1H NMR (CDCl3) 8.599-8.586 (d, 2H), 7.855 (s, 2H), 7.559-7.452 (d, 2H), 7.390-7.377 (d, 2H), 7.021-6.888 (m, 4H), 5.146 (s, 2H), 3.728-3.704 (m, 4H), 3.149-3.125 (m, 4H) ppm.
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C(C)=C)[CH2:21][CH2:22]C>CN1C(=O)CCC1.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]>[C:21]([C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1)([CH3:22])=[CH2:20]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: C=C(C)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 90 °C

Procedure:
To a solution of 4-(5-iodo-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.700 g, 1.90 mmol) (Example 2b) in NMP (5 mL) is added tris(dibenzylideneacetone)dipalladium (0.196 g, 0.19 mmol) and trifuryl-2-yl-phospane (0.066 g, 0.285 mmol). Tributylisopropenyltin (1.25 g, 3.80 mmol) is added to the reaction mixture and it is heated to 90° C. for 24 h. The mixture is then allowed to cooled to room temperature, washed with water and extracted with ethyl acetate. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 4-(5-isopropenyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; (ESI) m/z 283.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.21 (s, 3 H), 1.50 (s, 3 H), 2.24 (br. s, 3 H), 5.31 (br. s, 1 H), 5.56 (br. s, 1 H), 5.73 (s, 1 H), 7.02 (br. s, 1 H), 7.28 (br. s, 1 H), 7.51 (d, J=7.8 Hz, 1 H), 7.69 (td, J=7.8, 1.0 Hz, 1 H), 7.81 (td, J=7.6, 1.3 Hz, 1 H), 8.25 (d, J=7.8 Hz, 1 H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:20]1[N:24]=[CH:23][N:22]2[CH2:25][CH2:26][C:27](=[O:28])[C:21]=12.[Cl-].[NH4+]>CCCCCC.C1COCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:27]3([OH:28])[C:21]4[N:22]([CH:23]=[N:24][CH:20]=4)[CH2:25][CH2:26]3)[CH:8]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCn2cncc21
Reactant: Fc1ccc(-c2cccc(Br)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(-c3ccc(F)cc3)c2)CCn2cncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution (1.6 M; 1.98 ml) of n-butyl lithium in hexane was gently added dropwise to a solution of 3-bromo-4′-fluoro-1,1′-biphenyl (753 mg) in THF (10 ml) at −78° C., and the mixture was stirred at −78° C. for 30 min. A solution of 5,6-dihydro-7Hpyrrolo[1,2-c]imidazol-7-one (244 mg) in THF (10 ml) solution was gently added dropwise and the mixture was stirred at −78° C. for 1 h. A saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=5:1) and recrystallized from acetone-hexane to give the title compound (265 mg) as colorless needle crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2.[OH:24]O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24]
Reactant: O=C1CCc2cc(OCCCCSCc3ccco3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)Cc3ccco3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-furylmethyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([CH3:34])[CH:28]=[C:29]4[C:33]=3[NH:32][N:31]=[CH:30]4)[CH3:24])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([CH3:34])[CH:28]=[C:29]4[C:33]=3[NH:32][N:31]=[CH:30]4)[CH3:24])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCNCC2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-methyl-1H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (35 mg, 0.075 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 2 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 24 mg (87%). LC/MS (HPLC method 3): tR=2.658 min, 368.38(MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH3:16].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[C:6]([O:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=2)=[C:7]1[CH3:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Oc1cccc(Br)c1
Product: Cc1c(Oc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(3-bromo-phenoxy)-6-chloro-2-methyl-1H-indole and benzyl bromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([CH:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCC(c2cc(OC)c(N)cc2C)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 120 °C
Yield: 69.4 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (90 mg, 0.125 mmol, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.38 (d, J=6.41 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.69 (d, J=8.97 Hz, 1H), 7.52 (s, 1H), 7.41-7.46 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.95 (t, J=6.68 Hz, 1H), 6.89 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 2.91-3.01 (m, 2H), 2.58-2.67 (m, 1H), 2.20-2.30 (m, 2H), 2.18 (s, 3H), 1.92-2.03 (m, 2H), 1.62-1.73 (m, 4H), 1.40-1.49 (m, J=7.33, 7.33, 7.33, 7.33 Hz, 2H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 718 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]([F:19])[F:18])[CH:11]=2)[CH:9]=1)=[O:4].FC(F)OC1C=C(C(=O)/C=C(\O)/C(OC)=O)C=CC=1.Cl.NN>C(O)C>[F:19][CH:17]([F:18])[O:16][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2cccc(OC(F)F)c2)n[nH]1
Agent: COC(=O)/C(O)=C/C(=O)c1cccc(OC(F)F)c1
Agent: Cl
Agent: NN
Solvent: CCO
Product: O=C(O)c1cc(-c2cccc(OC(F)F)c2)n[nH]1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
5-(3-Difluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid methyl ester: To a solution of (Z)-methyl 4-(3-(difluoromethoxy)phenyl)-2-hydroxy-4-oxobut-2-enoate (CAS-832741-03-4) (800 mg, 2.94 mmol, Eq: 1.00) in Ethanol (20 ml) was added Hydrazine hydrochloride (220 mg, 3.21 mmol, Eq: 1.093) at rt to give an orange suspension. The resulting mixture was stirred overnight at the same temperature. After 1 day the reaction was complete. After stirring the solvent was removed under reduce pressure and to the mixture was added brine, the solution was extracted two times with AcOEt, and the combined organic layers were dried over MgSO4, filtered and concentrated to give the desired compound as a light-brown solid (630 mg, 79.9%). MS (ISP): 269.0 ([M+H]+).