Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:8]=[C:7](Cl)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=1)[NH2:24].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:8]=[C:7]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=4)=[C:21]([O:20][CH3:19])[CH:22]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)COCc1cc(N2CCC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(N3CCC3)n2)ccc1-c1cnnc(C)c1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
A mixture of 4-(azetidin-1-yl)-2-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (30 mg, 0.11 mmol), 3-methoxy-4-(6-methylpyridazin-4-yl)aniline (23 mg, 0.11 mmol), cesium carbonate (69 mg, 0.21 mmol), palladium(II) acetate (4 mg, 0.02 mmol) and 2-(dicyclohexyl-phosphino)biphenyl (6 mg, 0.02 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica plug which was washed with 10% solution of methanol in EtOAc (75 mL). The eluate was concentrated and the residue was purified by preparative HPLC to give the title compound as a solid 14 mg (29%).
Reaction SMILES: O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[N:40]1([S:46]([C:49]2[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.[CH2:56]([O:61][C:62](=[O:82])[C:63]1[C:68](I)=[CH:67][N:66]=[C:65]([NH:70][S:71]([C:74]2[CH:79]=[CH:78][C:77]([Cl:80])=[CH:76][C:75]=2[Cl:81])(=[O:73])=[O:72])[CH:64]=1)[CH2:57][CH2:58][CH2:59][CH3:60].CC(C)([O-])C.[K+]>CN1CCCC1=O.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]>[CH2:56]([O:61][C:62](=[O:82])[C:63]1[C:68]([S:55][C:52]2[CH:51]=[CH:50][C:49]([S:46]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)(=[O:48])=[O:47])=[CH:54][CH:53]=2)=[CH:67][N:66]=[C:65]([NH:70][S:71]([C:74]2[CH:79]=[CH:78][C:77]([Cl:80])=[CH:76][C:75]=2[Cl:81])(=[O:72])=[O:73])[CH:64]=1)[CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1I
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
A solution of (oxydi-2,1-phenylene)bis-(diphenylphosphine) (DPEphos) (43 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol) in N-methylpyrrolidinone (10 ml) was stirred at room temperature for 5 minutes under nitrogen. 4-(Piperidine-1-sulfonyl)-benzenethiol (121 mg, 0.4 mmol), 2-(2,4-dichloro-benzenesulfonylamino)-5-iodo-isonicotinic acid pentyl ester (218 mg, 0.4 mmol) and potassium t-butoxide (90 mg, 0.8 mmol) were added and the reaction stirred overnight at 100° C. The solvent was removed under reduced pressure and the residue taken up in chloroform. The chloroform solution was washed with brine (25 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to afford 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester as a yellow foam (15 mg, 6%). 1H NMR (CDCl3): 10.82 (1H, s, NH); 8.17 (1H, s, Ar); 8.09 (1H, d, Ar); 7.61 (2 H, m, Ar); 7.57 (1H, s, Ar); 7.38 (4H, m, py and Ar); 4.22 (2H, t, OCH2); 2.90 (4H, m, 2×CH2N pip); 1.66 (2H, m, OCH2CH2); 1.54 (4H, m, 2×CH2 pip); 1.33 (4H, m OCH2CH2CH2CH2CH3); 1.19 (2H, m, CH2 pip); 0.88 (3H, t, CH2CH3). HPLC (Luna 2, Gradient 5): rt=7.82 minutes. LCMS rt=8.34 minutes, 673 (M+H)+.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35](O)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1F)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1cccc(F)c1F)O2

Procedure:
2-(2,3-Difluorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 1.5 g of 2-(2,3-difluorophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 6.64 (dd, 1H, 9.0, 2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, 1H, J 10.2, 2.2 Hz), 2.93 (m, 1H), 2.66 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]([CH3:8])([CH3:7])[NH:5][C:4](=[O:9])[NH:3]1.[CH2:11]([Li])CCC.CCCCCC.CI.P([O-])(O)(O)=O.[K+]>O1CCCC1>[CH3:11][N:3]1[C:2]([CH3:10])([CH3:1])[C:6]([CH3:8])([CH3:7])[NH:5][C:4]1=[O:9]
Reactant: CC1(C)NC(=O)NC1(C)C
Reactant: [Li]CCCC
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)NC(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,5,5-tetramethylimidazolidin-2-one (100 mg; 0.70 mmol) in dry tetrahydrofuran (5 ml), a 1.57 N solution of n-butyl lithium in hexane (0.49 ml; 0.77 mmol) was added at 0° C. After stirring at the same temperature for 5 minutes, a solution of methyl iodide (109 mg; 0.77 mmol) in tetrahydrofuran (1 ml) was added at 0° C., followed by stirring at room temperature for 10 minutes. To the reaction mixture, a saturated aqueous solution of potassium dihydrogen phosphate was added to decompose the excess reaction agent, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily residue, which was purified by thin layer chromatography (chloroform:acetone=1:1) to give 1,4,4,5,5-pentamethylimidazolidin-2-one as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=O)[C:20](O)=[O:21]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:20](=[O:21])[C:19]([C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)=[N:12]2)=[O:13])[CH3:2]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Product: CCOC(=O)c1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-Diamino-benzoic acid ethyl ester and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-carboxylic acid ethyl ester.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([NH2:20])[C:12]([C:21]([NH2:23])=[O:22])=[CH:11]2.[C:24](OC(=O)C)(=O)[CH3:25].[OH-].[Na+]>O>[CH3:24][C:25]1[NH:23][C:21](=[O:22])[C:12]2[C:13]([N:20]=1)=[N:14][C:15]1[C:10]([CH:11]=2)=[CH:9][C:8]([O:7][CH3:6])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: COc1cc2cc(C(N)=O)c(N)nc2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cc3c(=O)[nH]c(C)nc3nc2cc1OC
Reaction time: 1.25 h

Procedure:
Concentrated sulfuric acid (1.5 ml.) is added to a slurry of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (5.0 g., 0.02 mole) and acetic anhydride (40 ml.) The slurry dissolves to give a dark orange solution from which a heavy yellow precipitate separates. Acetic anhydride (10 ml.) is added to facilitate stirring and heating continued for an additional 75 minutes. The mixture is cooled, water (50 ml.) added and the resulting solution made alkaline with 5N sodium hydroxide (225 ml.). It is chilled, the precipitate collected by filtration and air-dried. The yellow solid is recrystallized from ethanol. Yield = 2.37 g., M.P. 300°-302° (dec.).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](=[C:15]2[S:19][CH:18]=[CH:17][S:16]2)[C:11](=[O:20])[CH:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12](=[C:15]2[S:16][CH:17]=[CH:18][S:19]2)[C:11](=[O:20])[C:10]([CH2:26][CH3:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Product: CCOC(=O)C1(CC)CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Yield: 79.3 %

Procedure:
Ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-4.6-dioxopiperidine-3-carboxylate (2.70 g) and ethyl iodide (0.71 ml) are treated in the same manner as described in Example 25-(1), whereby ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-3-ethyl-4,6-dioxopiperidine-3-carboxylate (2.30 g, 79.3%) is obtained as pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([F:26])[F:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1.CS(C)=[O:29]>>[F:25][CH:24]([F:26])[C:21]1[CH:22]=[CH:23][C:18]([O:17][C:8]2[C:6]3[CH:7]=[C:3]([CH:2]=[O:29])[O:4][C:5]=3[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(CBr)oc2c1
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C=O)oc2c1
Yield: 81 %

Procedure:
A solution of ethyl 2-(bromomethyl)-4-[4-(difluoromethyl)phenoxy]-1-benzofuran-6-carboxylate (440 mg, 1.03 mmol) and IBX (579 mg, 2.07 mmol) in DMSO (2 mL) was heated at 65° C. for 3 h. The reaction was quenched with water and the product was extracted with CHCl3 (3×). The combined organic layers was washed with water (2×), dried over MgSO4 and concentrated. The product was purified via gradient silica gel chromatography using hexanes/EtOAc (100/0 to 50/50) to give the title compound (300 mg, 81%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.39 (t, J=7.16 Hz, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 6.67 (t, J=56.42 Hz, 1 H) 7.11-7.18 (m, J=8.67 Hz, 2 H) 7.48 (d, J=0.94 Hz, 1 H) 7.51 (d, J=0.94 Hz, 1H) 7.55 (d, J=8.67 Hz, 2 H) 8.08 (d, J=0.94 Hz, 1 H) 9.87 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:19])[N:13]=[C:14]([CH:17]=[O:18])[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.CC(=CC)C.[O-:26]Cl=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.O>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:19])[N:13]=[C:14]([C:17]([OH:26])=[O:18])[C:15]=3[N:16]=2)[CH2:6][CH2:7]1
Reactant: [O-][Cl+][O-]
Reactant: Cc1nc(C=O)c2nc(C3CCC(C)(C)CC3)sc2n1
Agent: CC=C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(C(=O)O)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methanol (500 mg) and DCM (10 mL) was added Dess-Martin periodinane (1.46 g) under ice-cooling, followed by stirring at 0° C. for 3 hours. To the reaction mixture was added an aqueous Na2S2O3 solution, followed by extraction with DCM. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine-7-carbaldehyde (492 mg). To a mixture of the obtained aldehyde, NaH2PO4 (245 mg), 2-methyl-2-butene (542 μL), water (5 mL), and acetone (10 mL) was added NaClO2 (231 mg) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous Na2S2O3 solution and Na2SO4, followed by extraction with a mixed solution (1:9) of 2-propanol and chloroform. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to obtain 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine-7-carboxylic acid (870 mg).
Reaction SMILES: [CH:1]1([C:7]([NH:9][NH2:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]([Cl:16])([Cl:15])[CH:13]=O>C1C=CC=CC=1>[Cl:11][C:12]([Cl:16])([Cl:15])[CH:13]=[N:10][NH:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NNC(=O)C1CCCCC1
Solvent: c1ccccc1
Product: O=C(NN=CC(Cl)(Cl)Cl)C1CCCCC1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
Cyclohexanecarboxylic acid (2,2,2-trichloroethylidene)hydrazide was prepared by refluxing a solution containing 23.0 grams (0.162 mol) of cyclohexanecarboxylic acid hydrazide and 44.2 grams (0.3 mol) of trichloroacetaldehyde in 300 ml milliliters of benzene. Water was removed as formed. After 3 hours, the reaction mixture was concentrated to a volume of 100 milliliters, diluted with 500 milliliters of hexane, chilled to 5° C., and filtered to yield 34 grams of the desired hydrazide as a white solid, melting point 178°-180° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[CH2:5][CH2:4]1.C[N:17](C=O)C>>[CH:3]1([C:6]2[N:7]([NH2:17])[C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[CH2:5][CH2:4]1
Reactant: Fc1ccc2[nH]c(C3CC3)cc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nn1c(C2CC2)cc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of NaH (1.9 g, 47 mmol, 60% in mineral oil) in DMF (20 mL) at 0° C. is treated with 2-cyclopropyl-5-fluoro-1H-indole (550 mg, 3.14 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (1.8 g, 15.7 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 5%-35% EtOAc in heptane to afford 2-cyclopropyl-5-fluoro-indol-1-ylamine (420 mg, 70%). MS: 191 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 7.11 (m, 1H), 6.92 (m, 1H), 5.90 (s, 1H), 4.57 (s, NH2, 2H), 2.07 (m, 1H), 1.02 (m, 2H), 0.75 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[CH:21]=[NH+:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2.[Br-].Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:33][C:34]#[N:35])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[CH:21]=[N:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(O)ccc3c2)c[nH+]n1-c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC#N)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 4-[(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamoyl]-2-phenyl-3-propyl-2H-pyrazol-1-ium; bromide (0.30 g, 0.646 mmol), prepared in the previous step, bromoacetonitrile (0.054 mL, 0.775 mmol), potassium carbonate (0.446 g, 3.23 mmol) and 10 mL of DMF was stirred under nitrogen at room temperature overnight. The reaction was diluted with ethyl acetate and extracted multiple times with water and with a saturated sodium chloride solution. The organic layer was separated, dried (MgSO4), and the solvent removed under reduced pressure to give a brown oil. The oil was chromatographed on a 90 g KP-SIL 60 Δ Biotage column using 15% ethyl acetate in methylene chloride as the eluent. All fractions containing product were combined and the solvent removed under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.196 g, 60%) as a light yellow solid, mp 175-176° C.
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:11]1([CH2:17][C@@H:18]([NH2:33])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(N(CC)CC)C>[CH:11]1([CH2:17][C@@H:18]([NH:33][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:9])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ccccc2O)CC1
Solvent: CCN(CC)CC
Product: CC1(C(=O)N[C@H](CC2CCCCC2)CN2CCN(c3ccccc3O)CC2)CCCCC1

Procedure:
A solution of 1-methylcyclohexanecarbonyl chloride, triethylamine and {(1R)-1-cyclohexylmethyl-2-[4-(2-hydroxyphenyl)-piperazin-1-yl]-ethyl}-amine is stirred at 0° C. under a nitrogen atmosphere for 1 hour. The mixture is then concentrated on a rotary evaporator and partitioned between ethyl acetate and saturated aqueous NaHCO3. The combined organic layers are washed with brine, dried and concentrated on a rotary evaporator to yield the desired product, which is purified by chromatography on alumina.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:6]([Cl:17])=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15][CH3:16])[CH:11]=[CH:10]2.[Cl-].[NH4+]>CN(C)C=O>[Cl:17][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[C:2]#[N:3])=[N:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2
Reactant: N#C[Cu]
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(C#N)c2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Copper(I) cyanide (39.3 g, 0.44 mol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (100 g, 0.37 mol, 1.0 eq) in N,N-dimethylformamide (1.5 L). After 8 hours stirring at 130° C., the reaction mixture is cooled down to room temperature and treated with a saturated ammonium chloride aqueous solution (1.5 L). The aqueous layer is separated and extracted with ethyl acetate (2×1.5 L). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is washed with ethanol (20 mL) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile as an off-white solid (49.5 g, 62% yield).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CN(C)C=O>[Si:11]([O:5][CH2:1][CH2:2][C:3]#[CH:4])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A mixture of 21 g of 3-butyn-1-ol and 27 g of imidazole in 100 ml of dimethyl formamide was treated with 45 g of t-butyldimethylsilyl chloride in several portions over a one hour period. After stirring under nitrogen for 18 hours the reaction mixture was diluted with 500 ml of ice water. The resulting aqueous solution was extracted with 300 ml of ether and the ethereal solution washed with water and then brine. The ethereal solution was dried over potassium carbonate. Evaporation of the ether and distillation of the residue gave 47.6 g of 3-butyn-1-ol t-butyldimethylsilyl ether, bp 80°-83° C./25 mm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[C:31]2=[N:32][CH2:33][CH2:34][N:30]2[CH:29]=[N:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:27]1[N:28]=[CH:29][N:30]2[CH2:34][CH2:33][N:32]([C:2]3[CH:3]=[C:4]([CH2:8][CH2:9][N:10]4[CH2:15][CH2:14][N:13]([C:16]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:17]=5[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]6)[CH2:12][CH2:11]4)[CH:5]=[CH:6][CH:7]=3)[C:31]=12
Reactant: C1=NNC2=NCCN12
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCn6cnnc65)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
5-{4-[2-(3-Iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (59 mg), 5,6-dihydro-1H-imidazo[2,1-c][1,2,4]triazole (50 mg, 3.5 equiv.), palladium(II)acetate (9 mg, 0.3 equiv.) 2-(dicyclohexylphosphino)-2′-methylbiphenyl (42 mg, 0.9 equiv.) and potassium phosphate (97 mg, 3.5 equiv.) were suspended in DME and stirred at 150 □C under microwave irradiation for 2 h. The mixture was cooled to room temperature, diluted with methanol and loaded onto an ion-exchange cartridge (SCX-2), which was eluted with methanol followed by ammonia-methanol solution (1M). The combined basic fractions were concentrated under vacuum and purified using column chromatography [SiO2; DCM-MeOH (90:10)] to afford the title compound as colourless solid (13 mg, 26% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH2:3]1.C1COCC1.[OH-].[Li+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: CCOC(=O)c1cc2c(s1)CC(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)sc2C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
In a 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 106b (4.00 g, 17.8 mmol) was dissolved in ethanol (50 mL). THF (50 mL), water (50 mL) and lithium hydroxide (854 mg, 35.6 mmol) were added, and the mixture was stirred at 60° C. for 4 h. After this time the reaction was cooled to room temperature and acidified with 2M hydrochloric acid to pH 1.5, and then extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with water (2×100 mL), followed by brine (100 ml) and dried over sodium sulfate. The drying agent was then separated by filtration. After evaporating the resulting filtrate, 106c was obtained in 91% yield (3.2 g) as a white solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 12.77 (s, 1H), 7.46 (s, 1H), 2.71 (s, 2H), 2.53 (s, 2H), 1.20 (s, 6H); MS (ESI−) m/z 195.0
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[O:27]([CH2:34][CH2:35][C:36](O)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:36]([CH2:35][CH2:34][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)CCOc1ccccc1
Product: CON=C1C[C@@H](c2noc(CCOc3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-phenoxypropanoic acid, the title compound was obtained in 84% purity by HPLC. MS(ESI+): m/z=483.3.