Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH:30]([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:31][CH:30]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[N:13]=2)[CH:10]=[N:9]1)[CH3:32]
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(3-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (325 mg, 0.85 mmol), 2-iodopropane (0.130 mL, 1.3 mmol), and K2CO3 (235 mg, 1.7 mmol) in DMF (3 mL) was stirred overnight at 50° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt followed by separation by preparative HPLC to give the title compounds.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:25])=[C:23]([Br:32])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(N)nc3)cn2)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(Br)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a well stirred solution of 4-[4-(6-aminopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (24.4 g, 71.1 mmol) in DCM (800 mL) was added solid Na2CO3 (11.2 g, 107 mmol), and the mixture was cooled to 0° C. A solution of bromine (3.6 mL, 71 mmol) in DCM (200 mL) was added dropwise during 30 min, and the reaction mixture was stirred for further 5 h at ambient temperature. The reaction mixture was then cooled to 10° C., and a cold solution of 10% sodium thiosulfate in water (100 mL) followed by saturated sodium bicarbonate solution (100 mL) was added. After stirring for 10 min, the organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a brown solid. It was triturated twice with tert-butyl methyl ether (100 mL) at 40-45° C., filtered, and dried in vacuo to yield the title compound as white solid. 1H NMR (300 MHz, CDCl3): δ=1.48 (s, 9H), 1.92-1.96 (m, 2H), 2.13-2.17 (m, 2H), 2.89 (m, 2H), 4.23-4.28 (m, 3H), 4.86 (s, broad, 2H), 7.56 (s, 1H), 7.66 (s, 1H), 7.75 (d, 1H, J=2.1 Hz), 8.15 (d, 1H, J=2.1 Hz).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][CH2:7][C:8]([NH:10][CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]1=2)=[O:9].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO>C(Cl)Cl.O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1)[CH2:6][CH2:7][C:8]([NH:10][CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]=[N:20][N:21]([CH3:37])[N:22]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]1=2)=[O:9]
Reactant: O=C(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCN(c2nnn[nH]2)c2cc(Cl)ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1nnc(N2CCCC(NC(=O)CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccc(Cl)cc32)n1
Temperature: 25 °C

Procedure:
To a solution of N-(3,5-Bis-trifluoromethyl-benzyl-N-[8-chloro-1-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.55 mmol, 0.29 g) in CH2Cl2 (5 mL) was added triphenyl phosphine (0.55 mmol, 0.14 g) and diethylazo dicarboxylate (0.55 mmol, 90.0 μL) at 0° C. To the above mixture, MeOH (2.75 mmol, 0.11 μL) was added and warmed to room temperature for 48 h. After completion, the reaction mixture was diluted with water (20 mL), extracted with EtOAC (3×25 mL) and the combined organic layers were washed with water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by flash column chromatography to afford the title compound as colorless foam; Rf 0.60 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 547 (M+H+).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH:29]([CH:31]([NH:40][C:41]([CH:43]([NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:42])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O>C1COCC1.O.C(OCC)(=O)C>[CH3:46][CH:45]([CH3:47])[CH2:44][CH:43]([NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:41](=[O:42])[NH:40][CH:31]([CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:29]=[C:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(C=O)CCc1ccccc1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)=CC(CCc1ccccc1)NC(=O)C(CC(C)C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 16.7 %

Procedure:
A solution comprised of isopropyltriphenylphosphonium iodide (13.02 g, 30.1 mmol) in TBF (80 mL) was cooled to −78° C. and then n-butyllithium (12.44 mL, 2.5M in hexane) was added. The mixture was stirred for 5 minutes, heated to room temperature and stirred for an additional 25 minutes. Benzyl 1-(1-formyl-3-phenylpropylcarbamoyl)-3-methylbutylcarbamate (4.12 g, 10.04 mmol), prepared as in the procedure set forth in Synthesis, 1983, pp 676-678, was dissolved in THF (40mL) and the solution was added dropwise. The mixture was stirred for 18 hours at room temperature and then diluted with water (5 mL) and ethyl acetate (250 mL). The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and concentrated to dryness in vacuo. Product was purified from the residue by column chromatography using 20% ethyl acetate/hexane to provide benzyl 3-methyl-1-(3-methyl-1-phenethylbut-2-enylcarbamoyl)butylcarbamate (0.75 g, 1.68 mmol) as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>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(O)(C)(C)C>[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]ccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Variant B: A mixture of 200 mg (1.31 mmol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine, 678 mg (3.93 mmol) of 2-chloro-4-nitroaniline, 60 mg (0.07 mmol) of tris(dibenzylideneacetone)dipalladium, 62 mg (0.13 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine and 399 mg (2.88 mmol) of potassium carbonate and 2.50 ml of degassed tert-butanol is stirred in a sealed pressure vessel at 100° C. for 3 h.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][NH:10][C:9]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:34][CH:35]([CH3:37])[CH3:36]>O1CCCC1.CN1CCCC1=O.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:9]1=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Reactant: CC(C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN1C[C@H](c2ccccc2F)C[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled 0° C. solution of tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate (0.85 g, 2.76 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 18 mL) was added lithium bis(trimethylsilyl)amide (3.58 mL, 3.58 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 30 min. 1-Iodo-2-methylpropane (0.48 mL, 4.13 mmol) was added and the resulting mixture was stirred at 0° C. for 2 h and then warmed to 23° C. and stirred for an additional 18 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→70% ethyl acetate/hexane) was followed by separation of the cis/trans diastereomers using supercritical fluid chromatography with a ChiralPak® AD column and eluting with 20% ethanol in carbon dioxide to afford the title compound as the second diastereomer to elute. MS: m/z=387.2 (M+Na).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH2:26]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)[CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:26]([N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9]([NH:10][C@H:11]4[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]4)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]3[CH:25]=2)[CH:30]=[N:29]1)[CH3:27]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1C[C@H](CF)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Product: CCn1cc(-c2cc3c(N[C@@H]4CN(S(C)(=O)=O)C[C@@H]4CF)c(C(N)=O)cnn3c2)cn1
Reaction time: 0.42 h
Yield: 48.7 %

Procedure:
A degassed solution of 6-bromo-4-(((3S,4S)-4-(fluoromethyl)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.115 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.4 mg, 0.173 mmol), 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5.49 mg, 0.012 mmol), Pd(OAc)2 (1.292 mg, 5.76 μmol) and 2 M aq. potassium phosphate solution (0.173 mL, 0.345 mmol) in DMF (0.5 mL) was heated to 105° C. for 2 hrs. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (25.2 mg, 48% yield). 1H NMR (500 MHz, 1:1, Chloroform-d3 & METHANOL-d4) δ 8.14 (s, 1H), 7.87 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.76 (s, 1H), 7.00 (d, J=1.5 Hz, 1H), 5.17-5.10 (m, 1H), 4.71-4.64 (m, 1H), 4.42 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.90-3.74 (m, 2H), 3.59-3.45 (m, 2H), 3.13-3.02 (m, 1H), 2.90 (s, 3H), 1.52 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 450.2 (M+H); HPLC: 99%, retention time: 1.739 min (analytical HPLC Method F).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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(OCC)(=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:9]2[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: Clc1ccc(CBr)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(Cl)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.70 g) in DME (14.0 mL) were added 1-(bromomethyl)-4-chlorobenzene (0.49 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.09 g) and 2 mol/L aqueous sodium carbonate solution (2.29 mL), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.50 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: COC(=O)COCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COCCOc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
[2-(4-Nitrophenoxy)-ethoxy]acetic acid methyl ester 22 (1 g, 3.9 mmol) was dissolved in anhydrous ethyl acetate (20 ml), palladium carbon (10%, 0.1 g) added and the mixture stirred under an atmosphere of hydrogen using balloon for 30 minutes. The catalyst was filtered, the filtrate concentrated, hexane (3 ml) added, and the solid filtered to give 23 (625 mg, 70.9%) as a light brown powder. The melting point was found to be 51-52.5° C. The structure was confirmed with IR and NMR.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)#[CH:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]=[O:34]>C(OCC)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]([OH:34])[C:6]#[C:5][C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: O=Cc1c(COC2CCCCO2)noc1-c1ccccc1Cl
Reactant: C#Cc1cncnc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(C#Cc1cncnc1)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Yield: 40.1 %

Procedure:
Add 3M ethylmagnesium bromide (36 mL, 109 mmol) in diethyl ether to a 0° C. solution of 5-ethynyl-pyrimidine (8.1 g, 77 mmol) in THF (75 mL). Add 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carbaldehyde (10 g, 31 mmol) in THF (75 mL) and stir 15 h at RT. Quench the reaction with 1N HCl and extract with diethyl ether (2×150 mL). Wash the organic phase with brine (150 mL), dry over sodium sulfate, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 1:1 to 3:7 hexanes/EtOAc) gives the title compound (5.3 g, 40%): 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.35 (s, 2H), 7.44–7.62 (m, 4H), 5.65 (t, J=14 Hz, 1H), 5.08–5.28 (m, 1H), 4.80–4.95 (m, 2H), 4.42–4.60 (m, 1H), 3.80–4.01 (m, 1H), 3.51–3.68 (m, 1H), 1.54–1.90 (m, 6H); TLC Rf=0.20 (3:7 Hexanes:EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]#[N:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O.[N:27]([Na])=[N+:28]=[N-:29]>CS(C)=O.Br[Zn]Br>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]4[N:27]=[N:28][NH:29][N:25]=4)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Reactant: [N-]=[N+]=N[Na]
Agent: Br[Zn]Br
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CCCN1c1nc2cc(-c3nn[nH]n3)ccc2nc1-c1ccc(F)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carbonitrile (100 mg, 0.30 mmol) in DMSO (10 mL) was added dibromozinc (33.8 mg, 0.15 mmol), water (10 mL), azidosodium (48.8 mg, 0.75 mmol) and water (5 mL). The resulting solution was stirred for 1 days at 125° C. and then quenched by the addition of water (100 mL), extracted with dichloromethane (3×30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% dichloromethane in methanol) to afford (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)-6-(2H-tetrazol-5-yl)quinoxaline as a yellow solid (70.9 mg, 63%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[F:28][C:29]([F:47])([F:46])[C:30]1[CH:31]=[C:32]([C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.[OH-].[Na+]>C(Cl)Cl>[F:28][C:29]([F:47])([F:46])[C:30]1[CH:31]=[C:32]([C:40]([CH3:45])([CH3:44])[C:41]([N:2]([CH3:1])[C:3]2[C:4]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=2)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1
Reactant: CNc1cnc(SC)nc1Oc1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Oc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a solution of 1.10 g (4.21 mol) methyl-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-amine and 1.44 ml (8.42 mmol) N-ethyldiisopropylamine in 30 ml CH2Cl2 a solution of 1.87 g (5.89 mmol) 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride in 5 ml CH2Cl2 was added and the reaction mixture stirred for 12 hrs at RT. The reaction mixture was poured into 50 ml 0.5 N NaOH-solution. The phases were separated and the aqueous phase three times extracted with 80 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, hexane/ ethyl acetate 2:1) to give 2.10 g (92%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide as a white foam, MS (ISP): 544.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CO.S1C=CC=C1C([O-])=O.[Cu+]>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N:37]5[CH:41]=[CH:40][N:39]=[CH:38]5)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Agent: [Cu+]
Agent: O=C([O-])[O-]
Agent: O=C([O-])c1cccs1
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(-n5ccnc5)cc4c3=O)cc2)CCC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 13.8 %

Procedure:
{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (55 mg, 0.1 mmol), imidazole (9 mg, 0.12 mmol), cesium carbonate (49 mg, 0.15 mmol) and copper (I)thiophene-2-carboxylate (4 mg, 0.02 mmol) were suspended in NMP (1.0 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated conventionally at 110° C. for 24 hours. Due to incomplete reaction, the temperature was increased to 130° C. After a further 24 hours, the reaction mixture was allowed to cool to RT, dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before eluting with 2 M ammonia in methanol solution. The eluent was collected and concentrated in vacuo. The resulting residue was dissolved in DCM (2 mL) and TFA (500 μL) and stirred at RT for 1.5 hours. The mixture was dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before eluting with 2 M ammonia in methanol solution. The eluent was collected and concentrated in vacuo. The resulting residue was purified on reverse phase HPLC (gradient 5% 20 mM TEA in acetonitrile/20 mM TEA in water to 98% 20 mM TEA in acetonitrile/20 mM TEA in water) to give the title compound as a white solid (6 mg, 14%). 1H NMR (400 MHz, DMSO-d6): δ 8.43-8.42 (m, 1H), 8.23 (d, J=3 Hz, 1H), 8.18 (dd, J=3 and 9 Hz, 1H), 7.94 (d, J=9 Hz, 1H), 7.93-7.92 (m, 1H), 7.47-7.33 (m, 7H), 7.16-7.13 (m, 3H), 2.40-2.32 (m, 2H), 2.11-2.02 (m, 2H), 2.02-1.95 (m, 1H), 1.70-1.61 (m, 1H). LCMS (Method F): RT=6.40 min, [M+H]+=434.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[S:17][C:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=3)[N:19]=2)=[C:15]2[CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH2:34][C:14]=12)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[S:17][C:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=3)[N:19]=2)=[C:15]2[CH2:31][CH2:32][C:33]([CH3:35])([CH3:36])[CH2:34][C:14]=12)[CH3:12]
Reactant: CCc1sc(-c2nc(-c3ccc(CO)cc3)no2)c2c1CC(C)(C)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1sc(-c2nc(-c3ccc(C=O)cc3)no2)c2c1CC(C)(C)CC2
Temperature: -40 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a cold solution (−70° C.) of oxalyl chloride (169 mg, 1.34 mmol) and DMSO (209 mg, 2.67 mmol) in DCM (4 mL) a solution of {4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (410 mg, 1.11 mmol) in DCM (5 mL) is added. The mixture is warmed to −40° C. within 30 min and then triethylamine (394 mg, 3.89 mmol) is added. Stirring is continued at −40° C. for 1 h, then at rt. The reaction is quenched by adding water and the mixture is extracted with diethyl ether. The organic extract is dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-benzaldehyde (180 mg) as a white solid; LC-MS: tR=1.24 min, [M+1]+=367.24.