Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12]3=[N:18][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][O:24][CH2:23]4)[C:20](=[O:21])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.O>CN(C)C=O.[Cu]Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:34][C:35]1[N:36]=[CH:37][C:38]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[C:14]4[CH:15]=[CH:16][S:17][C:13]=4[C:12]4=[N:18][N:19]([CH:22]5[CH2:27][CH2:26][CH2:25][O:24][CH2:23]5)[C:20](=[O:21])[C:11]4=[N:10]3)=[CH:4][CH:3]=2)=[CH:39][CH:40]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=c1c2nn(Cc3ccc(I)cc3)c3ccsc3c-2nn1C1CCCOC1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n(C5CCCOC5)nc-4c4sccc43)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-5-[(4-Iodophenyl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]thieno[2,3-e]pyridazin-3-one (50 mg, 0.10 mmol), cesium carbonate (66 mg, 0.20 mmol, 2 equiv), copper(I) chloride (10 mg, 0.10 mmol, 1 equiv), 2-methyl-5-pyridinylboronic acid (22 mg, 0.14 mmol, 1.4 equiv), palladium(II) acetate (2.3 mg, 10 μmol, 0.1 equiv), and 1,1′-bis(diphenylphosphino)ferrocene (11 mg, 20 μmol, 0.2 equiv) were combined in N,N-dimethylformamide (3 mL) and placed into a preheated oil bath at 90° C. for 30 minutes. The mixture was cooled to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexnaes:ethyl acetate containing 10% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.70 (1H, br s), 7.77 (1H, d, J=8.2 Hz), 7.65 (1H, d, J=5.6 Hz), 7.54 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.27-7.24 (2H, in), 5.81 (2H, s), 4.78-4.70 (1H, m), 4.02 (1H, dd, J=10.8, 3.9 Hz), 3.97 (1H, br d, J=11.4 Hz), 3.80 (1H, ap t, J=10.5 Hz), 3.49 (1H, td, J=11.3, 3.1 Hz), 2.62 (3H, s), 2.22 (1H, ddd, J=17.2, 12.3, 5.0 Hz), 2.10 (1H, br d, J=11.3 Hz), 1.94-1.80 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 458.1642 [(M+H)+; calculated for C25H24N5O2S: 458.1645].
Reaction SMILES: CN1C([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)=CC(C)=N1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[NH:13]1[C:14]2[CH:15]=[CH:9][CH:8]=[CH:7][C:17]=2[CH:16]=[CH:10][CH:11]=[CH:12]1
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C1=CNc2ccccc2C=C1
Reaction time: 4 h

Procedure:
To a stirred solution of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.37 g) and triethylamine (0.3 mL) in DCM (5 mL), at 0° C., trifluoroacetic anhydride (0.26 mL) was added dropwise. The ice bath was removed and the stirring continued for 4 h after which time aqueous saturated NaHCO3 (10 mL) was added, the reaction mixture was extracted twice with diethyl ether (10 mL), the organic phase dried over Na2SO4 and evaporated under reduced pressure to give the correspondent N-trifluoacetyl benzazepine derivative in 0.5 g yield. This product (0.11g) was dissolved in DMF (1 mL) and N-chlorosuccinimide (47 mg) was added, the reaction was warmed to 50° C. and stirred for 1 h. Then the reaction mixture was allowed to reach RT, water was added (4 mL), the mixture was extracted twice with ethyl ether (5 mL), the organic phase dried over Na2SO4 and evaporated under reduced pressure. The crude product so obtained was dissolved in MeOH (10 mL) and a solution of K2CO3 (0.36 g) in water (10 mL) was added, then the mixture was warmed to 55° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, extracted twice with DCM (10 mL), the organic phase dried over Na2SO4 and the solvent evaporated under reduced pressure to give the title compound (0.17 g) that was used as such.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[C:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 4-[2-(2-naphthoxy)ethoxy]benzaldehyde (1.24 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution was concentrated under a vacuum to give title compound (1.45 g, 84%).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N:9]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1>C1COCC1.O.CS(C)=O>[N:9]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:7][OH:8])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: NO
Reactant: O=Cc1ccc(-n2cncn2)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: ON=Cc1ccc(-n2cncn2)c2ccccc12
Reaction time: 5 h

Procedure:
Sodium acetate (262 mg) is added to a solution of hydroxylamine hydrochloride (193 mg) and 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde (455 mg) in THF (16 ml), water (2 ml) and DMSO (2 ml). After 5 hours at room temperature, the reaction is quenched with water and ethyl acetate. The organic phase is separated and the water phase is extracted with ethyl acetate. The combined organic phases are extracted with water and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde oxime. The crude product obtained (390 mg, beige crystals) is used without further purification. MS (HPLC/MS): 239 (MH+). Retention time 2.76 min.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(C(F)(F)F)nn2)CC1
Temperature: 150 °C
Yield: 92.9 %

Procedure:
To a stirred solution of 6-chloro-4-phenyl-3-trifluoromethyl-pyridazine (D3) (7.1 g, 0.0274 mol) and N-Boc-piperazine (5.62 g, 0.0302 mol) in acetonitrile (150 ml) was added diisopropylethylamine (5.1 ml, 0.0302 mol) and the mixture heated at 150° C. for 20 min., under microwave irradiation. After this period, the reaction mixture was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4) and the solvents evaporated in vacuo. The crude product was purified by column chromatography (silica; 20% ethyl acetate in heptane, followed by 10% ethyl acetate in dichloromethane). After evaporation of the solvent, the crude product was crystallised from heptane to yield D4 (10.4 g, 93%). C20H23F3N4O2 requires 408; Found 409 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:28]1[CH2:31][CH2:30][O:29]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:27]=3[CH:28]3[CH2:31][CH2:30][O:29]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20]
Reactant: Brc1cnccc1C1CCO1
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(-c3cnccc3C3CCO3)cc21
Temperature: 100 °C
Yield: 4.8 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (123 mg, 0.44 mmol), 3-Bromo-4-oxetan-2-yl-pyridine (96 mg, 0.44 mmol), Na2CO3 (2 M in water, 067 mL, 1.35 mmol) and PdCl2(PPh3)2 (16 mg, 0.02 mmol) in DMF (4 mL) was heated at 100° C. for 3 h. After concentration, the resulting residue was diluted with DCM and saturated NH4Cl solution. After filteration, the filtrates were concentrated and the residue was purified by flash column (MeOH/CH2Cl2, v/v, 0-3.5%) and afforded the title compound (6 mg, 5%); ESI-MS m/z: 283 [M+1]+, Retention time 1.03 min; 1HNMR (MeOD, 400.342 MHz) δ ppm 2.60-2.65 (m, 1H), 2.83-2.87 (m, 1H), 3.47 (s, 3H), 4.62-4.68 (m, 1H), 4.75-4.82 (m, 1H), 5.91 (t, J=7.6 Hz, 1H), 7.06 (dd, J=8, 1.6 Hz, 1H), 7.15 (d, J=1.6 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.94 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.67 (d, J=5.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH2:21][CH:20]=[CH2:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Reactant: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
To a slurry of hexanes-washed NaH (0.534 g of a 60% w/w suspension in mineral oil; 13.4 mmol) in dry DMF (10 mL) at 0° C., under N2, was added a solution of 4-[(2,2-dimethylpropyl)amino]-2-(trifluoromethyl)benzonitrile (1.71 g, 6.68 mmol, step A, Example 57) in DMF (4 mL), dropwise over 10 min. The mixture was stirred 15 min and allyl bromide (1.16 mL, 13.4 mmol) was added dropwise over 3 min. The mixture was stirred 1 h at 0° C. and poured into water. The whole was extracted with Et2O (×3). The combined organic portions were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.82 g of the title compound as a colorless syrup that slowly solidified: MS (El) m/z 296 (M+, 9%), 239 ([M-tBu]+, 100%), 197 (83%), 170 (99%).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][Cl:9].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[ClH:9].[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: ClCc1ccccn1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4ccccn4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound A1 and 2-picolylchloride hydrochloride as described for compound 18. M.p. 214-216° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(F)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light brown solid (69 mg, 90%), MS (ISP) m/z=309.3 [(M+H)+], mp 258.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][CH2:7][C@@H:8]([CH3:31])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C:18](=[O:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:3][C:2]([Si:5]([CH3:32])([CH3:33])[O:6][CH2:7][C@@H:8]([CH3:31])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([CH3:1])[CH3:4]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
iv)—A solution of the ketone 5 (140 g) obtained in the previous step in dry tetra-hydrofuran (1400 ml) was added in 30 min. to an ice-cooled suspension of lithium aluminium hydride (35 g) in tetrahydrofuran (1750 ml). After stirring of the mixture for 1 h at room temperature, the reaction was quenched by addition of a saturated aqueous solution of sodium sulfate (152 ml), followed by water (39 ml). Ethyl acetate (1750 ml) was added, and the mixture was filtered over celite. The filtrate was concentrated under reduced pressure to give (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregn-5-en-3-ol (6) (136.3 g), which was used in the following step without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1OCCOCCOCCOCCOCCOC1.C(OC([N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:49]3[S:50][C:51]([CH2:59][CH2:60][CH2:61]I)=[C:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[N:53]=3)[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)=O)(C)(C)C.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[O:13]([CH2:61][CH2:60][CH2:59][C:51]1[S:50][C:49]([C:46]2[CH:47]=[C:48]3[C:43]([CH2:42][CH2:41][CH2:40][NH:39]3)=[CH:44][CH:45]=2)=[N:53][C:52]=1[C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)sc1CCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)NCCC3)sc1CCCOc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.6 %

Procedure:
To K2CO3 (32 mg, 0.23 mmol), phenol (28 mg, 0.30 mmol) and 18-crown-6 (180 mg, 0.70 mmol) was added DMF (1 mL). After 5 minutes ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (23G) (129 mg, 0.23 mmol) in DMF (1 mL) was added to the reaction mixture and stirred at rt for 72 hours. The reaction was monitored by LCMS and starting material remained. To the reaction mixture was added K2CO3 (32 mg, 0.23 mmol) and phenol (28 mg, 0.30 mmol) and stirred at rt overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel to provide 50 mg as a mixture of starting material and product. To DMF (1 mL) was added NaH (4 mg) and phenol (13 mg) and stirred for 10 minutes. To the reaction mixture was added the isolated material (50 mg) as a mixture of starting material and product and allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried with MgSO4 and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel to provide 22 mg of the desired product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.C[O:16][C:17](=O)[NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([CH3:27])[N:20]=[C:19]([NH:18][C:17]([NH:14][S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[NH:3][CH:2]([CH3:1])[CH2:10]3)(=[O:13])=[O:12])=[O:16])[N:24]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2N1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2NC(C)C3)n1
Yield: 11.2 %

Procedure:
To a solution of 2,3-dihydro-2-methyl-1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene dichloride (100 ml) was added trimethylaluminum (3.0 ml of a 2.0M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to dryness. The residue was chromatographed on a silica gel column to give the pure product (0.2 g, m.p. 175°-177° C.).
Reaction SMILES: Cl[S:2]([C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[NH4+:17]>O1CCCC1>[NH2:17][S:2]([C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2cccc(S(=O)(=O)Cl)c2O1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Reaction time: 1 h

Procedure:
A solution of 0.5 gram (0.002 mole) of 7-chlorosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran and 4 ml of tetrahydrofuran was stirred and 2 ml of an aqueous solution of 29% ammonium hydroxide was added. The reaction mixture stirred for one hour, then was concentrated under reduced pressure to a residue. The residue was triturated with water and filtered to collect, when dried, 0.41 grams of 7-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran; m.p. 160.5°-162.5° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH:12]=[CH:11][CH:10]=[C:9]3[CH2:8]1>F>[C:4]([C:12]1[C:13]2[C:18]3[C:9]([CH2:8][CH2:7][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: c1cc2c3c(cccc3c1)CC2
Agent: F
Product: CC(=O)CC(=O)c1ccc2c3c(cccc13)CC2

Procedure:
42 g (0.5 mol) of diketene were added dropwise to 77 g of acenaphthene (0.5 mole) in 300 ml of anhydrous hydrofluoric acid at -30°C while stirring. The temperature was maintained for 9 hours. The hydrofluoric acid was distilled off under reduced pressure at a temperature of the still of -30°C, the residue was washed until it was free from acid and distilled under reduced pressure. 10 g of unreacted acenaphthene were recovered (87 % conversion). At a transition temperature of 150° - 155°C under 0.4 torr 85 g (82 % of theory) of slightly yellowish 5-acetoacetyl-acenaphthene melting at 59°C were then obtained.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:32][C:33]1[C:38]([CH:39]=O)=[CH:37][CH:36]=[CH:35][N:34]=1.CC(O)=O>ClCCCl>[NH2:32][C:33]1[C:38]([CH2:39][N:29]2[CH2:30][CH2:31][N:26]([C:24]([C:22]3[N:23]=[C:19]([CH2:18][N:4]([CH:1]4[CH2:2][CH2:3]4)[S:5]([C:8]4[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=4[CH3:14])(=[O:6])=[O:7])[O:20][CH:21]=3)=[O:25])[CH2:27][CH2:28]2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: Nc1ncccc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cccnc4N)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-amino-3-pyridinecarboxaldehyde (10 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([F:15])[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]=[C:7]([F:15])[S:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:24])(=[O:3])[CH3:2]
Reactant: CCCCCCSC(F)=CCOC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCS(=O)C(F)=CCOC(C)=O

Procedure:
To a solution of 3-fluoro-3-hexylthio-2-propenyl acetate (0.36 g, 1.5 mmol) in 5 ml of methylene chloride is added m-chloroperbenzoic acid (0.34 g, 1.7 mmol) at 5°. After the reaction is complete, the reaction mixture is diluted with methylene chloride, poured into aqueous saturated Na2CO3, extracted with methylene chloride (2X), washed with brine, dried and stripped of solvent to give 3-fluoro-3-hexylsulfinyl2-propenyl acetate. The product is purified by prep. TLC on silica gel eluting with 40% ethylacetate/hexane. The upper band is collected to give (E)-3-fluoro-3-hexylsulfinyl-2propenyl acetate (cpd. 1, Table A).
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([CH3:47])[CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([CH3:47])[CH:40]=2)=[CH:7][CH:6]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)ccc1C#N
Temperature: 85 °C
Yield: 72.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 180 mg) and 4-bromo-2-methylbenzonitrile (72 mg) in acetonitrile (8 mL) were treated with an aqueous solution of sodium carbonate (2M, 0.348 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was concentrated and purified by chromatography on silica eluting with 50 to 100% ethyl acetate/isohexane to afford the sub-titled compound (127 mg).