Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:13])[CH:9]=2)[NH:4][C:3]=1[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42](=[O:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:36])=[CH:30][CH:29]=1.[C:51]([Cu])#[N:52]>CN(C=O)C>[C:51]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:13])[CH:9]=2)[NH:4][C:3]=1[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42](=[O:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:36])=[CH:30][CH:29]=1)#[N:52]
Reactant: O=C(Nc1ccc(-c2[nH]c3ccc(NC(=O)[C@@H]4CCCN4C(=O)Cc4ccccc4)cc3c2Br)cc1)[C@@H]1CCCN1C(=O)Cc1ccccc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(NC(=O)[C@@H]3CCCN3C(=O)Cc3ccccc3)cc2)[nH]c2ccc(NC(=O)[C@@H]3CCCN3C(=O)Cc3ccccc3)cc12

Procedure:
A mixture of the bromo compound from Example 126 (150 mg, 0.2 mmol), CuCN (50 mg, 0.6 mmol) and DMF (3 mL) was refluxed under N2 protection overnight. The mixture was purified by RPLC to afford the product. MS (ESI) m/e (M+H+): 679. 1H NMR (CDCl3) δ: 7.73-7.70 (m, 4H), 7.38-7.29 (m, 4H), 7.21-7.04 (m, 6H), 4.63-4.60 (m, 1H), 4.49-4.47 (m, 1H), 3.81-3.59 (m, 4H), 2.48-1.97 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[OH-].[K+].[F:12][C:13]([F:17])=[C:14]([F:16])Cl>C1S(=O)(=O)CCC1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]2[O:6][C:13]([F:17])([F:12])[CH:14]([F:16])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: FC(F)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc2c(c1)OC(F)C(F)(F)O2

Procedure:
124 g of 4-methylpyrocatechol were initially introduced into 300 ml of tetramethylene sulphone, together with 110 g of potassium hydroxide, at 110° C. 170 g of trifluorochloroethylene were then passed in in the course of 4 hours. The mixture was then distilled over a column under 15 mm Hg, the distillate being removed up to a transition temperature of 85° C. After separating off the aqueous phase in the receiver, the product was again distilled. 133 g ( 65% of theory) of 6-methyl-2,2,3-trifluoro-1,4-benzodioxene were obtained at a boiling point 70°-72° C./12 mm Hg (nD20 : 1.4565).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.O.Cl.[O:14]([NH2:16])[CH3:15]>CO>[CH3:15][O:14][N:16]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:2][Br:1]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CO
Product: CON=C(CBr)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-4′-methyl-acetophenone (6.514 g, 27.5 mmol) in methanol at 50° C. was added water until the solution turned slightly cloudy. Methoxylamine hydrochloride (7.037, 85.7 mmol) was added and the mixture was stirred overnight. The solvent was removed under high vacuum and the residue was extracted with EtOAc and dried over MgSO4. The product was purified by flash chromatography on silicagel (CH2Cl2/hexanes) to give 2 isomers in 87% total yield: 2 isomers in 87% total yield: Z-isomer 1H NMR 500 MHz (DMSO-d6) δ 2.33 (s, 3H), 3.83 (s, 3H), 4.62 (s, 2H), 7.26 (dd, 2H, J=1.8, 8.2 Hz), 7.51 (d, 2H, J=7.6 Hz); FABHRMS: found M+, 242.0177 (calcd for C10H13ONBr: M+, 242.0175). E-isomer 1H-NMR 500 MHz (DMSO-d6) d 2.33 (s, 3H), 3.99 (s, 3H), 4.68 (s, 2H), 7.25 (d, 2H, J=8.2 Hz), 7.61 (d, 2H, J=7.3 Hz); FABHRMS: found M+, 242.0175 (calcd for C10H13ONBr: M+, 242.0175).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C@H:4]([NH:8][C:9](=O)OC(C)(C)C)[CH2:3]1.[Cl:16][C:17]1[CH:24]=C(F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[Cl:16][C:17]1[CH:24]=[C:9]([NH:8][C@H:4]2[CH2:5][C:6](=[O:7])[N:2]([CH3:1])[CH2:3]2)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CN1C[C@@H](NC(=O)OC(C)(C)C)CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
1,1-Dimethylethyl [(3S)-1-methyl-5-oxo-3-pyrrolidinyl]carbamate (0.96 g, 4.5 mmol) was suspended in 4N HCl in dioxane (3 mL) and the mixture was stirred at room temperature for 12 h. Solvent was removed and the residue was dissolved in DMSO (27 mL) and H2O (3 mL). To this solution, 2-chloro-4-fluorobenzonitrile (0.77 g, 4.90 mmol) and NaHCO3 (1.89 g, 22.5 mmol) were added and the reaction mixture was stirred at 75° C. for 18 h. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to give the titled product (0.598 g, 53%) as a white solid. 1H-NMR (CDCl3) δ: 2.350 (1H, m), 2.914 (4H, m), 3.305 (1H, m), 3.825 (1H, m), 4.200 (1H, m), 4.835 (1H, d, J=6.8 Hz), 6.492 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.626 (1H, d, J=2.4 Hz), 7.454 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 250.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>>[N:21]1([CH2:20][CH2:19][N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:41]6[CH:40]=[N:39][N:38]([CH2:37][CH2:36][OH:35])[CH:42]=6)[CH:28]=[CH:27][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3CCN3CCOCC3)nc1-2
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCN4CCOCC4)nc2-3)cn1

Procedure:
Following the procedure for 258, 8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 467. MS (ESI+) 494.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.38 (dd, J=8.3, 1.7, 1H), 7.30 (d, J=1.7, 1H), 4.95 (t, J=6.5, 2H), 4.91 (t, J=5.3, 1H), 4.39 (t, J=5.0, 2H), 4.16 (t, J=5.7, 2H), 3.77 (q, J=5.6, 2H), 3.51-3.38 (m, 6H), 2.82 (t, J=6.5, 2H), 2.46-2.36 (m, 4H)
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[C:14](=[O:43])[N:15]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[F:12][C:13]1[C:14](=[O:43])[N:15]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:39])=[O:40])[C:28]([NH:30][OH:31])=[O:29])[CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@](CCn1ccc(-c2ccccc2)c(F)c1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C[C@@](CCn1ccc(-c2ccccc2)c(F)c1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
Pyrinium p-toluenesulfonate (20 mg, 0.080 mmol) was added to a solution of (2R)-4-(3-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (110 mg, 0.236 mmol) in ethanol (5 ml) and heated at reflux for 3 hours. The solution was cooled to RT, and upon cooling, a solid precipitated. The solid was collected via filtration and washed with ethanol (5 mL), heptane (10 mL), and ether (10 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (38.4 mg, 42.6%). LC-MS m/z 383.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (s, 3H) 2.10-2.26 (m, 1H) 3.11 (s, 3H) 3.70-3.94 (m, 1H) 4.07-4.30 (m, 1H) 6.46 (t, J=6.93 Hz, 1H) 7.46-7.57 (m, 3H) 7.59-7.65 (m, 3H)
Reaction SMILES: C([Si](C#C)(CC)CC)C.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[O:15]([CH2:22]C(=O)C)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CC[O:29]CC>>[OH:29][C:12]([CH3:13])([CH2:22][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]#[CH:10]
Reactant: CC(=O)COc1ccccc1
Reactant: [Li]CCCC
Reactant: CCOCC
Agent: C#C[Si](CC)(CC)CC
Agent: Cl
Product: C#CC(C)(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.1 parts of triethylsilylacetylene in 15 parts by volume of ether at -30° C. is added 8 parts by volume of 2.5 molar n-butyl lithium. The reaction mixture is allowed to come to room temperature and 3 parts of phenoxyacetone in 5 parts by volume of ether is added. The reaction mixture is stirred at room temperature for one hour and then poured into ether and dilute (1 N) hydrochloric acid solution. The ether layer is washed with water and dried over anhydrous sodium sulfate. The solvents are removed at reduced pressure and the residual oil is dissolved in 15 parts by volume of dimethylformamide containing about 5 parts of powdered potassium fluoride. The reaction mixture is stirred at 70°-80° C. for about 1 hour. The reaction mixture is worked up by diluting with ether and washing several times with water. The ether layer is dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The residual oil is isolated by low pressure liquid chromatography on silica gel using 30% ethyl acetate/hexane as eluent to provide 3-hydroxy-3-methyl-4-phenoxy-1-butyne.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:17][C:18]1[C:30]([Cl:31])=[C:29]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:28]=[C:27]2[C:19]=1[C:20]1[C:25]([CH2:37][CH2:38]O)([CH2:26]2)[CH2:24][CH2:23][C:22](=[O:40])[CH:21]=1>O1CCCC1>[C:1]([O:4][CH2:38][CH2:37][C:25]12[CH2:24][CH2:23][C:22](=[O:40])[CH:21]=[C:20]1[C:19]1[C:27](=[CH:28][C:29]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[C:30]([Cl:31])[C:18]=1[Cl:17])[CH2:26]2)(=[O:3])[CH3:2]
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCO)C2
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reaction time: 0.5 h

Procedure:
A solution of dry tetrahydrofuran (50 ml) containing acetic acid (6.6 mg, 11 mMole) is treated with 1,1'-carbonyldiimidazole (178 mg; 11 mMole) and the mixture stirred under anhydrous conditions for 30 minutes. {[5,6-Dichloro-9a-(2-hydroxyethyl)-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (3.71 g, 10 mMole) is added and the mixture stirred for 16 hours. The solvent is removed by evaporation at reduced pressure. The residue is dissolved in methylene chloride, treated with 11 mM of HCl, washed with water, and dried over MgSO4. The solvent is removed by evaporation at reduced pressure to give the desired product which is recrystallized from acetonitrile.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:7][CH:8]=1.[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:26][N:25]=1.NC1ON=C(C)C=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][C:27]3[O:26][N:25]=[C:24]([CH3:23])[C:28]=3[CH3:29])=[O:32])[CH2:19][CH2:18]2)=[N:7][CH:8]=1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Reactant: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1noc(N)c1C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4onc(C)c4C)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (150 mg, 0.473 mmol, from Example 44, Step 5), phenyl 3,4-dimethylisoxazol-5-ylcarbamate (110 mg, 0.473 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc:CH2Cl2) to afford the title compound (86 mg) as a foamy white solid. MS APCI M+ 419.3, 378.2, 281.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.29 (s, 3H) 2.43 (td, J=5.86, 1.16 Hz, 2H) 2.55 (td, J=5.73, 1.20 Hz, 2H) 3.48-3.54 (m, 2H) 3.57-3.65 (m, 2H) 6.44 (s, 1H) 6.82-6.87 (m, 1H) 6.89-6.96 (m, 2H) 7.02-7.11 (m, J=7.60, 1.50, 1.06, 0.74 Hz, 1H) 7.35 (dd, J=8.77, 7.65 Hz, 1H) 7.61-7.69 (m, J=8.38, 2.46, 1.15, 0.45 Hz, 1H) 7.96 (td, J=1.60, 0.72 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][N:28]3C(=O)C4C(=CC=CC=4)C3=O)(=[O:25])=[O:24])[CH2:19][CH:18]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1.NN>C(O)C.CS(C)=O>[NH2:28][CH2:27][CH2:26][S:23]([N:20]1[CH2:19][CH:18]=[C:17]([C:5]2[N:6]=[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=3)[C:2]([NH2:1])=[N:3][CH:4]=2)[CH2:22][CH2:21]1)(=[O:25])=[O:24]
Reactant: Nc1ncc(C2=CCN(S(=O)(=O)CCN3C(=O)c4ccccc4C3=O)CC2)nc1-c1nc2ccccc2[nH]1
Agent: NN
Solvent: CS(C)=O
Solvent: CCO
Product: NCCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 80 °C
Yield: 22.3 %

Procedure:
To a suspension of 2-(2-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)ethyl)isoindoline-1,3-dione (24 mg, 0.045 mmol) in ethanol (240 μL) was added hydrazine (1.5 mg, 1.4 μL, 0.045 mmol), and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and was dissolved in 0.5 ml of DMSO and purified via reverse phase HPLC using 1 to 99% MeOH in H2O 2O (0.05% HCl as modifier) to obtain 5-(1-(2-aminoethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(1H-benzo[d]imidazol-2-yl)pyrazin-2-amine (4 mg, 18%). 1HNMR (400 MHz, MeOD) δ 8.59 (s, 1H), 8.12-8.03 (m, 2H), 7.78 (dd, J=6.1, 3.2 Hz, 2H), 7.16 (s, 1H), 4.43 (d, J=2.1 Hz, 2H), 3.95 (t, J=5.6 Hz, 2H), 3.81-3.67 (m, 4H), 3.12 (s, 2H). LC/MS m/z 400.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@:4]([CH:16]=[CH2:17])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].CO.[OH-].[Na+].[ClH:23]>O>[ClH:23].[ClH:23].[CH:16]([C@@:4]([C:3]([OH:18])=[O:2])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5])=[CH2:17]
Reactant: C=C[C@](N)(Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C[C@](N)(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Treatment of α-vinyltryptophan methyl ester in 1.1 methanol:water with two equivalents of sodium hydroxide, neutralization of the reaction mixture with 1N aqueous hydrochloric acid, and purification of the crude amino acid on DOWEX 50W-X4 cation exchange resin (elution with water and then 2 N aqueous hydrochloric acid) gives α-vinyltryptophan hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(O)(=O)C.[N:36]([O-])=O.[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[N:36][N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-n2nnc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a mixture of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol), 6 M hydrochloric acid (2.5 mL) and acetic acid (2.5 mL) was added an aqueous solution (0.25 mL) of sodium nitrite (41 mg, 0.59 mmol) at 0° C., and the obtained mixture was stirred at 0° C. for 30 min and at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (51.2 mg, yield 25%) as colorless crystals.
Reaction SMILES: ClC(N(C)C)=C(C)C.[S:9]1[CH:13]=[C:12]([CH2:14][C:15]([N:17]2[CH2:20][CH2:19][C:18]2([CH3:24])[C:21]([OH:23])=O)=[O:16])[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2.[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][CH2:35][NH:36][CH2:37][C:38]1[CH:46]=[CH:45][C:41]2[CH:42]=[CH:43][O:44][C:40]=2[CH:39]=1)[CH3:30]>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][CH2:35][N:36]([C:21]([C:18]1([CH3:24])[CH2:19][CH2:20][N:17]1[C:15](=[O:16])[CH2:14][C:12]1[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[S:9][CH:13]=1)=[O:23])[CH2:37][C:38]1[CH:46]=[CH:45][C:41]2[CH:42]=[CH:43][O:44][C:40]=2[CH:39]=1)[CH3:30]
Reactant: CCOC(=O)CCCNCc1ccc2ccoc2c1
Reactant: CC1(C(=O)O)CCN1C(=O)Cc1csc2ccccc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCN(Cc1ccc2ccoc2c1)C(=O)C1(C)CCN1C(=O)Cc1csc2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-N,N,2-trimethylpropenylamine (2 eq.) in DCM under nitrogen was added 1-(2-benzo[b]thiophen-3-yl-acetyl)-2-methyl-azetidine-2-carboxylic acid, Intermediate 121 (1 eq.). The solution was stirred at 20° C. for 1 h, then added to a solution of 4-[(Benzofuran-6-ylmethyl)-amino]-butyric acid ethyl ester, Intermediate 82 (1.2 eq.) in DCM at 0° C. TEA (2 eq.) was then added and the mixture was stirred at 0° C. for 3 h. The crude was diluted with DCM, washed twice with a saturated aqueous solution of NaHCO3, twice with aqueous HCl (0.5N), twice with water, dried over MgSO4, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (elution with heptane/EtOAc 25/75 to 10/90) to afford 4-{[1-(2-benzo[b]thiophen-3-yl-acetyl)-2-methyl-azetidine-2-carbonyl]-benzofuran-6-ylmethyl-amino}-butyric acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:12][CH:9]([CH:10]=[CH2:11])[CH:4]([CH:5]([OH:8])[CH2:6][OH:7])[O:3]1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:7][CH2:6][CH:5]([OH:8])[CH:4]2[O:3][C:2]([CH3:13])([CH3:1])[O:12][CH:9]2[CH:10]=[CH2:11])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CC1OC(C)(C)OC1C(O)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CC1OC(C)(C)OC1C(O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 100.6 %

Procedure:
3,4-(Dimethylmethylenedioxy)-5-hexene-1,2-diol (9.77 g) was mixed with 155 ml of pyridine and 52 ml of chloroform, and 11.39 g of p-toluenesulfonyl chloride was added gradually in four portions at 0° C. The mixture was stirred at 0° C. for 6 hours, poured into 6N hydrochloric acid with ice and extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence, dried with anhydrous ride aqueous solution in sequence, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 17.88 g of 3,4-(dimethylmethylenedioxy)-2-hydroxy-5-hexen-1-yl p-toluenesulfonate having the following properties.
Reaction SMILES: O=C1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=CN1.[H-].[Na+].[CH3:13]I.[CH3:15][N:16]([CH:18]=[O:19])[CH3:17]>>[CH3:15][N:16]1[CH:17]=[CH:5][C:6]([C:8]([O:10][CH3:13])=[O:9])=[CH:7][C:18]1=[O:19]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc[nH]c(=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (5 g, 1.0 eq) in 100 mL DMF was added 60% NaH (4.3 g, 3.0 eq) slowly at 0° C., and the mixture was stirred for 30 min at rt. Then CH3I (15.3 g, 3.0 eq) was added dropwise at 0° C. After the reaction was stirred at rt overnight, the reaction mixture was quenched with water and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (1.5 g, 25% yield). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=7.2 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.65 (dd, J=6.8 Hz, 2.0 Hz, 1H), 3.91 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:26])([CH3:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:27].CO>C1COCC1>[OH:26][C:8]1([CH3:25])[C:7]2[S:6][C:5]([C:3]([NH2:27])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (312 mg, 0.84 mmol) in THF (8 mL) at room temperature, NH3/CH3OH (self-made, 8 mL) was added. The mixture was stirred at room temperature for 3 h, and then concentrated to give a residue which was purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid (212 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.90 (s, 1H), 7.31 (dd, J1=8.3 Hz, J2=2.1 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.26 (s, 1H), 5.46 (s, 1H), 4.21 (d, J=11.7 Hz, 1H), 4.01 (d, J=11.8 Hz, 1H), 1.57 (s, 3H), 1.49 (s, 6H); LC-MS (ESI & APCI): 359.2 (M+1).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C@@H:13]2[OH:18])[CH3:7].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[OH:1][C:2]([CH3:20])([CH3:21])[CH2:3][CH2:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH3:7]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 104 mg (0.35 mMol) of (1S,4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl-decahydro-naphtalen-1-ol in 2 ml of CH2Cl2 are added under stirring 91.5 mg (0.42 mMol) of pyridiniumchlorochromate. The reaction mixture is kept stirring for 4 hours, diethylether is added and the slurry is filtered through Florisil using diethylether as eluant. The residue obtained after evaporation in vacuo is chromatographed over 5 g of silicagel with CH2Cl2 /ethylacetate 9/1 to yield 88 mg (85.5%) of oily pure (4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl-octahydro-naphtalen-1-one.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:13][C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.Cl.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[CH3:17][O:16][C:15]([CH:13]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]1=[O:12])=[O:18]
Reactant: O=C1CCCc2ccccc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccccc2C1=O
Temperature: 90 °C

Procedure:
A suspension of 60% dispersion of sodium hydride in mineral oil (1.64 g, 41 mmol) in dimethyl carbonate (50 mL) was treated dropwise with alpha-tetralone (4.6 mL, 34 mmol). The mixture was heated at 90° C. for 20 minutes, cooled to ambient temperature, treated with 2 M HCl (40 mL), and extracted with EtOAc (100 mL and 25 mL). The combined EtOAc layers were washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of hexane:EtOAc (20:1 and 10:1) to provide the title compound. MS (M+H)+ m/z 205.