Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:17]([OH:20])[OH:18])=[CH:3][C:4]=2[CH:9]=1)#[N:11]
Reactant: N#Cc1ccc2occc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(B(O)O)cc2c1
Reaction time: 0.5 h

Procedure:
To benzofuran-5-carbonitrile (500 mg, 3.49 mmol) in THF (9.98 mL) at −78° C. was added nBuLi 1.6M in hexanes (2.401 mL, 3.84 mmol) dropwise. The mixture was stirred for 30 min at this temperature, and then trimethyl borate (0.858 mL, 7.68 mmol) was added dropwise. The mixture was stirred for 20 min, and then HCl 2N (11.52 mL, 23.05 mmol) was added. The bath was removed, and stirring continued for 30 min. The mixture was diluted with water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated. Crude 5-cyanobenzofuran-2-ylboronic acid (623 mg, 87%) was then dried and used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:10]([O:24][CH:25]([F:27])[F:26])=[CH:11][CH:12]=[C:13]([C:14]4[O:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=4)[C:7]=3[C:6]=2[CH:28]=1.N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>O1CCCC1>[F:27][CH:25]([F:26])[O:24][C:10]1[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:28][C:6]=3[C:7]=2[C:13]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(N)cc4c23)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(NS(C)(=O)=O)cc4c23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of ethyl 2-(8-amino-4-(difluoromethoxy)dibenzo[b,d]furan-1-yl)oxazole-4-carboxylate (0.65 g, 1.667 mmol) in tetrahydrofuran (10 mL) was added pyridine (0.4 mL, 5.031 mmol). To this solution was added methane sulfonyl chloride (2.6 mL, 0.033 mol) at 0-5° C. After 30 minutes, the reaction slurry was stirred at room temperature for 18 hours. The reaction mass was poured into the cold water and extracted with dichloromethane (3×50 mL). The organics were dried over sodium sulphate and filtered. The organics were evaporated under reduced pressure to give the crude product. The product was purified by column chromatography by using gradient of ethyl acetate in hexane (0-20) %. Yield—44.8%. 1H-NMR (DMSO-d6) δ: 1.35-1.39 (m, 3H), 3.06 (s, 3H), 4.36-4.41 (m, 2H), 7.41 (s, 1H), 7.51 (d, 1H), 7.62 (d, 1H), 7.87 (d, 1H), 8.06 (d, 1H), 8.96 (s, 1H), 9.07 (s, 1H), 9.77 (s, 1H); HPLC (purity): 97.2%; Mass calculated for C20H16F2N2O7S-466.4, observed—467.0; Rf—0.47 (Ethyl acetate:Hexane (1:1)
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.N[C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].NC1C=CC=CC=1>CC#N>[CH2:3]([C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:1]=[CH2:2]
Reactant: CCOC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)ON=O
Solvent: C=CCBr
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=CCc1cc(C(=O)OCC)cc([N+](=O)[O-])c1
Temperature: 11 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), ethyl 3-amino-5-nitrobenzoate (631 mg, 3.0 mmol) was added during 20 minutes while maintaining the temperature of the reaction mixture at 10-12° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 47:3) gave 470 mg (67%) of ethyl 3-allyl-5-nitrobenzoate as a light yellow oil, which crystallized upon standing overnight in the refrigerator. 1H NMR (CDCl3, 400 MHz) δ 8.70, (m, 1H), 8.24, (m, 1H), 8.20, (m, 1H), 6.03-5.91, (m, 1H), 5.24-5.13, (m, 2H), 4.44, (q, 2H, J=7.1 Hz), 3.56, (d, 2H, J=6.5 Hz), 1.44, (t, 3H, J=7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 165.0, 148.8, 143.1, 135.9, 135.5, 132.6, 127.7, 122.9, 118.4, 62.3, 39.9, 14.7; Anal HRMS Calcd. for C12H13NO4 (M): 235.0845. Found: 235.0846.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH2:25][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:21]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Product: Cc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Yield: 87 %

Procedure:
Method 1 was followed using 4-fluoro-3-nitrotoluene (1.0 eq), 3-(N-Boc-amino) piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-methyl-2-nitrophenyl)piperidin-3-ylcarbamate (87%). LCMS (m/z): 336.1 (MH+); LC Rt=3.41 min.
Reaction SMILES: [N:1]1(O)C=[CH:5][CH:4]=[CH:3][CH2:2]1.[C:8](=[O:11])([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1>[Cu](I)I.O>[Br:26][C:24]1[CH:25]=[C:20]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:8]2=[O:11])[CH:21]=[N:22][CH:23]=1
Reactant: ON1C=CC=CC1
Reactant: O=C([O-])[O-]
Reactant: Brc1cncc(Br)c1
Agent: I[Cu]I
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccccn1-c1cncc(Br)c1
Temperature: 120 °C
Reaction time: 11 h
Yield: 12.2 %

Procedure:
Pyridin-1-ol (96 mg), cesium carbonate (412 mg), and copper iodide (50 mg) were added to a tube containing a DMF (4 ml) solution containing 3,5-dibromopyridine (200 mg) and the tube was sealed in a nitrogen atmosphere, followed by stirring at 120° C. for 11 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:5 to 1:1), and a brown solid of 5′-bromo-2H-[1,3′-bipyridine]-2-one (25.8 mg) was thus obtained.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)[C:10]([CH3:24])=[CH:9][N:8]=1)(=O)=O.[SH:25][C:26]1[NH:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(CC)CC)C>O1CCCC1>[CH3:23][C:19]1([CH3:22])[O:18][CH2:17][CH:16]([CH2:15][O:14][C:11]2[C:10]([CH3:24])=[CH:9][N:8]=[C:7]([CH2:6][S:25][C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)[C:12]=2[CH3:13])[CH2:21][O:20]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1cnc(COS(C)(=O)=O)c(C)c1OCC1COC(C)(C)OC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 95.5 %

Procedure:
To a mixture of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl methanesulfonate (500 mg, 1.39 mmol), 2-mercaptobenzimidazole (209 mg, 1.39 mmol) and tetrahydrofuran (5 ml), triethylamine (0.387 ml, 2.78 mmol) was added and the mixture was stirred at room temperature for 14 hours and 25 minutes. The reaction mixture was concentrated under reduced pressure, and toluene and a 0.1N aqueous sodium hydroxide solution were added to the residue and insoluble substance was removed by filtration. The organic layer was taken out and the aqueous layer was extracted again with toluene. The organic layers were combined, washed with a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (1/1) and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (549 mg, 95.5%) as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[NH:9][CH:10]=O)=[CH:4][C:3]=1[O:26][CH:27]([CH3:29])[CH3:28].CCN(CC)CC.P(Cl)(Cl)(Cl)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[N+:9]#[C-:10])=[CH:4][C:3]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Oc1cc(C(NC=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [C-]#[N+]C(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a solution of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine (2.8 g, 7.1 mmol) in CH2Cl2 (30 mL) at 0° C. was added acetic formic anhydride (2.8 mL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ISCO (120 g silica gel column, 0 to 60% EtOAc/hexane over 60 min gradient) to give N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (2.56 g, 85% yield) as a colorless oil. LCMS: RT=1.99 min [M+H] 422.0 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm). To a solution of N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (225 mg, 0.53 mmol) in THF (2 mL) at 0° C. was added Et3N (0.4 mL, 2.9 mmol) followed by phosphorous oxychloride (74 μL, 0.80 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was diluted with ice water (15 mL) and extracted with Et2O (3×15 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over 30 min) to yield 1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene (143 mg, 67% yield) as a pale yellow oil. LCMS: RT=2.13 min [M−NC] 377 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.07-7.13 (1H, m), 6.91-7.03 (4H, m), 6.84-6.86 (1H, m), 5.78-6.04 (1H, m), 5.82 (1H, s), 4.54 (1H, ddd, J=11.97, 6.15, 6.04 Hz), 1.35 (6H, t, J=5.05 Hz).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12][CH:13]=[C:14](Br)[N:15]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C.CCOC(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12][CH:13]=[C:14]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc2ccccc2s1
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2s1
Temperature: 100 °C
Yield: 91 %

Procedure:
Tert-butyl N-[3-(benzothiophen-2-yl)-5-bromo-pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (100 mg, 0.1975 mmol) was dissolved in DMF (781.2 μL) and treated with piperazine (170.1 mg, 1.975 mmol) and the reaction mixture heated at 100° C. for 30 minutes. The reaction was allowed to cool to ambient temperature and diluted with EtOAc/water and the layers separated. The organic layer was washed with water (3×), dried (MgSO4) and concentrated in vacuo. The material was used crude in the next step (92 mg, 91% Yield). 1H NMR (DMSO) d 1.23 (18H, s), 2.98 (4H, m), 3.59 (2H, m), 3.63 (2H, m), 7.29 (2H, m), 7.74 (3H, m), 7.89 (1H, s) ppm; MS (ES+) 511.98
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C([Li])CCC.[C:14](Cl)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)OC(N)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 27.9 %

Procedure:
1,1-Dimethylethyl carbamate (5 g, 42.7 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) In a 500 mL 3 necks round bottom flask and cooled at −78° C. under nitrogen. n-Butyl lithium (1.6 M in THF, 26.7 mL, 42.7 mmol) and (2E)-2-butenoyl chloride (4.55 mL, 42.7 mmol) were added in slow successive additions as follow: 1) n-Butyl lithium: 13.4 mL and (2E)-2-butenoyl chloride 2.28 mL; 2) n-Butyl lithium: 6.8 mL and (2E)-2-butenoyl chloride 1.14 mL; 3) n-Butyl lithium: 3.34 mL and (2E)-2-butenoyl chloride 0.57 mL; 4) n-Butyl lithium: 1.67 mL and (2E)-2-butenoyl chloride 0.28 mL (2×). A five to ten min waiting time was observed between each double addition, and the final mixture was stirred for an extra 30 minutes period at −78° C. The temperature was kept below −60° C. during the additions. The reaction mixture was then slowly poured into a stirred saturated NaHCO3 aqueous solution (250 mL). The aqueous layer was extracted with AcOEt (2×250 mL). The combined organic phases were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 100% AcOEt in Hexanes) gave 1,1-dimethylethyl (2E)-2-butenoylcarbamate (2.21 g, 11.93 mmol, 28%) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.Cl.[CH3:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:7][C:4]1[S:3][C:2]([N:12]2[CH2:13][CH2:14][CH:10]([CH3:9])[CH2:11]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: CC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCN(c2ncc(Br)s2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2,5-Dibromothiazole (250 mg, 1.029 mmole), 3-methyl-pyrrolidine hydrochloride (188 mg, 1.544 mmole), and K2CO3 (569 mg, 4.12 mmole) were combined in DMF (5 mL) then heated to 100° C. After stirring overnight the mixture was cooled to RT, diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-10 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (234 mg, 92%) as a pale yellow oil. 1H NMR (399 MHz, CDCl3): δ 7.06 (s, 1 H); 3.58-3.45 (m, 2 H); 3.45-3.35 (m, 1 II); 2.97 (dd, J=9.7, 7.7 Hz, 1 H); 2.47-2.36 (m, 1 H); 2.20-2.10 (m, 1 H); 1.73-1.63 (m, 1 H); 1.12 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccc(CC(=O)O)cc1
Agent: Cl
Product: COc1ccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)cc1
Yield: 66.1 %

Procedure:
By working in accordance with Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.28 g of (4-methoxyphenyl)acetic acid, 0.61 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 211° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3Br)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:37]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C1COCC1>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3[N:37]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C1CCCNCC1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3N3CCCCCC3)CC2)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 30.1 mg (0.7 mmol) 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-bromo-benzonitrile, 30 ul (0.175 mmol) DIPEA and 91 ul (0.91 mmol) of a 1M solution of azepane in DMF was heated to 100° C. for 24 h. After removal of THF 2 ml dioxane, 180 ul of a 1M solution of azepane in DMF and 30 ul (0.175 mmol) DIPEA were added and the mixture was heated to 120° C. for 16 h. After evaporation of all volatiles the residue was taken up in 1 ml MeOH/formic acid 6/1 and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 9.3 mg (30%) of the title compound. MS (m/e): 449.2 (MH+, 100%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[OH:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)(Cl)(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2O
Agent: O=[Cr](=O)(Cl)Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2=O
Yield: 76.4 %

Procedure:
5-[3′-(t-Butoxycarbonylamino)propyloxy]-1-hydroxy-8-nitro-1,2,3,4-tetrahydronaphthalene (2.46 g) is dissolved in dry methylene chloride (110 ml), and thereto are added molecular sieves 3A (6.73 g) and pyridinium dichlorochromate (1.5 equivalent), and the mixture is refluxed. After the reaction is completed, the mixture is diluted with ether, and the insoluble materials are removed by filtration through a pad of Celite. The filtrate is concentrated, and the residue is purified by silica gel column chromatography to give the title compound (1.87 g) as a colorless powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([NH:9][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
3-Chloropropylsulfonyl chloride 1 (1.456 g, 8.23 mmol) was dropwise added to a solution of aniline (0.5 ml, 8.23 mmol) in pyridine (5 ml) with cooling at −20° C. to −30° C. over about 5 minutes. After the completion of the addition, the reaction mixture was stirred for another 45 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:2), 1.683 g (88%) of N-phenyl-3-chloropropylsulfonamide (intermediate 3j) was obtained as a yellow oil. From the intermediate 3j, the desired compound 4j (yield: 57%) was yielded as a pale yellow solid in a manner as described in Preparation 1. IR (CHCl3)cm−1: 3020, 1598, 1495, 1315, 1139. NMR (CDCl3) δ: 2.46-2.60 (2H, m, CH2), 3.34-3.42 (2H, m, CH2), 3.78 (2H, t, J=6.6 Hz, CH2), 7.10-7.40 (5H, m, C6H5).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[O:25][C:24]([C:26]3[N:27]=[C:28]4[N:32]([CH:33]=3)[N:31]=[C:30]([O:34][CH3:35])[S:29]4)=[CH:23][C:22]2=C(O)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(Cl)Cl.C1C=CC=CC=1>[CH3:35][O:34][C:30]1[S:29][C:28]2=[N:27][C:26]([C:24]3[O:25][C:21]4[CH:20]=[C:19]([O:18][CH3:17])[CH:16]=[C:15]([O:14][CH2:12][C:10]5[S:11][C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[N:8][N:9]=5)[C:22]=4[CH:23]=3)=[CH:33][N:32]2[N:31]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1cc(OCc2nnc(-c3ccccc3)s2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reaction time: 0.01 h
Yield: 29.1 %

Procedure:
In a 200 mL round-bottomed flask, benzene was added to ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (Example 8B, 80 mgs, 0.252 mmol) and 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 58.2 mgs, 0.303 mmol) and the mixture was sonificated for 30 sec. and concentrated in vacuo to remove traces of water in the starting material. Triphenylphosphine (99 mgs, 0.378 mmol) was added and the mixture was dried on high vacuum for 10 min. THF (40 mL) were added and the mixture was sonificated/heated for 5 min. Diisopropyl azodicarboxylate (68.6 μl, 0.353 mmol) in THF (4 mL) was added dropwise on app. 1 h and LC/MS showed that the reaction was not complete. Diisopropyl azodicarboxylate (2 drops) were added again and the mixture was diluted in CH2Cl2, washed with sat. aqueous NaHCO3 (1×), brine (1×), and dried over anhydrous MgSO4 and concentrated. The residue was purified on silica gel chromatography (100% CH2Cl2 up to 15% EtOAc/CH2Cl2) to give a residue which was triturated with MeCN and afforded the title material (36 mgs, 29%). LC (Method A): 2.901 min. HRMS (ESI) calcd for C23H12N5O4S2 [M+H]+ m/z 492.0722. found 492.0806. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.96-8.02 (m, 2H), 7.87 (s, 1H), 7.45-7.55 (m, 3H), 7.10 (s, 1H), 6.73-6.78 (m, 1H), 6.48 (d, J=1.57 Hz, 1H), 5.63 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H).