Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]1[C:24](=O)[C:25](=[O:30])[C:26]=1[O:27]CC)[CH3:21]>C(O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:24]4[C:25](=[O:30])[C:26](=[O:27])[C:23]=4[O:22][CH2:20][CH3:21])=[CH:7][CH:6]=3)=[C:9]([CH2:18][CH3:19])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(-c3c(CC)sc4ncnc(N)c34)cc2)c(=O)c1=O
Yield: 55.8 %

Procedure:
A mixture of Example 78A (0.135 g, 0.5 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (0.22 mL, 1.5 mmol) in ethanol (5 mL) was heated at 70-80° C. for 48 hours, then filtered while still hot. The filtrate was concentrated and the resulting residue was washed with hexanes and diethyl ether, and dried to provide 0.11 g of the desired product. MS (ESI(+)) m/e 395 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5](=[O:40])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29]COCCOC)=[C:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:20]=2)=[O:18])=[CH:8][CH:7]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[C:5](=[O:40])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:22]([OH:29])=[C:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:20]=2)=[O:18])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCC(=O)c2cc(C(C)(C)C)c(OCOCCOC)c(C(C)(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OCCCCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 31 h
Yield: 78.8 %

Procedure:
4-Hydroxy-alpha-oxobenzeneacetic acid ethyl ester (1.44 g) and 55% sodium hydride (0.36 g) in dimethylformamide (30 mL) was stirred for 20 minutes and then treated with 5-bromo-1-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]pentanone (3.4 g) in dimethylformamide (6 mL). The mixture was stirred at room temperature for 20 hours and then after an additional 4 hours at 50° C., it was worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-toluene; 1:17) to give 2.7 g of 4-[5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil. A solution of the above 4-[5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester (2.1 g) was dissolved in dichloromethane (20 mL) containing trifluoroacetic acid (1.1 mL) was stirred at room temperature for 31 hours, then saturated sodium bicarbonate solution was added (25 mL). The separated organic layer was dried (MgSO4) and evaporated and the crude product was purified by HPLC (ethyl acetate-hexane; 4:21). Trituration of the resulting material with hexane afforded 1.4 g of 4-[5-[3,5-bis(1,1-dimethylethyl) -4-hydroxyphenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 95°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:26]=1[C:27](O)=[O:28]>>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([C:15]#[C:14][C@:9]2([O:23][C:27](=[O:28])[C:26]3[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[CH:33][C:25]=3[CH3:24])[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])[CH:17]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1c(C)cc(C)cc1C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2,4,6-trimethyl-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(m-tolylethynyl)-4-(2,4,6-trimethylbenzoyloxy)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester eliminated ion); RT=4.280 min; HPLC Method III
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:18]=[N-:19]
Reactant: Nc1cccc(OCC(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1cccc(OCC(=O)O)c1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
To a 100 mL recovery flask was added 3-aminophenoxyacetic acid 2 (2.00 g, 12.0 mmol, 1.0 eq.) and a stirbar. Acetic acid (5 mL), conc. HCl (2 mL) and H2O (3 mL) were added to the flask. The reaction mixture was cooled to 0° C. upon which a solution of NaNO2 (0.908 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added over a period of 20 sec. The mixture was stirred for 5 minutes. A solution of NaN3 (0.855 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added slowly to the reaction mixture upon which the mixture foamed. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 1 h. A light brown solid precipitates out of solution. The suspension was filtered and washed with cold H2O to yield a light-brown solid (1.48 g). Upon drying, the more precipitate formed in the filtrate. The precipitate was refiltered to yield more product (0.17 g). Total yield: 1.65 g, 71%. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 192.1 (M−H)−1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 7.31-7.27 (t, 1H), 6.73-7.69 (m, 2H), 6.59-6.58 (m, 1H), 4.62 (s, 2H) ppm.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[OH-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:12][N:10]1[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6][CH:5]([CH2:4][CH2:3][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:11]1
Reactant: C1CCNC1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Product: CN1CC(CCN2CCCC2)Oc2ncccc2C1=O
Temperature: 80 °C

Procedure:
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-one hydrochloride, 16 g (0.058 mole), was dissolved in 65 ml of pyrrolidine. The stirred solution was heated to 80° C. for 3 hr. The solution was cooled to room temperature and dilute sodium hydroxide solution (50 ml) was added. The resulting solution was extracted with chloroform (3×30 ml) and concentrated in vacuo. The residue was taken up in boiling isopropyl alcohol (500 ml/and fumaric acid (9.2 g, 0.079 mole) was added. The solution was filtered hot and the filtrate cooled to 20° C. for several hours. The resulting crystals, 14 g (47.8%) were collected and recrystallized from isopropyl alcohol, m.p. 147°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:20]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCc1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 2-(2-fluorophenyl)ethanol (5.5 g) and imidazole (8.0 g) in DMF (50 mL) was cooled in ice-water, treated with tert-butyldimethylchlorosilane (6.52 g), then removed as from the cooling bath and stirred at room temperature for 3.5 hours. The solution was poured into water and extracted three times with diethyl ether. The combined organic extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford the subtitled compound as a colourless oil. Yield 9.9 g.
Reaction SMILES: O(C[C:10]([CH2:19][O:20][Si](C(C)(C)C)(C)C)([CH:17]=[CH2:18])[CH2:11][C:12]([O:14][CH2:15]C)=[O:13])[Si](C(C)(C)C)(C)C.OS(O)(=O)=O>C1COCC1>[OH:20][CH2:19][C:10]1([CH:17]=[CH2:18])[CH2:15][O:14][C:12](=[O:13])[CH2:11]1
Reactant: C=CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C=CC1(CO)COC(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of 7a (8.34 g, 20 mmol) in aqueous THF (60 mL, 1:1) was treated with concentrated H2SO4 (10 mL) and stirred at room temperature for 24 h. The mixture was concentrated under vacuum, diluted with water, and the aqueous layer was extracted with CHCl3. The combined organic layer was washed with H2O , dried (NaSO4) and concentrated. The residue was purified by flash column chromatography over silica gel with EtOAc/hexane (2:1) as eluant to give 8b (2.50 g, 88%) as an oil; IR (neat) 3452 (OH), 1777 (C=O), 1641 cm-1 ; 1H NMR (CDCl3) δ 2.51 (d of AB, J=17.4 Hz, 1 H, H-3a), 2.63 (d of AB, J=17.4 Hz, 1 H, H-3b), 3.62 (s, 2 H, CH2OH), 4.16 (d of AB, J=9.2 Hz, 1 H, H-5a), 4.32 (d of AB, J=9.2 Hz, 1 H, H-5b), 5.19 (d, J=17.5 Hz, 1 H, CH=CHH), 5.29 (d, J=10.8 Hz, 1 H, CH=CHH), 5.85 (dd, J=17.5, 10.8 Hz, 1 H, CH=CH2); 13C NMR (CDCl3) δ 35.94, 47.61, 65.56, 73.33, 116.18, 137.55, 176.97. Anal. Calcd for C7H10O3 : C, 59.14; H. 7.09. Found: C, 59.05; H, 7.09.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[C:22](Cl)(=O)[CH2:23]CCCCCCCC=C>>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:22]=[CH2:23])[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCC(=O)N1CC(=O)N(C(C)=O)CC1=O
Product: C=CCCCCCCCCC(=O)N1CC(=O)N(C(C)=O)CC1=O

Procedure:
##STR27## Synthesized as for 1-Acetyl4-nonanoyl-2,5-piperazinedione in EXAMPLE I using 10-undecenoyl chloride in place of nonanoyl chloride.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C(O)C.O.C(Cl)Cl.[Fe]>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc(N)c2C)cc1
Temperature: 80 °C

Procedure:
The product from Example 6B (1.43 g, 3.67 mmoles) and NH4Cl (0.14 g, 2.57 mmoles) in ethanol (18.4 mL) and water (6.4 mL) were treated with iron powder (1.43 g, 25.7 mmoles) and heated at 80° C. for one hour. The reaction mixture was allowed to cool to room temperature, diluted with CH2Cl2 (100 mL), filtered through Celite with ethyl acetate, and the filtrate was concentrated under reduced pressure to provide the title compound which was used without further purification.
Reaction SMILES: C=CCCCCCCCC.CCCCCCCCC=CCCCCCCCC.CC=CCCCCCCCCCCC.CC=CCCCCCCCCCCCCC.C=CCCCCCCCCCCCCC.[CH3:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH:82]=[CH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94]CC>>[CH3:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH:82]=[CH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH3:94]
Reactant: CCCCCCCCC=CCCCCCCCCCCCCC
Agent: C=CCCCCCCCC
Agent: C=CCCCCCCCCCCCCC
Agent: CC=CCCCCCCCCCCC
Product: CCCCCCCCC=CCCCCCCCCCCC

Procedure:
A process according to claim 1, wherein (a) is 1-decene or 9-octadecene and (b) is a mixture of 2-tetradecene with 2-hexadecene or 1-pentadecene, whereby a mixture of 9-tricosene and 9-heneicosene is formed.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3(O)C4C(=CC=CC=4)C(C4C=CC5OCOC=5C=4)=C3C(OCC)=O)=CC=2O1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Ethyl (RS)-1,3-Di-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: N#N.[CH2:3]([O:5][CH2:6][C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)[O:10][CH:11]=1)[CH3:4].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:3]([O:5][CH2:6][C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[O:10][CH:11]=1)[CH3:4]
Reactant: CCOCc1coc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOCc1coc(Cn2ncc(N)n2)n1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(ethoxymethyl)-2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)oxazole (115 mg, 0.45 mmol), iron powder (77 mg, 1.36 mmol) and NH4Cl (123 mg, 2.27 mmol) in a mixture of EtOH (2.4 mL) and water (1.2 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (25 mL) was added followed by 1N NaOH (25 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (5×25 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.48 min; [M+H]+=224.09.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.075 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.44 mmol) and methylamine (0.136 g, 4.40 mmol). mp 141-143.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH:29]([CH3:48])[C:30]([C:36]1[CH:47]=[CH:46][C:39]2[N:40]([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:38]=2[CH:37]=1)([OH:35])[C:31]([F:34])([F:33])[F:32]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([O:28][C:26]2[CH:25]=[CH:24][C:23]([CH:29]([CH3:48])[C:30]([C:36]3[CH:47]=[CH:46][C:39]4[N:40]([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:38]=4[CH:37]=3)([OH:35])[C:31]([F:32])([F:33])[F:34])=[C:22]([Cl:21])[CH:27]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Reaction time: 96 h
Yield: 58.5 %

Procedure:
Copper(II)acetate (657 mg), 3-fluoro-4-methoxycarbonylphenylboronic acid (CAS Reg. 505083-04-5, 716 mg), and pyridine (0.3 ml) were added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 500 mg) in DCM (20 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 days and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 2:1 EtOAc/heptane) to give the title compound (400 mg) as a light yellow oil. MS (m/e)=567.1 [M+H+].
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([CH3:40])[C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH2:33][CH:34]([CH3:40])[C:35]([OH:37])=[O:36])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CC(C)C(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.82-6.88 (m, 2H), 5.19 (s, 2H), 2.89-2.97 (m, 1H), 2.75 (q, J=7.6 Hz, 2H), 2.58-2.65 (m, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H20F5NO3S, 486.1 (M+H). found 486.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([S:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38](Br)[N:37]=2)=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:35])[N:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(c1ccccc1)c1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(S(=O)c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzenesulfinyl-6-bromo-pyridine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[CH3:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: Cc1cccc(C(=O)OCCl)c1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)OCn2c(-c3cc(C(F)(F)F)ccn3)noc2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.19 g of chloromethyl 3-methylbenzoate was added, and the mixture was stirred at 70° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.08 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3-methylbenzoate (present compound (34)).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18](=O)[NH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1C=CC=C[CH:24]=1>O=P(Cl)(Cl)Cl>[C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18]([NH:23][CH3:24])=[N:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nn2c(=O)[nH]c(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nc(C)nc2c(S(=O)(=O)c3ccccc3)c(SC)nn12
Temperature: 110 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A suspension of 0.36 g (1 mmol) of 8-benzenesulphonyl-2-methyl-7-methylsulphanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one in 20 ml of POCl3 was treated with 0.12 ml (1.5 mmol) of pyridine and heated 110° C. for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was dried azeotropically twice with 50 ml of toluene each time. The thus-obtained residue was taken in 10 ml of 2N methylamine in tetrahydrofuran and stirred at room temperature for 4 hrs. The reaction solution was evaporated and partitioned between H2O and AcOEt. The organic phase was washed with H2O and sat. NaCl solution, dried (MgSO4), filtered and evaporated. Chromatography (SiO2, AcOEt/hexane 1:1) yielded 0.28 g (80%) of (8-benzenesulphonyl-2-methyl-7-methylsulphanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-methylamine as white crystals, m.p. 285° (dec).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18])=[C:11]([Cl:24])[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[Cl:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18]
Reactant: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2n1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)cc(O)cc2n1C
Yield: 92.4 %

Procedure:
In 60 ml of tetrahydrofuran was dissolved 2.20 g (6.40 mmol) of ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate. After 0.3 g of 10% palladium/carbon was added to the solution, catalytic hydrogenation was performed at ambient temperature under normal pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.50 g (92.4%) of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate. 1H NMR (CDCl3) δ: 1.38-1.44 (3H, m), 3.98 (3H, s), 4.33-4.40 (2H, m), 5.07 (1H, s), 6.67 (1H, t, J=0.99 Hz), 6.78 (1H, d, J=1.98 Hz), 7.30 (1H, d, J=0.99 Hz)