Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C@@H:25]3[CH2:28][C@H:27]([OH:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-:34][Si](C)(C)C)(C)C.[Na+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>C1COCC1>[NH2:34][C:20]1[C:19]2[N:18]([C:17]([C@@H:25]3[CH2:28][C@H:27]([O:29][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn32)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
cis-tert-Butyl ({3-[8-chloro-1-(3-benzyloxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}oxy) acetate: cis-3-[1-(3-Benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]cyclobutanol (1.58 mmol, 640 mg) was dissolved in THF (8 mL) and cooled to −78° C. when it was charged with sodium bis(trimethylsilyl)amide (2.37 mmol, 2.37 mL), followed by adding tert-butyl bromoacetate (3.15 mmol, 0.47 mL) portion by portion. The reaction mixture was stirred under −20° C. for 30 min and 0° C. for 1 h before it was allowed to warm to rt slowly and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, dissolved in DCM, washed with water (3×15 mL) and dried over Na2SO4. The crude oil was purified by silica gel column chromatography (Jones Flashmaster, 50 g/150 mL cartridge, eluting with EtOAc:Hexane (2:3)), yielding the title compound as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=4.8 Hz, 1H), 7.46 (d, 1H, J=8.0 Hz, 1H), 7.40-7.27 (m, 7H), 7.04 (dd, J=2.0, 8.0 Hz, 1H), 5.14 (s, 2H), 4.25 (p, J=8.0 Hz, 1H), 3.36-3.27 (m, 1H), 2.90-2.84 (m, 2H), 2.70-2.62 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:14])=[O:8])[N:3]=[CH:2]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)Cc1c[nH]cn1
Product: Cl

Procedure:
5.0 g (30.75 mmol) of 4-imidazoleacetic acid were dissolved in 50 ml of methanol and then 5.6 ml (76.87 mmol) of thionyl chloride were added. The resulting solution was heated under reflux for 4 h and, after cooling, evaporated to dryness. Drying under reduced pressure afforded 5.3 g of the desired product in the form of a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[NH2:5].Cl.[N:21]([O-:23])=[O:22].[Na+].[N+:25]([CH2:28][CH2:29][CH3:30])([O-])=O.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][N:25]=[C:28]([N+:21]([O-:23])=[O:22])[CH2:29][CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: O=N[O-]
Reactant: CCC[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=NNc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluoro-4-[3-(trifluoromethyl)phenoxy]aniline (1.35 g) prepared as described in Step 2 of Example 1, water (18.2 mL), and conc. HCl (1.5 mL) was stirred overnight at room temperature. The suspension mixture was cooled to −5° C. and was added dropwise of NaNO2 (0.36 g in 2 mL water) over a period of about 10 min. The reaction mixture was further stirred for 30 minutes, and added CH3CO2Na3H2O (6.6 g). The resulting salt was added to a previously prepared solution of nitropropane (0.44 g) and NaOH (0.20 g) in ethanol (8 mL) and water (2 mL). The resulting mixture was stirred at 0° C. and then at room temperature overnight. It was filtered to give a red solid that was subsequently purified by column chromatography on silica (40% dichloromethane/hexane).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])C.[CH3:15][CH:16]([NH:18][CH2:19][CH2:20][OH:21])[CH3:17].C1(C)C=CC=CC=1>CCOCC>[CH3:15][CH:16]([N:18]([CH2:19][CH2:20][OH:21])[C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:17]
Reactant: CCOC(=O)c1noc2ccccc12
Reactant: CC(C)NCCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)N(CCO)C(=O)c1noc2ccccc12
Temperature: 140 °C
Yield: 81.6 %

Procedure:
A mixture of ethyl-1,2-benzisoxazole-3-carboxylate (10.0 g), 2-(1-methylethylamino)ethanol (16.1 g) and toluene (80 ml) was heated to 140° C. in a bomb for 4 hrs. The solution was diluted with ether (50 ml), washed with 5% sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 60% ethyl acetate in hexanes to give 10.6 g (81.4%) of product. Recrystallization from dichloromethane/hexanes afforded the analytical sample, mp 92°-94° C.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[Cl-].[Na+]>>[Br:3][C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=C(O)c1cc(O)nc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)c1cc(Br)nc2ccccc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Phosphorus oxybromide (5.00 g, 17.4 mmol) was added to commercially available 2-hydroxy-4-quinolinecarboxylic acid (1.00 g, 5.29 mmol), and the mixture was heated with stirring at 90° C. for 4 hours. The reaction solution was added to ice water. To the mixture, sodium chloride was added, and the deposited crystal was collected by filtration, washed with water, and dried to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.C(O[C:23]1(O[Si](C)(C)C)[CH2:25][CH2:24]1)C.C([BH3-])#N.[Na+]>CO>[CH:23]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:25][CH2:24]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.3 %

Procedure:
To a solution of 1-(4-nitrophenyl)piperazine (1.04 g, 5.00 mmol) in methanol (25 mL) under nitrogen was added molecular sieves (1.0 g), acetic acid (3.00 g, 2.86 mL, 50.0 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (5.22 g, 5.99 mL, 30.0 mmol), sodium cyanoborohydride (1.41 g, 22.5 mmol). The mixture was stirred at room temperature for 2.5 d, filtered, and concentrated. To the residue was added water and 1N aq. NaOH to adjust the PH>11. The mixture was extracted ethyl acetate, and the organic layer was dried over Na2SO4, concentrated to give the title compound (1.24 g, 100%) as a yellow solid. MS (ES+): m/z=247.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[S:32][CH:31]=[C:30]([C:33](O)=[O:34])[CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:40][NH2:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:40][NH:41][C:33]([C:30]1[CH:29]=[C:28]([C:7]2[C:8]3[C:15](=[O:16])[N:14]4[C@H:10]([C:9]=3[N:17]=[C:18]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]4)[S:32][CH:31]=1)=[O:34]
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)O)cs1)C(=O)N1CCC[C@@H]21
Reactant: NCc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)NCc3ccc(F)c(F)c3)cs1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-thiophenecarboxylic acid (0.100 g, 0.202 mmol) was dissolved in CH2Cl2. 3,4-difluorobenzylamine (0.036 mL, 0.303 mmol) was added followed by EDCI (0.047 g, 0.243 mmol) and HOBt (0.033 g, 0.243 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 3:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.065 g, 0.105 mmol, 52% yield): 1H NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.17–7.03 (m, 5H), 6.97 (t, J=8.6 Hz, 2H), 6.96 (m, 1H), 4.69 (dd, J=10.4, 6.3 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.16 (dd, J=14.3, 7.0 Hz, 2H), 3.73–3.63 (m, 1H), 3.42–3.36 (m, 1H), 3.19–2.99 (m, 4H), 2.51–2.43 (m, 1H), 2.39–2.27 (m, 2H), 1.41–1.34 (m, 1H), 1.09 (t, 7.1 Hz); ESMS m/z 620 (M+H)+, 618 (M−H)+; Anal. Calcd. For C33H28F3N3O4S: C, 63.96; H, 4.55; N, 6.78; found C, 64.03; H, 4.58; N, 6.73.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:10][CH2:1]/[C:2](/[CH3:9])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C(\C)CBr

Procedure:
A mixture of ethyl 3,3-dimethylacrylate (12.8g, 100 mmol), N-bromosuccinimide (11.8g, 66 mmol), dry benzene (50 ml) and benzoyl peroxide (20 mg) was heated under reflux for 0.5h. After cooling, filtration, concentration and distillation, ethyl 4-bromo-3-methylcrotonate was obtained. The latter (33.8 mmol) was added dropwise to triethylphosphite (47.17 mmol) at 100°. The mixture was warmed to 150o and the residue purified by distillation to give triethyl 4-phosphono-3-methylcrotonate (b.p. 120° at 0.5 mm.Hg) as a cis/trans mixture.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][N:12]([CH3:30])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([N+:27]([O-])=O)[CH:14]=1>C(#N)C.[Pd]>[NH2:27][C:15]1[CH:14]=[C:13]([N:12]([CH3:30])[CH3:11])[CH:18]=[CH:17][C:16]=1[CH:19]=[C:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
In a dark room, 20.5 g (0.07 mol) of (E) ethyl 3-(4-dimethylamino-2-nitrophenyl)-2-methyl-2-propenate, 33.4 g (0.33 mol) of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.), and 2.1 g of 10% Pd/C were dissolved in 200 ml of acetonitrile, and 13.8 g (0.30 mol) of formic acid (manufactured by Wako Pure Chemical Industries, Ltd.) were added dropwise thereto at room temperature. Along with the dropping, the reaction temperature rose up to 45° C. After the completion of dropping, the reaction liquid was heated to 60° C. and was stirred for 1 hour. After the completion of the reaction was verified by TLC, the reaction liquid was cooled to room temperature, and insoluble matters were filtered out. The filtrate was concentrated under a reduced pressure and then was dissolved in 400 ml of ethyl acetate. The resulting solution was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution; and was further dried with sodium sulfate anhydride. Thus dried product was concentrated under a reduced pressure, whereby 17.4 g of a crude product were obtained. This product was further recrystallized from normal hexane/ethyl acetate, whereby 4.67 g of the aimed compound were obtained (yield: 27%).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([S:22][CH3:23])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.C[O:25]CCO>>[CH3:23][S:22]([C:21]1[N:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)[C:18]3[C:13]([C:12]2=[N:19][N:20]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:25]
Reactant: COCCO
Reactant: COc1ccc(-c2nn3c(SC)nnc3c3ccccc23)cc1
Product: CS(=O)c1nnc2c3ccccc3c(-c3ccccc3)nn12

Procedure:
This compound is obtained by following the procedure of the foregoing example but substituting 6-phenyl-3-methylthio-1,2,4-triazolo[3,4-a]phthalazine for 6-(4-methoxyphenyl)-3-methylthio-1,2,4-triazolo[3,4-a]phthalazine. M.p. 215°-217° C. (Methylcellosolve®).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:11][C:12](Br)([F:14])[F:13]>CN(C)C=O>[Br:11][C:12]([F:14])([F:13])[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: FC(F)(Br)Br
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)(F)Br)cc1
Temperature: 25 °C

Procedure:
According to this reference, 1 mole of sodium salt of p-hydroxybenzo-nitrile and 1.7 moles of dibromodifluoromethane are dissolved in dimethylformamide, stirred at the room temperature for a day and distilled to obtain desired p-(bromodifluoromethoxy)-benzonitrile. However, the yield is only about 31.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.O>[CH3:34][S:35]([O:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15](=[O:26])[NH:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:13][CH:12]=2)=[CH:23][CH:22]=1)(=[O:37])=[O:36]
Reactant: O=C(/C=C/c1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 2.3 g (6.3 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-hydroxymethylphenyl)acrylamide in 200 mL of dichloromethane is combined with 1.94 mL (13.9 mmol) of triethylamine and then with 0.54 mL (6.92 mmol) of methanesulfonic acid chloride. The reaction mixture is stirred for 18 hours at ambient temperature, diluted with water, and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered through silica gel and the filtrate is evaporated down. Yield: 1.85 g (67% of theory); C23H20ClN04S (M=441.93); calc.: molecular ion peak (M+H)+: 442/444 (Cl); found: molecular ion peak (M+H)+: 442/444 (Cl); Rf value: 0.73 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: CC1(C)[O:19][CH:5]2[CH:6]3[CH2:11][O:10][CH:9]([OH:12])[CH:8]=[C:7]3[CH2:13][CH:14]([O:15][CH2:16][O:17][CH3:18])[CH:4]2[O:3]1.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[CH3:18][O:17][CH2:16][O:15][CH:14]1[CH2:13][C:7]2=[CH:8][CH:9]([O:12][CH3:21])[O:10][CH2:11][CH:6]2[CH:5]([OH:19])[CH:4]1[OH:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COCOC1CC2=CC(O)OCC2C2OC(C)(C)OC12
Solvent: CO
Solvent: CCN(CC)CC
Product: COCOC1CC2=CC(OC)OCC2C(O)C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
1,5,6,7,8,8a-Hexahydro-7,8-(dimethylmethylenedioxy)-6-methoxymethoxy-3H-2-benzopyran-3-ol (3.8 mg) was dissolved in 0.6 ml of dry methanol, and a catalytic amount of p-toluenesulfonic acid was added at room temperature. After the mixture was stirred at room temperature for 2 hours, triethylamine was added, and concentrated with water cooling under reduced pressure. The obtained residue was purified through a short silica gel column to provide 1.3 mg of 1,5,6,7,8,8a-hexahydro-6-methoxymethoxy-3-methoxy-3H-2-benzopyran-7,8-diol having the following properties (yield 68%).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[C:19]([O:38][CH3:39])=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[C:19]([O:38][CH3:39])=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)nc2OC)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2nc(OC)c(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2-fluoro-5-methoxyphenyl)-5-isobutoxy-2-methoxypyridin-3-yl)methoxy)phenyl)propanoate (120 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure. The crude crystals were recrystallized (ethyl acetate/hexane) to give the title compound (98 mg) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]([N:29]=C=O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([NH:29][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:13])[C@H:8]([C:18]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C1COCCN1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)N2CCOCC2)N(C(=O)NC(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and morpholine the title compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=401.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: Oc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(Oc2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (169 mg, 0.5 mmol), 3-methylsulfonylphenylboronic acid (200 mg, 1 mmol), Cu(OAc)2 (181 mg, 1 mmol), and NEt3 (35 μL, 2.5 mmol) and molecule sieves (4A) in DCM was shaken overnight at 20° C. Solid was removed by filtration and filtrate was evaporated to give a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4 to 1:2) to afford 1-(2-chlorophenyl)-5-(4-{[3-(methylsulfonyl)phenyl]oxy}phenyl)-3-(trifluoromethyl)-1H-pyrazole (88 mg). 1H-NMR: CDCl3: 7.68 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 7.62-7.40 (m, 2H), 7.27 (m, 2H), 7.21 (m, 1H), 6.93 (m, 1H), 6.80 (s, 1H), 3.04 (s, 3H), MS(ES): 493 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH2:12])[CH2:6]1)=[O:4].[Cl:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH:12][C:19]([C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:20])[CH2:6]1)=[O:4].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH:12][C:19]([C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:21])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1C[C@H](OC)[C@@H](N)C1
Reactant: O=C(O)c1ccc(Cl)s1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1

Procedure:
In analogy to example 10B, (3S,4S)-3-amino-4-methoxy-cyclopentanecarboxylic acid methyl ester was coupled with 5-chloro-2-thiophenecarboxylic acid. The epimers were separated by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-cyclopentanecarboxylic acid methyl ester and (1S,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-cyclopentanecarboxylic acid methyl ester, both as off-white solids. MS: 318.0 ([M+H]+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:17])[CH3:16].[C:18](O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:18][CH2:16][C:15]#[N:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CC#N
Reactant: CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CCCOc1cccc(Oc2ccccc2)c1
Yield: 726.2 %

Procedure:
To a solution of 3-phenoxyphenol (3.0 g, 16.1 mmol) in acetonitrile (10.6 mL, 161 mmol) was added tert-BuOH (120 mg, 1.6 mmol) and K2CO3 (225 mg, 1.6 mmol). The mixture was refluxed for 2 days. The reaction was filtered and concentrated, and the residue was purified by HPLC to get give 2.78 g (72%) of the title compound as a colorless gum. 1H NMR (400 MHz, CDCl3): δ 2.80 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.0 Hz), 6.55 (1H, s), 6.64 (2H, d, J=8.0 Hz), 7.02 (2H, d, J=7.6 Hz), 7.12 (1H, t, J=7.2 Hz), 7.23 (1H, t, J=8.0 Hz) 7.35 (2H, t, J=8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]1[CH2:20][CH2:19][CH2:18]1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(S)ccc1Br
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(SC2CCC2)ccc1Br
Temperature: 70 °C
Yield: 95.2 %

Procedure:
A stirred mixture of 4-bromo-3-fluorobenzenethiol (Preparation 26, 400 mg, 1.93 mmol), cesium carbonate (691 mg, 2.12 mmol) and bromocyclobutane (287 mg, 2.12 mmol) in DMSO (8 mL) was heated at 70° C. for 19 hours. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with 2-methoxy-2-methylpropane (30 mL), washed with water (30 mL), dried over sodium sulfate and concentrated in vacuo. This gave the title compound as a colourless oil 95% yield, 480 mg.