Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([Si](C)(C)C)[O:4][N:3]=1.N>C(O)C>[CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][O:4][N:3]=1
Reactant: Cc1noc([Si](C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Agent: N
Solvent: CCO
Product: Cc1nocc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a sealed vessel were charged 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trimethylsilyl)isoxazole (169 g, 0.569 mol), 25% aqueous ammonia (1500 mL), and ethanol (1500 mL). The reaction mixture was heated to 60° C. After 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified via chromatography on silica gel (0-5% methanol/dichloromethane, linear gradient) to give 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole. MS ESI calc'd. for C10H16BNO3 [M]+ 209. found 209. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 2.40 (s, 3H), 1.31 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].N1C[CH2:26][O:25][CH2:24]C1.C(#N)C>Cl.CCOCC>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:18][CH2:26][O:25][CH2:24][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: C1COCCN1
Reactant: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared using procedures analogous to the ones used for Intermediate 39, but using morpholine for Step 1, a saturated solution of hydrogen chloride in ether, and diethyl ether as a solvent for Step 2 and acetonitrile for Step 3. MS (ES+APCI) (M+H) 336.1; LCMS retention time: 4.033 min (Method I).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[N:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[N:7]([CH2:18][CH:17]=[CH2:16])[C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CN1CCNC1=Nc1c(Cl)cccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCN(C1=NCCN1C)c1c(Cl)cccc1Cl

Procedure:
A mixture consisting of 4.9 gm (0.02 mol) of 1-methyl-2-(2,6-dichlorophenyl-imino)-imidazolidine, 2.1 ml of allyl bromide (125% of the stoichiometrically required amount), 2.7 gm of sodium carbonate and 25 ml of ethanol was refluxed for 5.5 hours while stirring. Thereafter, the reaction mixture was filtered, the filtrate was evaporated in vacuo to dryness, the residue was dissolved in dilute (about 1 N) hydrochloric acid, and the resulting solution was extracted with ether (the ethanol extracts were discarded). The acidic aqueous phase was then fractionally extracted with ether at stepwisely increasing pH-values (addition of 2 N sodium hydroxide). The thin-layer chromatographically uniform fractions were combined, dried over magnesium sulfate, and the ether was evaporated in vacuo, leaving an oil which crystallized gradually throughout. 2.3 gm (40.5% of theory) of the compound of the formula ##STR7## having a melting point of 59°-61° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[F:21][C:22]([F:37])([F:36])[C:23]1[C:31]2[N:30]=[C:29]([CH2:32][C:33](O)=[O:34])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:33](=[O:34])[CH2:32][C:29]1[NH:28][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:36])([F:37])[F:21])[C:31]=2[N:30]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nc2c(C(F)(F)F)cccc2[nH]1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)Cc1nc2c(C(F)(F)F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (70 mg, 0.19 mmol, prepared as described in WO PCT 0250019) was dissolved in 5 mL of 2:1 CH2Cl2/DMF. The resultant solution was charged sequentially with the lithium salt of (4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid (46 mg, 0.19 mmol, see procedure 28a), N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) and HATU (85 mg, 0.22 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (87 mg, 95% yield). MS found: (M+Na)+=511.3.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9](O)=[O:10]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]([Cl:3])=[O:10]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1Br
Reactant: O=S(Cl)Cl
Product: CCCCCCCOc1ccc(C(=O)Cl)cc1Br
Yield: 97.1 %

Procedure:
11 g of thionyl chloride was added to 14.5 g (0.046 mol) of the 3-bromo-4-n-heptyloxybenzoic acid prepared in Step II and was gently refluxed for two hours. Excess thionyl chloride was removed by distillation or vacuum distillation to yield 14.9 g of 3-bromo-4-n-heptyloxybenzoyl chloride. The yield was calculated to be 96.8%.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[CH3:9][C:10]([O:13][C:14]([N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:17]([C:25]1[C:30]([F:31])=[C:29](Cl)[N:28]=[C:27]([Cl:33])[N:26]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:12][C:10]([O:13][C:14]([N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:17]([C:25]1[C:30]([F:31])=[C:29]([N:4]2[CH2:5][CH2:6][O:7][CH2:8][C@@H:3]2[CH3:2])[N:28]=[C:27]([Cl:33])[N:26]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:15])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: C[C@H]1COCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C[C@H]1COCCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of (3S)-3-methylmorpholine hydrochloride (0.2059 g, 1.496 mmol) in DMF (7.5 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.7451 g, 1.498 mmol), and N,N-diisopropylethylamine (0.575 mL, 3.301 mmol). The solution was stirred overnight, and then diluted with Et2O (150 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This Et2O layer was washed with a fresh portion of water (50 mL), and the combined organic phase was diluted with DCM (50 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and azeotroped with EtOAc. The solid was collected by vacuum filtration and washed with hexanes. The supernatant was concentrated in vacuo, and purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N). The desired fractions were concentrated in vacuo, and the resulting solid was collected by vacuum filtration, washed with hexanes, and combined with the first crop of solid to give tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.6610 g, 79%) as a white solid. LCMS: (M+H)+: 562.2.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([OH:18])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([Cl:22])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1sccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
3-Benzenesulfonylaminothiophene-2-carboxylic acid (0.61 g, 2.15 mmol) was suspended in dichloromethane (8.6 mL). The resulting mixture was sequentially treated with N,N-dimethylformamide (1 drop), and, in two portions, oxalyl chloride (0.42 mL, 4.8 mmol). After stirring briefly at room temperature, the foaming subsided and the solution was refluxed until the reaction was complete. The mixture was concentrated to dryness, re-dissolved in dichloromethane, and filtered through very small pad of course silica gel, eluting with dichloromethane. Upon concentration of the eluent, the desired 3-benzenesulfonylaminothiophene-2-carboxylic acid chloride was obtained as a yellow solid (0.32 g, 49%), which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:11]([NH:19][C@H](C(O)=O)CCC(O)=O)(=[O:18])C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11]([NH2:19])=[O:18])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: NC1CCCc2sccc21
Reactant: O=C(O)CC[C@H](NC(=O)c1ccccc1)C(=O)O
Product: NC(=O)NC1CCCc2sccc21

Procedure:
Similarly, the salt of (+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine and (S)-(-)-N-benzoyl glutamic acid is treated in the above manner to afford (+)-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point 218° C. to 220° C.; [α]58925 +60°, [α]436 +149.8°, [α]365 +272.5°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1C(OCC)=O.S(=O)(=O)(O)O>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Agent: O=S(=O)(O)O
Product: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
100 g (0.270 mol) of 5-amino-4-ethoxycarbonyl-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole are suspended in 250 ml of 50 percent strength aqueous sulphuric acid and the suspension is warmed to 120° C. in the course of 2 hours; the more highly volatile constituents are thereby distilled off over a bridge. The mixture is kept at 115° C.-120° C. for a further 3 hours and is cooled and diluted with 400 ml of water, the pH is brought to 2 with dilute aqueous sodium hydroxide solution and the precipitate formed is filtered off with suction. It is washed neutral with water and dried in vacuo. 77.3 g (96% of theory) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 103° C.-104° C. are obtained.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@H:24]4[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:19]=[CH:18][C:17]=3[N+:29]([O-])=O)[CH:13]=2)=[O:7])[CH2:4][CH2:3]1.[CH3:34]O>[Pd].C(O)C>[CH:2]1([NH:5][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([N:14]3[C:15](=[O:32])[C:16]4[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH2:23][C@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[CH:21]=4)[N:29]=[CH:34]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC[C@H]2CCCN2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@H]3CCCN3)cc2c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-[(2R)-pyrrolidin-2-ylmethoxy]benzamide hydrochloride salt (3.32 g) and 10% Palladium on carbon (0.332 g) were stirred in ethanol (65 ml) and methanol (40 ml) under an atmosphere of hydrogen gas for 2 hours at room temperature. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (65 ml) and stirred with triethylorthoformate (3.14 ml) and glacial acetic acid (0.18 ml) at 80° C. for 1.5 hours and then concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 20% methanol/ethyl acetate followed by 20% methanol/ethyl acetate+1% aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[4-oxo-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (AZ12304521) (0.763 g) as a yellow/brown foam solid; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.70 (m, 2H), 1.49 (m, 1H), 1.68 (m, 2H), 1.86 (m, 1H), 2.14 (s, 3H), 2.85 (m, 3H), 3.44 (m, 1H), 3.94 (d, 2H), 7.53 (m, 2H), 7.59 (s, 1H), 7.72 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[N:29]=[N:28][N-:27][N:26]=3)=[CH:17][CH:18]=2)[C:10]([CH2:30][OH:31])=[C:9]([Cl:32])[N:8]=1.[K+].I([O-])(=O)(=O)=[O:35].[Na+]>O.[Ru](Cl)(Cl)Cl.O>[CH2:6]([C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:10]([C:30]([OH:35])=[O:31])=[C:9]([Cl:32])[N:8]=1)[CH2:5][CH2:4][CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Agent: Cl[Ru](Cl)Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Water (10 L) was added to a 22 L 4-neck round bottom flask. The water was cooled to 0° C. At 0° C., potassium hydroxide (855 g, 15.24 mol) was added followed by losartan potassium (500 g, 1.09 mol)), sodium periodate (554 g, 2.59 mol) and ruthenium (III) chloride hydrate (12 g, 0.05 mol) and the reaction mixture was stirred at 0° C. overnight. The reaction mixture was filtered. IPA (90 mL) was added to the filtrate while stirring. The solution was warmed to 25° C. and stirred for 2.5 hrs. After 2.5 hrs., phosphoric acid (1200 mL) was added, maintaining the temperature below +30° C. The mixture was stirred for 30 min and the product was filtered, washing with water. The residue was dried in the vacuum oven at 55° C. overnight. The solid was dissolved in methanol (4 L) and isopropyl acetate (12 L), and charcoal (activated carbon) (100 g) was added. The mixture was stirred at rt for 3.5 hrs, filtered and concentrated. The product was redissolved in DCM/MeOH and precipitated with heptane to afford the title compound as a greenish/brown foam which was used in subsequent steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]#[N:26])[CH:20]=[CH:21][C:22]=1[Cl:23].N>O1CCOCC1.Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:24][C:25]1[NH:26][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc2c1
Reaction time: 48 h

Procedure:
420 Milligrams of dimethyl aminoterephthalate and 446 mg of 3,4-dichlorophenylacetonitrile were added to 10 mL of 4N hydrogen chloride dioxane solution and stirred for about 2 days. Pouring the reaction mixture into ice, its pH was adjusted to 8-9 with 25% aqueous ammonia. The precipitated crystals were recovered by filtration and washed with water. The crude crystals were dissolved in chloroform-ethyl acetate (1:1) mixed solvent, and after removing the insoluble matter by filtration, the remaining solution was concentrated. The residue was purified on silica gel column chromatography (hexane:ethyl acetate=4:1) to provide 253 mg of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CSC=1C(O)=O.CC1C=CSC=1C(Cl)=O.[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([N:31]=[C:32]=[S:33])=[O:30].[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[C:51]([F:56])[CH:50]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:32]([NH:31][C:29]([C:25]2[S:26][CH:27]=[CH:28][C:24]=2[CH3:23])=[O:30])=[S:33])=[C:51]([F:56])[CH:50]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1ccsc1C(=O)N=C=S
Agent: Cc1ccsc1C(=O)Cl
Agent: Cc1ccsc1C(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4sccc4C)c(F)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-methyl-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-methyl-2-thiophenecarbonyl isothiocyanate was prepared using the resultant 3-methyl-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 3-Methyl-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 53%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:25])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:15][C:16]([CH3:25])=[CH:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(C)cc1)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 57 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene, the title compound was synthesized according to Reference Example 17b. Yield: 57%. Melting point: 167-169° C. (Ethyl acetate-hexane)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](Cl)[N:3]=1.[CH3:13][O-:14].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: C[O-]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)c(C(=O)O)cc1F
Yield: 65 %

Procedure:
A solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (51.12 g, 243 mmol) in methanol (400 ml) was treated with sodium methoxide in methanol (25% w/v, 100 ml, 535 mmol) and the mixture heated to reflux for 4 hours. The cooled mixture was treated with water (400 ml) and acidified to pH2 with aqueous hydrochloric acid (2M) then concentrated to ca 400 ml. Filtration, washing with water and drying in vacuo over P2O5 for 18 h afforded the product as a white solid (32.65 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:26]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([N:8]([C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: BrC(Br)(Br)Br
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CBr)cc2)CC1

Procedure:
710 mg of trans-N-(4-chlorobenzoyl)-N-methyl-4-(4-hydroxymethylphenyl)cyclohexylamine are reacted in 20 ml of methylene chloride with 723 mg of tetrabromomethane and 572 mg of triphenylphosphine. 250 mg of the title compound are obtained, melting point 181°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[CH2:11][C:12]([O:14]CC)=[O:13].C(O)C.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CC1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CC2CC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 0.31 g (1 millimole) of ethyl [1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidinyl]-acetate and 4 ml of ethanol a solution of 0.04 g (1 millimole) of sodium hydroxide and 6 ml of water are added. The reaction mixture is stirred at room temperature for 2 hours. The solution is extracted three times with 3 ml of dichloromethane each. The aqueous layer is acidified with concentrated aqueous hydrochloric acid to pH 2 and extracted three times with 3 ml of dichloromethane each. The united organic layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residue is crystallized from benzene. Thus 0.27 g of the desired compound are obtained, yield: 88%, M.p.: 112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2
Reactant: CCCCC(O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
The solution of 1-[2-(6-methoxy-naphthalen-2-yl)-benzofuran-3-yl]-pentan-1-ol (15.5 g, 43 mmol) and triethyl silane (10 g, 86 mmol) in methylene chloride (300 mL) was cooled in an ice bath. Trifluoro acetic acid (50 mL) was added gradually. The mixture was stirred at while cooling for 2 hours then was allowed to warm to room temperature. The solvent was evaporated. The residue was dissolved in ether and washed with sodium bicarbonate solution, then with water. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using 4% ethyl acetate in hexane as the mobile phase. The product was obtained as a clear oil (8.9 g). 1HNMR (300 MHz, DMSO-d6): δ8.22 (s, 1H), 7.98-7.92 (m, 2H), 7.95-7.90 (m, 2H), 7.64 (d, 1H, J=8.8 Hz), 7.65 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.38-7.20 (m, 4H), 3.90 (s, 3H), 2.96 (t, 1H, J =9.9 Hz), 1.70 (p, 1H, J=7.0 Hz), 1.42-1.26 (m, 4H), and 0.82 ppm (t, 3H, J=7.4 Hz).