Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O:31]C(/N=N/C(OC(C)C)=O)=O)C.[CH2:42]1[CH2:46][O:45][CH2:44][CH2:43]1>CCOC(C)=O>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][C@@H:43]([CH3:42])[C:44]([O:45][CH3:46])=[O:31])[CH:1]=1
Reactant: Cc1cccc(O)c1
Reactant: C1CCOC1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)Oc1cccc(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of m-cresol (5.0 g, 46 mmol, 1 equiv), methyl-D(+) lactate (4.8 g, 46 mmol, 1 equiv) and PPh3 (14.5 g, 55.2 mmol, 1.2 equiv) in anhydrous THF (200 mL) under argon and at 0° C., was added dropwise DIAD (9.96 g, 48.2 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. until room temperature overnight. The crude mixture was dissolved in AcOEt (200 mL) and washed with a 0.5 N HCl aqueous solution (×2), a saturated NaHCO3 solution (×2), brine and then dried over Na2SO4. After filtration, solvent was evaporated. The crude product was purified by flash chromatography on silica gel (AcOEt/hexane 0->60%) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20](Cl)[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:36][N:37](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20]([C:36]#[N:37])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(Cl)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(C#N)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of methyl 2-(2-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)-4-chloro-6-(m-tolylamino)pyrimidine-5-carboxylate (399.7 mg, 0.816 mmol), tetrakis(triphenylphosphine)palladium(0) (96.3 mg, 0.083 mmol), and zinc cyanide (53.2 mg, 0.453 mmol) in DMF (5 mL) was stirred at 120° C. for 1 h under microwave irradiation. Water (50 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic layers were washed with saturated aq NaHCO3 (50 mL), water (50 mL), and brine (50 mL), were dried over anhydrous Na2SO4, and then filtered (DM1020). The filtrate was concentrated under reduced pressure and was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a colorless oil (315.0 mg, 80%). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.77 (m, 15H), 2.36-2.39 (m, 3H), 3.00-3.21 (m, 2H), 3.49-3.69 (m, 1H), 3.97 (s, 3H), 4.49-5.10 (m, 3H), 6.96-7.02 (m, 1H), 7.24-7.41 (m, 3H), 10.14-10.45 (m, 1H). [M+H] calc'd for C25H33N6O4, 481. found, 481.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22](N)=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N([O-])=[O:34].[Na+].[OH-].[Na+]>>[CH2:1]([C@@:4]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:34])[NH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)[nH]c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 3.47 mmol.) in 3.5 MH2SO4 (25 mL) was added 2 M NaNO2 (15 mL) at 0° C. The reaction mixture was stirred at rt overnight. The reaction was treated with aqueous NaOH solution (8%), and the mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (891 mg, 59%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.15-2.38 (m, 3H), 2.51-2.60 (m, 2H), 2.94 (m, 1H), 4.99-5.11 (m, 2H), 5.65-5.74 (m, 2H), 6.67 (m, 1H), 6.89 (d, 2H), 7.00 (t, 2H), 7.13-7.20 (m, 2H), 7.20-7.27 (d, 2H), 7.33 (m, 1H), 7.46 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:22])([C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH2:8][C:7]([F:22])([F:6])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Methanesulfonyl chloride (2.8 ml, 36.72 mmol) was added to a solution of 4,4,5,5,6,6,7,7,7-nonafluoroheptan-1-ol (6.0 g, 21.6 mmol) and triethylamine (6.0 ml, 43.2 mmol) in dichloromethane (60 ml) at 0° C., followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3) to give 1-methanesulfonyloxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane (6.73 g, Yield 92.2%) as a colorless oil.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pt]>[CH:10]1[C:9]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[O:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Pt]
Product: c1ccc2c(c1)oc1ccccc12

Procedure:
Commercial use of these materials has been hampered however, by reason of high costs, presence of impurities, and general unavailability. Commercially available dibenzofuran for example is presently obtained from coal tar and frequently contains impurities such as acenaphthene and fluroene which cannot conveniently be separated by commercially suitable methods such as washing, recrystallization, or distillation. In some cases dibenzofuran having greater purity as compared to that obtained from coal tar may be synthesized, but the prior art methods are costly because of expensive starting materials, complicated procedures, low yields or the like. For example, dibenzofuran has been obtained in a 30% yield by Graebe and Ullman [Ber. 29, 1877 (1896)] by diazotization and subsequent hydrolysis of 2-aminodiphenyl oxide, while Tauber and Halberstadt [Ber. 25, 2745 (1892)] obtained a yield of 75% by similar treatment of 2,2'-diaminodiphenyl. These two methods however are not adapted to commercial operation due to the high cost and difficulty of obtaining the starting materials required. Hale and Stoesser (U.S. Pat. No. 1,808,349) obtained dibenzofuran by intramolecular dehydrogenation of orthophenylphenol over a refractory oxide catalyst, but again the high cost of the starting material limits the commercial utility of this route. Cullinane [J. Chem. Soc., 2267 (1930)] obtained dibenzofuran in 20% yield in eight hours by pyrolysis of phenol over litharge at 150° C. The low yield limits commercial utility of this route. Walsh and Preston (U.S. Pat. No. 3,108,121) reacted diphenyl ether, also known as diphenyl oxide, over a relatively expensive and sensitive 5% platinum on charcoal catalyst to obtain dibenzofuran. Shiotani and Itatani [Angew. Chem. 86 478 (1974)] used a palladium acetate catalyst to produce dibenzofuran from diphenyl oxide but obtained much dimerized product as well.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:6]
Reactant: Nc1ncc[nH]1
Reactant: Cc1cc(Cl)c(C(=O)O)cc1CNC(=O)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)Nc2ncc[nH]2)cc1CNC(=O)C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a mixture of 2-chloro-4-methyl-5-[(2-methylpropanoylamino)methyl]benzoic acid (75.0 mg, 0.28 mmol, 1.0 equiv) and 2-aminoimidazole monosulfate (51.4 mg, 0.28 mmol, 1.0 equiv) in DMF (0.56 mL), add DIEA (0.204 mL, 1.17 mmol, 4.2 equiv) and BOP (152 mg, 0.33 mmol, 1.2 equiv). Stir at 60° C. for 5 h and isolate the resulting precipitate by filtration. Triturate with 9:1 dichloromethane:methanol (800 mL), and filter through a pad of silica gel. Concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (57 mg, 61% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.76 (br s, 2H), 8.20 (t, 1H, J=6.0 Hz), 7.33 and 7.33 (s and s, 1H and 1H, isochronous), 6.75 (br s, 2H), 4.21 (d, 2H, J=5.7 Hz), 2.42 (sep, 1H, J=6.8 Hz), 2.28 (s, 3H), 1.00 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 335/337 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(N)=O)cc1
Yield: 63 %

Procedure:
A mixture of p-hydroxybenzamide (3.43 g), methyl bromoacetate (2.37 ml) and K2CO3 (3.45 g) was stirred for 12 hr in 25 ml of DMF. The reaction mixture was diluted with water (150 ml); the solid was filtered, washed with water, and air dried. Crystallization from ethanol gave 3.3 g (63%) of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].CCO.[BH4-].[Na+].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with compound 10.4 (34.9 g, 95.7 mmol), EtOH (175 mL) and THF (17.5 mL). Next, sodium borohydride (1.10 g, 29.1 mmol) was added in 3 portions at 0° C., and the reaction was vigorously stirred at 0° C. for 1 h. The reaction mixture was poured into 463 mL of 0.25 N HCl at 0° C. and the product was extracted with 3×200 mL of AcOEt. The combined organics were washed sequentially with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 20% AcOEt/hexane-30% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (33.5 g). 1H NMR (400 MHz) (CDCl3) δ 7.37 (1H, d, J=1.5 Hz); 7.31-7.28 (2H, m); 7.05 (1H, dd, J=1.8, 8.2 Hz); 6.77 (1H, d, J=8.2 Hz); 6.72 (1H, d, J=8.3 Hz); 4.67 (2H, s); 4.61 (2H, d, J=5.9 Hz); 4.28 (2H, q, J=7.2 Hz); 2.29 (3H, s); 1.66 (1H, t, J=5.9 Hz); 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH3:13])[C:11]=1[NH2:12].[OH-].[Na+].O1CCOCC1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>O>[NH2:12][C:11]1[N:10]([CH3:13])[N:9]=[CH:8][C:7]=1[NH:6][C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1ncc(N)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc(NC(=O)Oc2ccccc2)c1N
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 4,5-diamino-1-methylpyrazole sulfuric acid salt (158 g) in water (1.1 L) was neutralized to pH 6.9 with 4N aqueous sodium hydroxide solution, and dioxane (474 ml) was added to this solution. To the resulting mixture was added dropwise phenyl chloroformate (124 g) maintaining pH of the mixture at 6.9 with 4N aqueous sodium hydroxide solution at a temperature below 10° C. The reaction mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give 5-amino-1-methyl-4-phenoxycarbonylaminopyrazole (155 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][CH2:11]1.[H][H]>>[CH:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Reactant: C1=Cc2ccccc2C1
Reactant: [H][H]
Product: c1ccc2c(c1)CCC2
Product: c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 4 h

Procedure:
A portion of the 2:1 fraction (by molar ratio) of indene and tetrahydrofluorene obtained in Example 1 was charged in an autoclave, and was then reacted and processed in a similar manner as in Example 1 except that the hydrogen transfer reaction was conducted for 4 hours. As a result of an analysis by gas chromatography, fluorene and indane were found to have been formed with a yield of 98% (based on tetrahydrofluorene) and with a yield of 99% (based on indene), respectively.
Reaction SMILES: [NH2:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[C:18](OC)(=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30].C(SCCCCCCCCCC(NC1C=CC=CC=1SCCCC(OCC)=O)=O)(C)C>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:32])([OH:31])=[O:30]
Reactant: CCOC(=O)CCCSc1cccc(C)c1N
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Agent: CCOC(=O)CCCSc1ccccc1NC(=O)CCCCCCCCCSC(C)C
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1SCCCC(=O)O

Procedure:
When amine (11) is acylated with acid chloride (7) as per procedure Step (E), and the resultant diester (ethyl 4-(2-(11-carbomethoxyundecanoylamino)phenylthio)butyrate 12 is hydrolyzed in Step I as per procedure (F), the title compound, 13 m.p. 113.5°-115° C. is obtained.
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]([Cl:35])[CH:37]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then 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 (55 mg, yield 63%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH:15]=O.[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23].N1CCCCC1>C(O)C.O>[CH2:28]([O:27][C:25]([C:24]1[CH:15]([C:14]2[CH:13]=[C:12]([F:11])[C:19]([F:20])=[C:18]([F:21])[CH:17]=2)[C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[O:10][C:22]=1[NH2:23])=[O:26])[CH3:29]
Reactant: CCOC(=O)CC#N
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N)Oc2cc3c(cc2C1c1cc(F)c(F)c(F)c1)OCO3
Temperature: 80 °C

Procedure:
3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml, stirred for 1 h, solids were collected by filtration, washed with 60% aq. ethanol and dried (280 mg, 0.71 mmol, 71%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14].[C:17]([NH:21][S:22]([C:25]1[S:26][CH:27]=[C:28](C(O)=O)[N:29]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].CN([C:36]([O:40]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:17]([NH:21][S:22]([C:25]1[S:26][C:27]([C:36]([NH:1][N:2]2[CH:6]=[CH:5][C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:3]2[C:13]([O:15][CH3:16])=[O:14])=[O:40])=[CH:28][N:29]=1)(=[O:23])=[O:24])([CH3:18])([CH3:19])[CH3:20]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)NS(=O)(=O)c1nc(C(=O)O)cs1
Reactant: COC(=O)c1c(-c2ccccc2)ccn1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)ccn1NC(=O)c1cnc(S(=O)(=O)NC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 14 h
Yield: 29.2 %

Procedure:
Methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (0.400 g, 1.85 mmol) and 2-(N-(tert-butyl)sulfamoyl)thiazole-4-carboxylic acid (0.733 g, 2.77 mmol) (Johnson et al., WO 2011/28741) were dissolved in DMF (10 mL) and cooled to 0° C. HATU (1.41 g, 3.70 mmol) was added slowly, followed by DIPEA (1.29 mL, 7.40 mmol). The reaction mixture was allowed to reach ambient temperature over 14 h and was diluted with water (25 mL) and extracted with ethylacetate (3×20 mL). The organic layer was separated and the combined organic portions dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 38% EtOAc/hexanes) to afford methyl 1-(2-(N-(tert-butyl)sulfamoyl)thiazole-5-carboxamido)-3-phenyl-1H-pyrrole-2-carboxylate (0.250 g, 29.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 9H), 3.50 (s, 3H), 6.31 (d, J=3.2 Hz, 1H), 7.25-7.43 (m, 6H), 8.39 (s, 1H), 8.77 (s, 1H), 11.83 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O-:15])([O-])=O.[Cs+].[Cs+].[CH:18](O)([CH3:20])[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:15][CH2:12][CH2:19][C@@H:18]1[CH2:20][C@H:1]1[C:3]1[CH:8]=[CH:7][C:6]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)O
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Product: N#Cc1ccc(-c2ccc([C@@H]3C[C@H]3CCO)cc2)cc1

Procedure:
A solution of Example 26F (1.2 g, 5 mmol), 4-cyanophenylboronic acid [CAS 126747-14-6] (1.46 g, 2 equivalents), Pd(PPh3)2Cl2 (350 mg), and Cs2CO3 (6.5 g) in isopropanol (80 mL) under N2 was stirred at reflux overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous NaHCO3 and then with brine. The organic layer was then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4.1 hexanes/ethyl acetate to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85-1.03 (m, 2H), 1.12-1.2 (m, 1H), 1.65-1.7 (m, 3H), 3.78 (t, J=6 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.68 (q, J=9 Hz, 4H). MS (DCl—NH3) m/z 264 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([OH:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([O-:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
3.790 g of Donepezil is dissolved in 70 ml of ethyl acetate. A solution (35 ml) of benzenesulfonic acid (1.852 g) in isopropanol is added slowly and drop-wisely. The solid precipitated is filtered under suction to give the title compound.
Reaction SMILES: C(#N)C.[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[Br:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][CH:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](Cl)=[O:24])=[CH:19][CH:18]=1>O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]([C:26]([CH3:27])([CH3:29])[CH3:28])[C:23]([N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[O:24])=[CH:30][CH:31]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(Cc1ccc(Br)cc1)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(Cc1ccc(Br)cc1)C(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.2 %

Procedure:
To 30 ml of acetonitrile were added 0.75 g of imidazole and 1.2 g of triethylamine, and 3.0 g of α-(p-bromobenzyl)-tert-butyl-acetic acid chloride was then added dropwise at room temperature. Thereafter, the mixture was stirred at room temperature for 6 hours, poured into 300 ml of water and extracted with 300 ml of chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily product obtained was recrystallized from diisopropyl ether to obtain 2.39 g of N-[α-(p-bromobenzyl)-tert-butylacetyl]imidazole (compound No. 4). m.p. 101°-102° C.