Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14]>CC(O)C.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCCOCCO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C1N=C(NCCOCCO)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-thioxo-1,3-thiazolidin-2-one (10 g) in 2-propanol (25 mL) and ethyl acetate (75 mL) was added 2-(2-aminoethoxy)ethanol (7.50 mL), and the mixture was stirred at room temperature for 2 hr and further stirred for 2 hr under ice-cooling. The precipitate was collected by filtration, and the obtained solid was washed with ethyl acetate to give the title compound (12.5 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[F:19][C:20]1[C:28]([N:29]([CH3:38])[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[OH-].[Na+]>O1CCCC1>[F:19][C:20]1[C:28]([N:29]([CH3:38])[C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])=[O:23]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CN(C(=O)c1ccccc1)c1cccc(C(=O)Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1cccc(C(=O)Nc2ccccc2C(F)(F)F)c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
26.8 g (166.3 mmol) of 2-(trifluoromethyl)aniline, 37.0 g (365.9 mmol) of triethylamine, and 100.9 g (365.9 mmol) of 2-fluoro-3-(N-methylbenzamido)benzoyl chloride were added to tetrahydrofuran (400 mL), and the mixture was stirred at 50° C. for 3 hours. The reaction liquid was filtered through a filter, and an aqueous solution (125 mL) containing 14.6 g (365.9 mmol) of sodium hydroxide was added to the filtrate, followed by stirring at 50° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the obtained residue was extracted with ethyl acetate, and washed with aqueous potassium carbonate solution and saturated saline solution, sequentially. The organic layer was dried over magnesium sulfate. Then, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The obtained solid was washed with n-hexane and isopropyl ether, followed by drying, to obtain 63.2 g (yield 91%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:3].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>ClCCl>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:22])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (230.1 mg, 0.600 mmol) is added a solution of HCl in 1,4-dioxane (3.00 mL, 12.00 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride. A solution of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720 mmol) and DIPEA (0.126 mL, 0.720 mmol) in dichloromethane (4 mL) is allowed to stir for 1 hour. The reaction is quenched with 10% aqueous citric acid and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (148.2 mg). HPLC retention time=1.64 minutes (condition A); MS (m+1)=384.1; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.21 (t, J=7.07 Hz, 3 H) 2.31-2.39 (m, 2 H) 2.40-2.56 (m, 4 H) 2.77-2.92 (m, 2 H) 4.08 (q, J=7.24 Hz, 2 H) 4.33-4.48 (m, 1 H) 6.62 (d, J=8.34 Hz, 1 H) 7.30 (d, J=8.08 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.41-7.49 (m, 2 H) 7.54-7.60 (m, 2 H) 7.60-7.67 (m, 2 H) 10.02 (br. s., 1 H).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:22]3[CH:21]=[C:20]([NH2:19])[CH:25]=[CH:24][CH:23]=3)[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: Nc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, and using 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 3-aminophenylboronic acid, a mixture of the E and Z isomers of the title compound is prepared.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[NH2:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:25])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(N)=O)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 14.7 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-aminocarbonylphenyl)boronic acid (0.603 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 64 hours and allowed to cool to room temperature. A precipitate formed and was isolated by filtration, washed with water and DME, and recrystallized from methanol (100 mL/900 mg). The crystals were isolated by filtration, washed with methanol, and dried in a vacuum oven at 65° C. to provide 191 mg of 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-7-yl]benzamide as an off-white solid, mp >250° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([CH:16]=[O:17])=[CH:14][N:15]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([CH2:28][N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[O:17]1[C:16]([C:13]2[N:10]3[CH:11]=[CH:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]3=[N:15][CH:14]=2)=[CH:30][N:29]=[CH:28]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cnc2cc(-c3ccccc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2ccn3c(-c4cnco4)cnc3c2)cc1

Procedure:
7-Phenylimidazo[1,2-a]pyridine-3-carbaldehyde (7-1, 0.030 g, 0.14 mmol), tosylmethyl isocyanide (0.032 g, 0.16 mmol) and K2CO3 (0.022 g, 0.16 mmol) were dissolved in 1 ml MeOH and the resulting solution was heated to reflux. After 4 h the reaction was quenched by the addition of water. The resulting mixture was extracted 3× with EtOAc, and the combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of DCM to 95:5 DCM/MeOH. The product was further purified by reverse phase preparative HPLC to afford the title compound. 1H NMR (CDCl3) δ 8.63 (d, 1H, J=7.1 Hz), 8.52 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.78 (m, 2H), 7.74 (dd, 1H, J=1.4, 7.3 Hz), 7.67 (s, 1H), 7.58 (m, 3H). LCMS m/z (M+1) Calc: 262.1, found 262.2.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C(O)C.C(O)(=O)/C=C/C(O)=O>CS(C)=O>[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)CO3
Temperature: 80 °C
Yield: 60.9 %

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.45 g, 1.2 mmole) and 4-(4-fluorobenzoyl)piperidine (0.73 g, 3.54 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 4 hours. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.28 g of the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.30 g of pale yellow solid, m.p. 229-230° C.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2[N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:26]([CH:29]4[CH2:31][CH2:30]4)(=[O:28])=[O:27])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[OH:35][NH2:36]>C(O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15]1[CH:16]=[C:11]([N:8]2[C:7]3[CH:32]=[CH:33][C:4](/[C:1](=[N:36]\[OH:35])/[CH3:2])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:12]=[C:13]([NH:25][S:26]([CH:29]2[CH2:31][CH2:30]2)(=[O:27])=[O:28])[CH:14]=1
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cc(NS(=O)(=O)C2CC2)cc(-c2ccc(F)cc2F)c1
Agent: Cl
Solvent: CCO
Product: C/C(=N/O)c1ccc2c(c1)ncn2-c1cc(NS(=O)(=O)C2CC2)cc(-c2ccc(F)cc2F)c1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of N-(5-(5-acetyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (110 mg, 0.235 mmol) in ethanol was added hydroxyl amine hydrochloride (24.7 mg, 0.353 mmol) and the mixture was heated at 80° C. for 2 h. The mixture was concentrated under vacuum and washed with ether to afford the product in 49% yield (55 mg). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.03 (s, 1H), 7.82-7.70 (m, 3H), 7.60-7.58 (d, 2H), 7.52 (s, 1H), 7.46-7.40 (m, 1H), 7.27-7.24 (m, 1H), 2.86-2.83 (m, 1H), 2.25 (s, 3H), 1.01-1.00 (m, 4H); LC-MS (ESI): Calculated mass: 482.5; Observed mass: 483.1 [M+H]+ (rt: 1.475 min).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[N-:22]=[N+:23]=[N-].[Na+]>CS(C)=O>[N:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:22]=[N-:23]
Reactant: Nc1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(N)cc1)C2=O
Yield: 99.8 %

Procedure:
13.5 g (0.047 mol) of 4-(3-nitrophthalimidyl)aniline and 3.4 g (0.051 mol) of sodium azide in 120 ml of dimethylsulphoxide are heated for 18 hours at 80° C. The reaction mixture is then concentrated in vacuo at 80° C. and diluted with 100 ml of water, the mixture is filtered with suction and the filter residue is washed with 20 ml of water and dried for 24 hours in a drying cabinet at 80° C./100 mm Hg. 13.1 g (100% of theory) of 4-(3-azidophthalimidyl)-aniline are obtained; melting point 176° C. (with decomposition). IR spectrum (KBr): 1780 and 1725 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)[CH:7]=1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(C(F)(F)F)c(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-(5-fluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9, 0.542 g, 1.58 mmol) and HCl (2 N solution in Et2O, 10 mL) in CH2Cl2 (20 mL) stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (30 mL), and the resulting precipitate was collected by filtration to provide 4-(5-fluoro-2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10) as a white solid (0.393 g, 88%): 1H NMR (300 MHz, DMSO-d6) δ 9.26-9.00 (m, 2H), 7.84 (dd, J=8.7, 5.4 Hz, 1H), 7.46-7.36 (m, 1H), 7.24 (dd, J=9.3, 2.4 Hz, 1H), 5.67 (br s, 1H), 3.76-3.64 (m, 2H), 3.27 (t, J=5.1 Hz, 2H), 2.70-2.40 (m, 2H).
Reaction SMILES: O.[P:2]([Cl:6])(Cl)([Cl:4])=[O:3].[CH2:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)(Cl)(Cl)Cl>[P:2]([Cl:6])([Cl:4])(=[O:3])[O:12][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCO
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCCOP(=O)(Cl)Cl
Reaction time: 18 h
Yield: 102.9 %

Procedure:
To a tap water cooled solution of 79 g of phosphorous oxychloride in 200 ml of carbon tetrachloride is added dropwise with stirring a solution of 50 g of 1-pentanol in 125 ml of carbon tetrachloride. The temperature rises to 30° C. and stirring is continued for 18 hours. The solvent is evaporated and the syrup evaporated with toluene several times. The residue is distilled rom a Kugelrohr still to give 108.7 g of the desired product as a colorless oil, B.P. 85°-90° C./0.3 mm.
Reaction SMILES: Cl.Cl.[C:3](=[NH:11])([O:9][CH3:10])[CH2:4][C:5](=[NH:8])[O:6][CH3:7].C(N(C(C)C)C(C)C)C.[F:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=O>ClCCl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([O:9][CH3:10])[N:11]=[C:23]([CH:22]([F:21])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1
Reactant: O=C(Cl)C(F)c1ccccc1
Reactant: COC(=N)CC(=N)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)nc(C(F)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
Dimethyl malonimidate dihydrochloride (11.0 g) was suspended in dichloromethane (100 ml) at -40° C. Ethyl diisopropylamine (38.9 ml) was added dropwise over 15 minutes at -40° C., followed by 2-fluoro-2-phenylacetyl chloride (11.0 g) in dichloromethane (15 ml) over 10 minutes at -40° C. The reaction mixture was allowed to warm to room temperature and stand overnight. It was then diluted further with dichloromethane, washed with ammonium chloride solution, then with water, and was dried over magnesium sulfate. The dichloromethane solution was evaporated to dryness to give 13.9 g of the desired product.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[C:15]1(=O)[O:18][CH2:17][CH2:16]1.Cl>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[O:14][CH2:15][CH2:16][C:17]2=[O:18]
Reactant: Oc1ccccc1F
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCOc2c(F)cccc21
Reaction time: 1 h

Procedure:
Potassium t-butoxide (2.42 g) was added to a solution of the compound 1-1 (2.20 g) in tetrahydrofuran (100 ml) at room temperature. After stirring for five minutes at the same temperature, beta-propiolactone (2.71 ml) was added. Because of heat generation, the mixture was moved to an ice bath and stirred at the same temperature for one hour. After further stirring at room temperature for four hours, the mixture was made acidic with 1 N hydrochloric acid to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a mixed solvent of 20% ethyl acetate-hexane to obtain the title compound (1.44 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[CH3:23][C:24]1([CH3:37])[CH:33]2[O:34][CH:32]2[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:35]#[N:36])[CH:30]=2)[O:25]1.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:37])[CH:33]([OH:34])[CH:32]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:35]#[N:36])[CH:30]=2)[O:25]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2phenylpyrazolo[1,5-a]pyridine (0.60 g), 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-chromene (0.80 g), and 60% sodium hydride (0.16 g) in dimethylsulfoxide (6 ml) was stirred for 5 hours at 60° C., and then diluted with ethyl acetate. The mixture was washed with water (10 ml) and sodium chloride aqueous solution (10 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) with a mixture of n-hexane and ethyl acetate (2:1). The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-[2-(2,2-dimethyl-3-hydroxy-6-cyano-3,4-dihydro-2H-chromen-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2phenylpyrazolo[1,5-a]pyridine (0.51 g).
Reaction SMILES: CN(C=[O:5])C.FC1C(O)=C(F)C(F)=C(F)C=1F.[CH:18]1([N:24]=[C:25]=[N:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[C:25]([NH:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5]
Reactant: CN(C)C=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
Suspended in 200 ml of acetonitrile are N-(9-fluorenylmethoxycarbonyl)-4-L-hydroxyproline (20.5 g, 50 mmol), followed by the addition of 12 ml of N, N'-dimethylformamide under ice cooling. The resulting mixture is stirred, to which 11.9 g (1.1 equivalents) of pentafluorophenol and 13.2 g (1.1 equivalents) of dicyclohexylcarbodiimide are added. The resulting suspension is stirred for one hour and then, stirred overnight at room temperature. Dicyclohexylurea produced by the reaction is removed by filtration and the filtrate is concentrated. The concentrate is dissolved in ethyl acetate. Dicyclohexylurea, which remained undissolved, is removed by filtration. The operations of dissolution in ethyl acetate, filtration, and concentration are additionally repeated twice. N,N'-Dimethylformamide contained in the concentrate is completely distilled off under reduced pressure. The concentrate is dissolved in ethyl acetate, and to the resulting solution is added n-hexane for re-precipitation, whereby 28.0 g of the product is obtained (yield: 93%).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][C:8]2([CH3:27])[S:12][C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH3:15])=[N:10][C:9]2=[O:26])[CH2:3][CH2:2]1.[O:28]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([N:4]([CH2:5][CH2:6][CH2:7][C:8]2([CH3:27])[S:12][C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:25])[F:24])[CH3:15])=[N:10][C:9]2=[O:26])[C:33]([C:30]2[CH:31]=[CH:32][O:28][CH:29]=2)=[O:34])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccoc1
Reactant: C[C@H](NC1=NC(=O)C(C)(CCCNC2CC2)S1)c1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC1=NC(=O)C(C)(CCCN(C(=O)c2ccoc2)C2CC2)S1)c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
The mixture of 5-(3-(cyclopropylamino)propyl)-5-methyl-2-((S)-1-(2-(trifluoromethyl)-phenyl)ethylamino)thiazol-4(5H)-one (0.106 g, 0.265 mmol), 3-furoic acid (0.0297 g, 0.265 mmol), TBTU (0.0895 g, 0.279 mmol), and N,N-diisopropylethylamine (0.0555 ml, 0.318 mmol) in DMF (3.0 mL) was stirred at ambient temp. overnight. The mixture was partitioned between EtOAc and Na2CO3 (aq), and the combined organic portions were washed with brine. The solvents were removed in vacuo, and the residue was purified by flash column chromatography (0 to 100% of EtOAc in hexanes) to give the title compound as a white solid. MS m/z: 494.1 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(C(C)C)C(C)C.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([NH:11][CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:13][CH:12]=1)=[O:23]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-nitrophenethylamine hydrochloride (50 g, 0.247 mole), DIEA (128 mL, 0.74 mole, 3 eq.) and CH2Cl2 (500 mL) in a 1 L round bottom flask equipped with a magnetic stirrer was added (CF3CO)2O (52.5 mL, 0.37 mole, 1.5 eq) dropwise at 5-10° C. (with ice/water bath). After stirring for another 1 h after the addition at RT, the reaction was quenched with water (200 mL) and transferred into a separatory funnel. The organic layer was separated, washed with water and sat. NH4Cl, dried over Na2SO4, filtered, concentrated to give a brown oil. The crude was triturated with water (300 mL), filtered and dried on vacuum overnight to give the desired 2,2,2-trifluoro-N-[2-(4-nitro-phenyl)-ethyl]-acetamide as a yellow solid. This can be used for next step without further purification. An analytical sample was obtained through recrystallization from CH3OH/H2O as a yellow solid.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(OCC)C>C(#N)C>[F:1][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: [F-]
Reactant: O=C(CBr)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: O=C(CF)c1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A suspension of potassium fluoride (3.091 g) and 18-crown-6-ether (0.341 g) in acetonitrile (25 mL) was stirred at 55° C. for 1 hour. α-Bromoacetophenone (5.12 g) was added to the reaction mixture, followed by stirring for 20 hours. Subsequently, diethyl ether was added to the reaction mixture, and then the insoluble matter that was formed was removed by filtration. Water was added for partitioning the filtrate. The organic layer was sequentially washed with water and saturated brine. Subsequently, the organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the residue.