Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:66][CH2:65]2)[CH:59]=1.C(NC(C)C)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:66][CH2:65]2)[CH:59]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: c1ccc2c(c1)CCN2c1cc([C@@H]2CCCN2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (99 mg, 0.39 mmol), HOBt (57 mg, 0.42 mmol) and HBTU (160 mg, 0.42 mmol) in DMF (10 mL) is stirred at room temperature for 30 min. Then a solution of 1-((S)-4-pyrrolidin-2-yl-pyridin-2-yl)-2,3-dihydro-1H-indole (6) in DMF (10 mL) is added, followed by diisopropylamine (226 mg, 1.75 mmol). After stirring at room temperature for 2 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜40%) to give ((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester as white solid (120 mg, 68%). M/Z=505.3 [M+1]
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=O)[CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)([Cl:20])=O.CN(C)[CH:25]=[O:26]>>[Cl:20][C:3]1[CH:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:1][C:10]2[C:5]([C:4]=1[CH:25]=[O:26])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1Cc2ccccc2OC1c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: O=CC1=C(Cl)C(c2ccccc2)Oc2ccccc21
Reaction time: 1 h

Procedure:
As in example 1, but using 2.2 g flavan-3-one, 12 ml dimethylformamide and 3 ml phosphorous oxychloride. Reaction time is one hour at 0°-5°. After hydrolysis and usual work up the residual oil is purified by column chromatography. The best fractions give a pale yellow oil of pure 3-chloro-4-formyl-flav-3-ene. TLC (n-hexane/acetone 4:1, SiO2) single spot, Rf =0.47. NMR (90 MHz, CDCl3):δ(ppm)=5.86 [1H, s, H-C(2)]; 6.7-7.5 [3H, m, H-C (6,7,8)]; 7.35 [5H, S,C6H5 ]; 8.15 [1H, dd, H-C(5)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[CH3:10][N:11]([CH3:17])[CH2:12][CH2:13][C:14](O)=[O:15].C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH3:17])[CH3:10])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CN(C)CCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)CCC(=O)Nc1cncc(Br)c1
Temperature: 50 °C

Procedure:
To a solution of 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 11.2 mmol, 2.00 g) and 3-dimethylaminopropionic acid hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1 eq, 11.2 mmol, 1.74 g) in DCM (50 ml), tributylamine (3.6 eq, 40.4 mmol, 9.8 ml) and 2-chloro-1-methylpyridinium iodide (1.2 eq, 13.5 mmol, 3.54 g) are added. The resulting mixture is heated at 50° C. for 4 h, then the solvents are removed in vacuo, aqueous NaOH solution (1 M) is added, and the mixture is extracted with DCM. The organic layer is dried with MgSO4, filtered, and the solvent is removed in vacuo. Purification by column chromatography (DCM/MeOH) yields the title compound; [M+H]+=273.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10]S([O-])(=O)=O)[CH:7]=1.C1C[O:27][S:24](=[O:26])(=[O:25])[CH2:23]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:17]([CH3:18])([CH3:19])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][CH2:23][S:24]([O-:27])(=[O:26])=[O:25])[CH:7]=1
Reactant: O=S1(=O)CCCCO1
Reactant: CC1=Nc2c(cc(Cl)c[n+]2CCCS(=O)(=O)[O-])C1(C)C
Product: CC1=Nc2c(cc(Cl)c[n+]2CCCCS(=O)(=O)[O-])C1(C)C

Procedure:
Compound 26 is prepared analogously to compound 5 (Example 5), except that 1,4-butanesultone is used as a starting material.
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1(C)C=CC=CC=1.CCO.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:13]#[N:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(C#N)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2ccccc2Cl)c(C#N)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
5-Bromo-4-cyano-3-nitroanisole [prepared by the method of Harrison et al, J. Chem. Soc. C, 1769 (1966)] (250 mg, 0.86 mmol) and 2-chlorophenylboronic acid (150 mg, 0.96 mmol) were dissolved in a mixture of toluene (10 ml), EtOH (5.6 ml), and 1N aqueous sodium carbonate (1.7 ml). The solution was placed under a nitrogen atmosphere and tetrakis(triphenylphosphine)palladium (30 mg, 0.03 mmol) added. After refluxing for 3 h, the solvent was removed from the reaction mixture under reduced pressure. The residue was partitioned between H2O (50 ml) and EtOAc (50 ml) and the EtOAc layer washed with H2O (2×50 ml), and dried over MgSO4. Following removal of the solvent, the crude material was purified on silica gel, eluting with hexane/ether (1/1, v/v). This gave the subtitle compound as a colourless gum (252 mg, 100%). Rf 0.38 (hexane/ether 1:1, v/v). MS m/z 306 and 308 (MNH4+).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>N([C@H]1CCO[C@@H](C(C2C=CC=CC=2)C2C=CC=CC=2)C1)=[N+]=[N-]>[N:25]([C@@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [N-]=[N+]=N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 80.6 %

Procedure:
Cis-2-diphenylmethylpyran-4-yl methanesulfonate 4b (0.38 g, 1.10 mmol) was reacted with sodium azide (0.29 g, 4.4 mmol) in dry DMF (Procedure B) to yield compound 5b (0.26 g, 80%) as a liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([CH2:18][C:19](O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[CH2:18]([C:19]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Product: O=[N+]([O-])c1ccc2[nH]c(Cc3ccccc3)nc2c1
Temperature: 110 °C
Yield: 33 %

Procedure:
A mixture of 4-nitro-o-phenylene diamine (1.54 g) and phenylacetic acid (2.04 g) in 5N aqueous HCl (16 ml) were heated at 110° C. under nitrogen for 22 hours. The mixture was cooled to room temperature and the accumulated black solid collected by filtration. This crude residue was then adsorbed onto silica and chromatographed to give the title compound (0.84 g) as a purple foam; δH CDCl3 9.70 (1H, bs), 8.15 (1H, d), 7.30 (7H, m), 4.30 (2H, s); m/z (M+1)+ 254.
Reaction SMILES: C([CH:3]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)#N.C(=O)([O-])[O-:19].[K+].[K+]>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)=[O:19])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccnc(C(C#N)c2ccc(F)cc2)c1
Agent: [K+]
Solvent: O
Product: Cc1ccnc(C(=O)c2ccc(F)cc2)c1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
2-(α-cyano-4-fluorobenzyl)-4-methylpyridine (3.1 g) and potassium carbonate (2.9 g) were suspended in 20% hydrated dimethylsulfoxide (150 ml), and the suspension was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 2-(4-fluorobenzoyl)-4-methylpyridine (1.6 g) as brown crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](NC(=O)OCC)[NH:16][C:17](=[O:21])OCC)=[CH:11][CH:10]=1)#[N:8]>C1C=CC=CC=1>[Cl:2][CH:15]([N:16]=[C:17]=[O:21])[C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1
Reactant: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: N#Cc1ccc(C(Cl)N=C=O)cc1

Procedure:
Phosphorous pentachloride (83.3 g, 400 mmol) is added to a suspension of diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1, 53.0 g, 182 mmol) in benzene (200 mL) and the mixture is heated at reflux for 2 h. The benzene is evaporated and the mixture is then purified by distillation under reduced pressure. The first fraction (ca. 40° C., ca. 0.01 mbar) is discarded. The second fraction (ca. 110° C., ca. 0.6 mbar) is collected. Yield: 28.4 g; ESI mass spectrum: [M+MeOH−HCl+H]+=189; Retention time HPLC: 0.65 min (Z003_004).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CO[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@@H]1C[C@@H](C(N)=NO)N(C(=O)OCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To benzyl-(2S,4R)-2-cyano4-methoxypyrrolidine-1-carboxylate, dissolved in ethanol (0.4 M), hydroxylamine hydrochloride (1.3 eq.) and triethylamine (1.5 eq.) were added. The mixture was stirred at 40° C. for 4 hours then at room temperature overnight. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate washed with brine, dried over Na2SO4, filtered and concentrated to give title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].CS(C)=O.[F:12][C:13]1[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C:38]4[C:33](=[CH:34][C:35]([S:39](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:41])=[O:40])=[CH:36][CH:37]=4)[CH:32]=[CH:31][C:30]3=[O:54])=[C:25]([O:55][CH3:56])[CH:24]=2)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C.C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C:38]4[C:33](=[CH:34][C:35]([S:39]([NH:7][C:2]5[CH:3]=[N:4][CH:5]=[CH:6][N:1]=5)(=[O:40])=[O:41])=[CH:36][CH:37]=4)[CH:32]=[CH:31][C:30]3=[O:54])=[C:25]([O:55][CH3:56])[CH:24]=2)[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: COc1cc(-c2cc(F)cc(C(F)(F)F)c2)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(-c2cc(F)cc(C(F)(F)F)c2)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cnccn3)ccc21
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
A RBF was charged with pyrazin-2-amine (0.047 g, 0.493 mmol) and DMSO (0.948 ml) to give a solution. Perfluorophenyl 1-(3′-fluoro-3-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.250 g, 0.379 mmol) and THF (2.84 ml) were added, and the mixture remained a solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.872 ml, 0.872 mmol) was added dropwise. The reaction was stirred for 15 minutes. The reaction was diluted with ethyl acetate and washed twice with 1N HCl solution. The organic layers was washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-50% [3:1 EtOAc/EtOH]:Heptane) to afford 1-(3′-fluoro-3-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxo-N-(pyrazin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (0.153 g, 0.268 mmol, 70.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.62 (br. s., 1H), 8.47 (d, J=2.2 Hz, 1H), 8.36 (d, J=1.1 Hz, 1H), 8.29-8.19 (m, 3H), 8.09 (d, J=9.9 Hz, 1H), 8.03 (s, 1H), 7.94 (dd, J=2.2, 9.0 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.58 (dd, J=1.9, 8.1 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 6.79 (dd, J=9.3, 13.7 Hz, 2H), 3.80 (s, 3H). m/z (ESI) 571.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:11](=[O:15])[CH2:12][O:13][CH3:14])=[CH:9][N:10]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:15])[CH2:12][O:13][CH3:14])=[CH:9][N:10]=1
Reactant: COCC(=O)c1cnc(C2OCCO2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COCC(O)c1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2-methoxyethanone (2.00 g) in a mixed solvent of tetrahydrofuran (10 mL) and ethanol (10 mL) was slowly added sodium borohydride (0.18 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, the title compound (1.84 g, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 232 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>C(O)C.O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:17])=[CH:6][CH:5]=1)=[O:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)=O)cc1

Procedure:
In 200 ml of ethanol was dissolved 30.0 g of 4-hydroxyacetophenone, and a solution of 11.3 g (1.28 eq.) of sodium hydroxide in 60 ml of water and 33.9 g (1.22 eq.) of dimethyl sulfate were added dropwise consecutively. After the reaction mixture was refluxed for 30 minutes', a solution of 2.8 g (0.32 eq.) of sodium hydroxide dissolved in 10 ml of water was added, followed by heating under for 3 hours' reflux. After the solvent was distilled off, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Then, the solvent was distilled off. The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=[O:12])[CH2:6][C:7](OCC)=O)[CH3:2].[CH3:16][C:17]([CH3:21])=[CH:18]CCl.[O-]CC.[Na+].[OH-].[Na+]>>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:12])[CH2:6][CH2:7][CH:16]=[C:17]([CH3:21])[CH3:18])[CH3:15]
Reactant: CC(C)=CCCl
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(OCC)C(=O)CCC=C(C)C
Yield: 57.2 %

Procedure:
Following the procedure stated in Referential example 1, reaction of 7.3 g of ethyl 4,4-diethoxyacetoacetate with 4.0 g of 3-methyl-2-butenyl chloride was carried out in the presence of sodium ethoxide and the resultant was decarboxylated with the alcoholic sodium hydroxide to yield 4.1 g of the desired product, b.p. 102°-103° C./ 1 mmHg.
Reaction SMILES: [F:1][C:2]([F:27])([C:23]([F:26])([F:25])[F:24])[C:3]([F:22])([F:21])[C:4]1([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[O-:28][C:29]#[N:30].[Na+].FC(F)(F)C([O-])=O.O>C(Cl)Cl>[F:17][C:12]([F:18])([C:13]([F:16])([F:15])[F:14])[C:11]([F:19])([F:20])[C:4]1([C:3]([F:21])([F:22])[C:2]([F:1])([F:27])[C:23]([F:24])([F:25])[F:26])[O:8][CH:7]([CH2:9][O:10][C:29](=[O:28])[NH2:30])[CH2:6][O:5]1
Reactant: N#C[O-]
Reactant: OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC(=O)OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Reaction time: 24 h

Procedure:
A solution of 44.0 grams (0.1 mol) of 2,2-bis(heptafluoropropyl)-4-hydroxymethyl-1,3-dioxolane prepared by the method disclosed in patent application Ser. No. 873,660 filed Nov. 3, 1969, in 250 ml methylene dichloride is treated with 13.0 grams of sodium cyanate while 22.8 grams trifluoroacetate acid is added dropwise. The reaction is carried out at 25°-35° C. for 24 hours. After the reaction is completed, a small amount of water is added to dissolve the salts and the methylene dichloride solution is separated and washed with water. Vacuum-stripping yields the desired product. The product, 2,2-bis(heptafluoropropyl)-4-carbamoyloxymethyl-1,3-dioxolane, is purified by crystallization from a mixture of benzene and hexane.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[N:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1
Reactant: ClCCCc1ccncc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCCc1ccncc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 465.9 %

Procedure:
To a suspension of NaH (0.4 g) in DMF (8 mL) was added diethyl malonate (0.16 g) at 0° C. The mixture was stirred at RT for 30 min. To the mixture was added a solution of 4-(3-chloropropyl)pyridine (1.2 g) prepared in (1) in DMF (4 mL). The reaction mixture was stirred at 80° C. for 10 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/1) to give the title compound (1.3 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10](I)[C:3]=12.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1B1OC(C)(C)C(C)(C)O1)[N:21]([CH3:34])[CH2:20][CH2:19]2.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10]([C:24]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][N:21]4[CH3:34])=[CH:17][C:16]=3[F:15])[C:3]=12
Reactant: CC(C)n1cc(I)c2c(Br)ccnc21
Reactant: CN1CCc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(Br)ccnc21
Temperature: 60 °C
Yield: 57 %

Procedure:
To a stirred suspension of 4-bromo-3-iodo-1-isopropyl-1H-pyrrolo[2,3-b]pyridine (D10) (1.500 g, 4.11 mmol), 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (1.367 g, 4.93 mmol), bis(triphenylphosphine)palladium(II) chloride (0.288 g, 0.411 mmol), 2M sodium carbonate aq. solution. (20.55 mL, 41.1 mmol) in ACN (10 mL), DMF (10 mL) and DCM (5 mL) at RT was degassed under nitrogen for 10 mins. The reaction mixture was heated to 60° C. under nitrogen atmosphere for an hour. The reaction mixture was cooled to RT and partitioned between ethyl acetate/water (ca. 50 mL each). The aqeuous layer was separated and extracted with ethyl acetate (ca. 30 mL twice). The combined organic layer was dried over MgSO4 and solvent removed in vacuo. The residue was purified using silica chromatography (eluted with 0-20% ethyl acetate/cyclohexane) to afford the title compound (910 mg). LCMS (A): m/z (M+H)+ 388/390, C19H19BrFN3 requires 387/389 (acidic).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:24](=[C:26]([C:34](=[O:37])[CH2:35][OH:36])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N-:25].C([O-])(O)=O.[Na+]>O1CCCC1.C(Cl)Cl>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:36][CH2:35][C:34](=[O:37])[C:26](=[N+:24]=[N-:25])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Yield: 73.9 %

Procedure:
90 μl of boron trifluoride etherate were added to a suspension of 564 mg (3.0 mmol) (1R,5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 1.08 g (5.4 mmol-1.8 equiv.) tert.-butyl 2-diazo-4-hydroxy-3-oxo-butanoate in 12 ml of anhydrous tetrahydrofuran at 0° C. The cooling bath was removed and after 10 minutes a clear, light yellow solution formed. After 20 minutes it was poured into a mixture of NaHCO3 solution, ice and methylene chloride. The mixture was extracted with methylene chloride (3×), washed with water and dried over magnesium sulphate. After the solvent had been evaporated off in vacuo and the residue had been crystalized from methylene chloride-ether-pentane, 861 mg (74%) of the title compound were obtained as light yellow crystals, melting point: 98° C., RF : 0.29 (toluene:ethyl acetate 2:3). Spectroscopical data identical to Example 4.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[CH:16]([NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24](C2C=CC=C(Br)C=2)[CH:23]=1)=[O:21])([CH3:18])[CH3:17]>>[CH:16]([NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([C:7]#[C:8][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:2]=2)[CH:23]=1)=[O:21])([CH3:17])[CH3:18]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#Cc1ccccc1
Reactant: Brc1cccnc1
Product: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of Step 5 of EXAMPLE 1, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 5 for phenylacetylene and 3-bromopyridine for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a light brown solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23](O)=[O:24]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][N:17]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1cnccn1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1cnccn1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and pyrazine-2-carboxylic acid