Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[CH2:8][N:7]([C@@H](C2C=CC=CC=2)C)[C:6](=[O:17])[CH2:5]1)[CH3:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C@H:2]([C@H:4]1[CH2:8][NH:7][C:6](=[O:17])[CH2:5]1)[CH3:3]
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O)[C@H]1CNC(=O)C1
Reaction time: 1.5 h

Procedure:
A solution of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one (500 mg, 2.1 mmol) in TFA (3.6 mL) was heated to 150° C. in a microwave reactor. After 90 min, the resulting mixture was diluted with DCM and concentrated in vacuo. The resulting residue was dissolved in DCM (15 mL) and water (20 mL). The phases were separated, and the organic phase was extracted with water (4×20 mL). The combined aqueous phase was concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10% to 30% MeOH in DCM) to afford (R)-4-((S)-1-hydroxyethyl)pyrrolidin-2-one 1.18.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.ClC1C=CC=CC=1N1C(=O)C2C(=CC=C(F)C=2)N=C1C.C[C:34]1[C:35]([F:42])=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[O:38]>O1CCCC1>[F:42][C:35]1[CH:34]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=[O:38]
Reactant: Cc1cccc(C=O)c1F
Agent: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1ccccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (0.60 mL, 4.57 mmol) in tetrahydrofuran (27 mL) was chilled to -78° C. and butyllithium (1.30 mL, 3.25 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (1.04 g, 3.60 mmol) in tetrahydrofuran (7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of 2-fluorobenzaldehyde (0.575 mL, 6.33 mmol) in tetrahydrofuran (20 mL) was prepared and chilled to -78 ° C. The cold red anion solution was added to the cold methyl 2-fluorobenzaldehyde solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was concentrated and the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL). This mixture was stirred 1 h and then repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (45×150 mm) with elution proceeding as follows: 20% ethyl acetate/hexane (500 mL), nil; 30% ethyl acetate/hexane (500 mL) and 40% ethyl acetate/hexane (500 mL), two diastereomers of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-fluoro-phenyl)-2-hydroxy-ethyl]-3H-quinazolin-4-one, both as viscous oils. The faster eluting diastereomer weighed 0.231 g (17%) and had: 1H NMR δ7.92 (dd, J=3, 8.5 Hz, 1 H), 7.77 (dd, J=5, 9 Hz, 1 H), 7.60 (dd, J=1.5, 7.5 Hz, 1 H), 7.57-7.55 (m, 1 H), 7.53 (dd, J=3,8 Hz, 1 H), 7.48-7.42 (sym m, 2 H), 7.36-7.31 (m, 1 H), 7.24-7.18 (m,1 H), 7.12 (t, J=7.5 Hz, 1 H), 6.96-6.90 (m, 1 H), 5.65 (br s, 1 H), 5.55 (dd, J=2.5, 9 Hz, 1 H), 2.70 (dd, J=2.5, 17 Hz, 1 H), 2.61 (dd, J=9, 17 Hz, 1 H). The slower eluting diastereomer weighed 0.283 g (21%) and had: 1H NMR δ7.91 (dd, J=3, 9 Hz, 1 H), 7.76 (dd, J=5, 9 Hz, 1 H), 7.58 (dd, J=1.5, 8 Hz, 1 H), 7.54 (dd, J=3, 9 Hz, 1 H), 7.51 (dd, J=1.5, 8 Hz, 1 H), 7.44 (dt, J=2, 8 Hz, 1 H), 7.39 (dt, J=1.5, 8 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.13-7.07 (m, 2 H), 6.98-6.91 (m, 1 H), 5.61 (br s, 1 H), 5.57 (dd, J=4, 8 Hz, 1 H), 2.72-2.60 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(NCCO)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(NCCO)(c1ccccc1)C(=O)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-(2-hydroxyethylamino)-3-phenylindolin-2-one (32 g, 0.1 mmol) in dichloromethane (500 mL) was added trifluoroacetic acid (20 g) and triethylsilane (20 g). The brown solution was stirred at ambient temperature for 3 h and concentrated in vacuo to dryness. The residue was diluted with dichloromethane (500 mL), washed with saturated ammonium chloride solution (200 mL), brine (3×400 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ether to give the title compound. 1H NMR (400 MHz, DMSO-d6): δH 10.63 (s, 1H), 7.18-7.36 (m, 6H), 6.99-7.04 (m, 2H), 4.82 (s, 1H), 2.32 (s, 3H), 2.15 (s, 3H). MS (ESI) m/e [M+1]+ 305.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[C:28](=[O:44])[N:29]([CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:30]2=[O:35].C(N(CC)CC)C>CN(C=O)C>[O:43]=[C:37]1[CH:36]([N:29]2[C:28](=[O:44])[C:27]3[C:31](=[CH:32][CH:33]=[CH:34][C:26]=3[CH2:25][NH:24][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)=[O:10])[C:30]2=[O:35])[CH2:41][CH2:40][C:39](=[O:42])[NH:38]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(Br)n4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of 6-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 97:3 methylene chloride-methanol. This material was further purified by preparative HPLC, eluting with 1:1 acetonitrile-water, providing 0.50 g of the purified product in 53% yield: mp 181-183° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.52-2.65 (m, 2H), 2.84-2.93 (m, 1H), 4.96 (d, J=6.3 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.67-7.72 (m, 1H), 7.80-7.82 (m, 2H), 7.90 (dd, J=7.8 Hz, J=1.0 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 8.07 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 9.39 (t, J=6.3 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 121.7, 121.9, 127.1, 131.2, 131.6, 133.0, 134.8, 138.9, 140.3, 141.0, 151.0, 163.1, 167.0, 167.6, 169.8, 172.8; Anal. calcd for C20H15BrN4O5.0.5H2O: C, 50.01; H, 3.35; N, 11.66. Found: C, 49.97; H, 3.21; N, 11.56.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C@@H:21]([OH:31])[C@@H:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:23])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.O>C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([C@@H:21]([OH:31])[C@@H:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH3:23])=[CH:8][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1

Procedure:
Methanesulfonyl chloride (14 mL) was added to a mixture of N-[(1S,2R)-2-(3-amino-4-benzyloxyphenyl)-2-hydroxy-1-methylethyl]-2,2,2-trifluoroacetamide (62 g) and pyridine (34 mL) in ethyl acetate (558 mL) at room temperature with stirring, and the mixture was stirred at 40° C. for 1 hr. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with 1 mol/L hydrochloric acid, water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from n-hexane/ethyl acetate to afford the title compound (42 g).
Reaction SMILES: C1(N[C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)CC1.C(OCC)(=[O:33])C>Br>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:33])=[O:30])=[CH:7][C:8]=1[N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)[CH:20]=2)[N:15]=[CH:14]1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@H]3CCNC3)cc2c1=O
Agent: Br
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O[C@H]3CCNC3)cc2c1=O

Procedure:
A solution of N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]quinazolin-3(4H)-yl]benzamide (0.5 g) in 48% hydrobromic acid (5 ml) was heated to 130° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with ethyl acetate and extracted with water. The aqueous extracts were combined and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]quinazolin-3(4H)-yl]benzoic acid as a solid (224 mg); NMR Spectrum: (DMSOd6) 2.13 (m, 7H), 3.30 (m, 2H), 4.89 (s, 1H), 5.26 (s, 1H), 7.45 (m, 2H), 7.58 (t, 1H), 7.70 (d, 1H), 7.80 (s, 1H), 7.92 (m, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 366.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([N:17]2[C:21](=[O:22])[O:20][N:19]=[C:18]2[C:23]2[C:24]([NH:28][C:29](=O)[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:25][O:26][N:27]=2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:16][C:15]1[CH:14]=[CH:13][C:12]([N:17]2[C:21](=[O:22])[O:20][N:19]=[C:18]2[C:23]2[C:24]([NH:28][CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[N:25][O:26][N:27]=2)=[CH:11][C:10]=1[C:8]#[N:9]
Reactant: N#Cc1cc(-n2c(-c3nonc3NC(=O)c3ccncc3)noc2=O)ccc1F
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(-n2c(-c3nonc3NCc3ccncc3)noc2=O)ccc1F
Reaction time: 3 h

Procedure:
A solution of N-{4-[4-(3-cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}isonicotinamide trifluoroacetate (37 mg, 72 μmol) in pyridine (1.5 mL) at 0° C. was treated with phosphorus pentachloride (45 mg, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with ethanol (2.5 mL), treated with sodium cyanoborohydride (14 mg, 0.22 mmol), and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the intermediate 2-fluoro-5-[5-oxo-3-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-4(5H)-yl}benzonitrile trifluoroacetate. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL), and stirred for 45 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (8 mg, 24%). LCMS for C16H13FN7O2 (M+H)+: m/z=354.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([C:11]1([CH3:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1)(O)=[O:9]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2([CH3:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC1(C(=O)O)CCC(=O)O1
Reactant: Fc1ccccc1
Product: CC1(C(=O)c2ccc(F)cc2)CCC(=O)O1

Procedure:
acylating fluorobenzene with gamma-carbonylhalide-gamma-valerolactone, gamma-carboxy-gamma-valerolactone or gamma-carboxy-gamma-valerolactone anhydride in the presence of gallium trihalide, aluminum trihalide, antimony trihalide, titanium tetrahalide, boron trihalide or iron trihalide to form gamma-(para-fluorobenzoyl)-gamma-valerolactone; or acylating fluorobenzene with gamma-methyl-glutaconic anhydride in the presence of aluminum chloride, polyphosphoric acid, hydrogen fluoride, sulfuric acid, fluoroboric acid, boron trifluoride, boron trichloride or boron tribromide at a temperature of from 0°-85° C to form 4-(para-fluorobenzoyl)-3-pentenoic acid;
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[OH:13][CH:14]([C:16]1[CH:24]=[CH:23][C:22]2[CH2:25][NH:26][CH2:27][C:28](=[O:29])[N:20]3[C:21]=2[C:17]=1[CH:18]=[CH:19]3)[CH3:15]>CS(C)=O>[C:14]([C:16]1[CH:24]=[CH:23][C:22]2[CH2:25][NH:26][CH2:27][C:28](=[O:29])[N:20]3[C:21]=2[C:17]=1[CH:18]=[CH:19]3)(=[O:13])[CH3:15]
Reactant: CC(O)c1ccc2c3c1ccn3C(=O)CNC2
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Product: CC(=O)c1ccc2c3c1ccn3C(=O)CNC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.7 %

Procedure:
o-Iodoxybenzoic acid (Frigerio, et al., J. Org. Chem. 1995, 60, 7272) (2.217 mmol, 0.621 g) was added to a solution of 7-(1-Hydroxy-ethyl)-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 163) (0.739 mmol, 0.170 g) in DMSO (8 mL) at rt. The reaction mixture was stirred at rt for 2.5 h. The solvent was removed in vacuo and the residue was taken up in EtOAc and washed with 5% Na2S2O3/5% NaHCO3, H2O and brine. The organic layer was dried over anhydrous MgSO4 and concentrated to give an orange solid. The solid was purified by flash silica gel chromatography eluting with a gradient of 0-5% MeOH in CHCl3 to give 0.094 g (75%) of a pale pink solid: mp=285-287° C.; 1H NMR (DMSO-d6) δ 2.42 (s, 3H), 3.56-3.61 (m, 2H), 4.44 (br s, 2H), 7.32 (t, 1H, J=6.0 Hz), 7.92 (d, 1H, J=6.0 Hz), 8.40-8.44 (m, 3H); HRMS calcd. for C13H12N2O2 (M+) 228.0899, found (M+) 228.0890; Anal. (C13H12N2O2) C, H, N.
Reaction SMILES: Br[C:2]1[C:3]([OH:25])=[C:4]([C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]([O:20][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:2]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:3]([OH:25])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)ccc(Br)c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)ccc(-c2ccccc2)c1O
Temperature: 80 °C
Yield: 41.3 %

Procedure:
To a mixture of methyl 3-bromo-6-{4-[(tert-butoxycarbonyl)amino]butoxy}-2-hydroxybenzoate (56 mg, 0.134 mmol), tetrakis(triphenylphosphine) palladium (7 mg), 2M Na2CO3 (134 μL, 0.268 mmol) in toluene (1 mL) and ethanol (0.5 mL) was added phenylboronic acid (18 mg, 0.147 mmol). The reaction mixture was heated to 80° C. in a sealed tube overnight, taken up in ethyl acetate, washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel with hexane/ethyl acetate to provide the titled compound (23 mg). MS (ESI(+)) m/e 416 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C.Cl>CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.8 %

Procedure:
0.91 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.82 g of toluene, 0.41 g of acetic anhydride, 24 mg of 4-dimethylaminopyridine and 0.14 g of triethylamine were fed, and stirred for 20 hours at room temperature. 1 ml of water and 0.3 ml of concentrated hydrochloric acid were added and separated. The organic phase was washed with saturated aqueous solution of sodium bicarbonate, and the solvent was distilled off under reduced pressure. 0.89 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])[CH:20]=[C:19]([Cl:29])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NOCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCON=Cc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of 0.15 g of benzaldehyde and 10 ml of pyridine was added 0.56 g of O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-propyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.50 g (yield, 79.4%) of benzaldehyde O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)-oxime, nD22.5 1.5797.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=O)[C:5](=[O:12])[NH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Cl>C(N)C=C>[CH2:5]([NH:6][C:13]([C:4]1[C:5](=[O:12])[NH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([Br:1])[CH:3]=1)=[O:15])[CH:4]=[CH2:3]
Reactant: COC(=O)c1cc(Br)c(C(F)(F)F)[nH]c1=O
Agent: Cl
Solvent: C=CCN
Product: C=CCNC(=O)c1cc(Br)c(C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 250 mg (0.83 mmol) of methyl 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate were stirred in 5 ml of allylamine for 18 h. By addition of 2N hydrochloric acid, the pH was then adjusted to 2, resulting in the precipitation of a colorless solid. Filtration with suction and drying gave 134 mg (50% of theory) of the product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH2:12])=[O:11])[C:5]([C:13]#[N:14])=[C:4]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:3]=1[C:21]#[N:22].[N:23]1([CH2:28][CH2:29][CH2:30]N)[CH:27]=[CH:26][N:25]=[CH:24]1>>[NH2:14][C:13]1[C:5]2[C:6](=[N:7][C:2]([NH:1][CH2:30][CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:3]([C:21]#[N:22])[C:4]=2[C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[S:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(-c2c(C#N)c(N)nc(SCC(N)=O)c2C#N)o1
Product: Cc1ccc(-c2c(C#N)c(NCCCn3ccnc3)nc3sc(C(N)=O)c(N)c23)o1

Procedure:
“2c” is subsequently reacted analogously to steps 2.1 to 2.3 according to Example 2, using 3-imidazol-1-ylpropylamine as “E2” in step 2.2. 3-Amino-5-cyano-6-(3-imidazol-1-ylpropylamino)-4-(5-methylfuran-2-yl)thieno[2,3-b]-pyridine-2-carboxamide “A59” is obtained.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].C(=O)([O-])O.[Na+]>O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
6-O-(2-keto-L-gulonoyl)-L-ascorbate substantially free from 2-keto-L-gulonic acid, 1.2 g (3.4 mmol), was dissolved in 50 ml of water, to which 1.4 g (17 mmol) of sodium hydrogencarbonate was added and stirred at 40° C. for about 1.5 hours. High performance liquid chromatography analysis of the reaction mixture showed that 1.14 g (yield: 95.2%) of L-ascorbic acid was present with 0.07 g of 2-keto-L-gulonic acid but the starting substance 6-O-(2-keto-L-gulonoyl)-L-ascorbate was not found. Condition of high performance liquid chromatography:
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC([O-])(C)C.[K+].[CH2:18]1[C:21]2([CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=O>C1COCC1>[CH2:20]1[C:21]2([CH2:24][CH2:23][CH2:22]2)[CH2:18][C:19]1=[CH:3][C:1]#[N:2]
Reactant: O=C1CC2(CCC2)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC2(CCC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
Diethyl cyanomethylphosphonate (3.15 mL, 20.0 mmol) was suspended in THF (30 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (2.35 g, 21.0 mmol) was added portion-wise and stirred at 0° C. for 15 minutes. Spiro[3.3]heptan-2-one (2.100 g, 19.06 mmol) as a solution in THF (20 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was partitioned between water, saturated aqueous NH4Cl and EtOAc. The organic layer was washed with saturated aqueous NH4Cl, brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material. The crude was purified by flash column chromatography, eluting with 2.5% EtOAc/Hexanes to provide 2-(spiro[3.3]heptan-2-ylidene)acetonitrile (1.40 g, 10.5 mmol, 55% yield). 1H NMR (CDCl3) δ 5.14-5012 (m, 1H), 2.93-2.91 (m, 2H), 2.82-2.80 (m, 2H), 2.10-2.04 (m, 4H), 1.91-1.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([NH2:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CCN
Product: CCNS(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) were stirred together for 16 hours. 4-bromo-N-ethyl-3-fluorobenzenesulfonamide (0.38 g, 92%) was provided after purification. HRMS: calcd for C8H9BrFNO2S, 280.95214; found (EI, M+.), 280.951. HPLC purity 100.0% at210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.