Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-:16].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:11]([O:16][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH3:2])[CH:12]=[CH2:13]
Reactant: O=C([O-])[O-]
Reactant: C=CCBr
Reactant: O=C(CO)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)=O
Temperature: 25 °C

Procedure:
542 g (3.9 mol) of 2-hydroxyacetophenone are heated to reflux with 592 g (4.9 mol) of allyl bromide, 1000 g (7.2 mol) of potassium carbonate and 13.2 g (79 mmol) of potassium iodide in 2.4 liters of acetone for 24 h. Cooling to room temperature is followed by filtration, and the solvent is removed in vacuo. The residue is dissolved in toluene and washed with 10% strength sodium hydroxide solution and water. Concentration results in 689 g (98% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
A mixture of 3-(8-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (49 mg, 0.12 mmol), tert-butyl 4-aminobenzoate (23 mg, 0.12 mmol), EDCI (92 mg, 0.48 mmol), N-methyl-imidazole (40 mg, 0.48 mmol) and dichloromethane (3 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the residue was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=40:1˜100:1) to give tert-butyl 4-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoate (43 mg, 61%) as a yellow oil. [M+H]+, 590.2, tR=2.283 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH2:26][CH2:25][CH2:24][CH2:23][C:6]=2[C:7]=1[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN1CCN(C)C1=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>O>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH2:26][CH2:25][CH2:24][CH2:23][C:6]=3[C:7]=2[C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:44][CH:45]=1
Reactant: CNc1sc2c(c1C(=O)N[C@@H](C)c1ccc(C(=O)OC)cc1)CCCC2
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(N(C)Cc3ccc(Cl)cc3)sc3c2CCCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothien-3-yl]carbonyl}amino)ethyl]benzoate (0.41 g) was added 1,3-dimethyl-2-imidazolidinone (4.0 mL), and potassium carbonate (0.30 g) and 1-(bromomethyl)-4-chlorobenzene (0.34 g) were added thereto under ice-cooling, followed by stirring at 50° C. overnight. The reaction mixture was cooled to room temperature, and then water (50 mL) was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 15/1-4/1) to obtain methyl 4-{(1S)-1-[({2-[(4-chlorobenzyl)(methyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]ethyl}benzoate (0.15 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.O>ClCCl>[N:26]1([C:32]([N:13]2[CH2:14][CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=3)[CH2:10][CH:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(NC1CNCC(c2cccc(C(F)(F)F)c2)C1)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., 165 mg (0.47 mmol) of N-{5-[3-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 17 ml of dichloromethane, and 71 mg (0.47 mmol) of morpholine-4-carbonyl chloride and 132 μl (0.95 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 202 mg (92% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cc(-c2ccccc2)no1
Product: CCOC(=O)n1c(C(=O)c2cc(-c3ccccc3)no2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 5-(bromoacetyl)-3-phenylisoxazole. 1H-NMR (CDCl3) δ: 8.27 (1H, d, J=1.8 Hz), 7.89-7.84 (2H, m), 7.56-7.47 (5H, m), 7.30 (1H, dd, J=1.8, 8.4 Hz), 6.18 (2H, s), 4.13 (2H, q, J=7.2 Hz), 1.10 (3H, t, J=7.2 Hz)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH:16]1([CH2:19][CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[C:22]2=[O:31])[CH2:18][CH2:17]1>C1COCC1.ClCCl>[CH:16]1([CH2:19][CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([OH:30])([C:7]3[C:8]([OH:10])=[CH:9][C:4]4[O:3][CH2:2][O:1][C:5]=4[CH:6]=3)[C:22]2=[O:31])[CH2:18][CH2:17]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (1.25 g, 9.06 mmol) in THF (20.0 mL) was added dropwise a solution of isopropylmagnesium chloride solution (4.53 mL, 9.06 mmol, 2.0 M in THF) at 0° C. over 5 min. The reaction mixture was stirred for 0.5 h upon which time colorless precipitate was formed. After the solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (20.0 mL) and cooled to 0° C. A solution of 1-(2-cyclopropylethyl)-1H-indole-2,3-dione (1.77 g, 8.23 mmol) in dichloromethane (20.0 mL) was added to the above solution at 0° C. The resulting mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride solution (30.0 mL). The organic layer was separated and washed with water (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ethyl acetate and ether to give the title compound (2.22 g, 76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.52 (s, 1H), 7.46 (d, 1H), 7.37 (dt, 1H), 7.18 (dt, 1H), 6.90 (d, 1H), 6.56 (s, 1H), 6.23 (s, 1H), 5.84 (dd, 2H), 4.55 (s, 1H), 3.87-3.63 (m, 2H), 1.64-1.44 (m, 2H), 0.68-0.55 (m, 1H), 0.41-0.27 (m, 2H), −0.02-(−0.07) (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.1, 152.4, 148.8, 142.7, 141.3, 130.3, 129.1, 126.3, 123.7, 117.3, 109.5, 106.9, 101.9, 101.4, 79.3, 40.6, 32.2, 8.6, 4.3, 4.2; MS (ES+) m/z 337.6 (M−17).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2)([O-:22])=[O:21].CN(C(ON1N=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>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)=[O:33])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2cc(CNC(=O)c3cc4cc([N+](=O)[O-])ccc4[nH]3)ccc2Cl)c1
Yield: 36.7 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-nitro-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-nitro-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.36 (s, 1H), 9.34 (t, 1H), 8.67 (d, 1H), 8.04 (dd, 1H), 7.76 (t, 1H), 7.60 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.41 (s, 1H), 7.35 (t, 1H), 7.28 (dd, 1H), 7.25 (d, 1H), 4.50 (d, 2H). MS: m/z 481.0 (M+1).
Reaction SMILES: [NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[C:11]=2[S:10][C:9]=1[C:27]([O:29]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:32]>C(OC(O)C)C>[NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[C:11]=2[S:10][C:9]=1[C:27]([NH2:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc3[nH]ccc3c2)c1Nc1ccccc1
Reactant: N
Agent: CCOC(C)O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccc3[nH]ccc3c2)c1Nc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of Example 37 (200 mg) and liquid ammonia (5 mL) in ethoxyethanol (10 mL) was heated in a sealed vessel at 80° C. at 400 p.s.i. for 48 h. The solvent was removed in vacuo and purification by column chromatography (silica, 10% to 40% EtOAc in DCM) gave the title compound (42 mg). δH (CDCl3) 9.00 (1H, br s), 8.65 (1H, br s), 7.57 (1H, s), 7.37 (1H, d, J 8.5 Hz), 7.30-7.24 (2H, m), 7.20-7.18 (2H, m), 7.16 (1H, d, J 9.7 Hz), 7.18-6.98 (3H, m), 6.52 (1H, br s), 6.33 (1H, d, J 9.7 Hz), 5.20 (2H, br s). LCMS (ES+) RT 3.77 minutes, 430 (M+H)+. LCMS (ES+) RT 2.93 minutes, 401 (M+H)+.
Reaction SMILES: FC(F)(F)C(O[I:6](OC(=O)C(F)(F)F)[C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=O.[CH:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[CH3:47][S:48]([OH:51])(=[O:50])=[O:49]>FC(F)(F)C(O)=O>[CH3:47][S:48]([O-:51])(=[O:50])=[O:49].[F:19][C:13]([F:18])([C:14]([F:16])([F:15])[F:17])[C:12]([F:21])([F:20])[C:11]([F:23])([F:22])[C:10]([F:25])([F:24])[C:9]([F:26])([F:27])[C:8]([F:28])([F:29])[C:7]([F:30])([F:31])[I+:6][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CS(=O)(=O)O
Reactant: c1ccccc1
Reactant: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)[O-]
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Yield: 25.7 %

Procedure:
1.0 g (1.30×10-3 mol) of di(trifluoroacetoxy)iodoheptadecafluoro-n-octane was suspended in 6.0 ml of trifluoroacetic acid, and 0.173 ml (1.95×10-3 mol) of benzene and then 0.0843 ml (1.30×10-3 mol) of methanesulfonic acid were added dropwise to the suspension, followed by allowing the mixture to react for 2 weeks at room temperature. The reaction mixture was dried up and a small amount of acetonitrile was added thereto to obtain 240 mg (26% yield) of heptadecafluoro-n-octylphenyliodonium methanesulfonate as white crystals. A sample of the resulting product was recrytallized from acetonitrile for elementary analysis and measurements of spectra. The data obtained are shown below. Melting Point: 140°-141° C.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH:17]1[C:28](=[O:29])[N:19]2[CH:20]([C:25]([OH:27])=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12>C(OCC)(=O)C.CS(C)=O>[NH2:16][CH:17]1[C:28](=[O:29])[N:19]2[CH:20]([C:25]([O:27][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 32 h
Yield: 68.1 %

Procedure:
A solution of diphenyldiazomethane (1.7 mol) in ethyl acetate (2.13 l) was added to a mixture of 7-amino-3-hydroxycepham-4-carboxylic acid (186 g) in dimethyl sulfoxide (1.5 l). The mixture was stirred at room temperature for 32 hours and filtered. To the filtrate was added water and the mixture was extracted with ethyl acetate. The extract was washed three times with water, dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was tritulated with diisopropyl ether to give benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (223 g) as powder.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[CH3:10].[OH-].[K+]>C(O)C>[CH3:10][C:9]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)c1ccccc1
Temperature: 50 °C

Procedure:
Diethyl (α, α -dimethylbenzyl)malonate was prepared by the conjugate addition of phenyl magnesium bromide to diethyl isopropylidenemalonate as described by C. Holmberg [Liebigs Ann. Chem., 748 (1981)]. A solution of this diester (42.1 g, 0.15 mol) in ethanol (100 ml) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mol) in 100 ml of ethanol. After heating at 90° C. for 1 h and at 50° C. for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5° C., acidified to pH 3 with 6N HCl, and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate. Evaporation of the solvent gave 27.3 g (84%) of liquid product. NMR (CDCl3): 1.05 (3H,t), 1.6 (6H,s), 3.78 (1H,s), 3.96 (2H,m), 7.2-7.4 (5H,m).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([OH:23])=O)[C:6](=[O:20])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O.[C:30]1(=[O:37])[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1.C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([C:31]1[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]=1[OH:37])=[O:23])[C:6](=[O:20])[N:7]2[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)nc3c(F)cccc32)cc1
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)c(C(=O)C3=C(O)CCCC3=O)nc3c(F)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
11.1 g (35 mmol) of 5-fluoro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in chloroform (300 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 6.7 g (53 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in chloroform (100 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 4.4 g (39 mmol) of 1,3-cyclohexanedione and 4.3 g (43 mmol) of triethylamine in chloroform (200 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then 1.5 g (18 mmol) of acetone cyanohydrin and 4.3 g (43 mmol) of triethylamine were added thereto. The mixture was stirred for 12 hours at room temperature. The reaction solution was washed with 10% hydrochloric acid and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with methanol, to obtain 13.6 g (yield: 94%) of 5-fluoro-3-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-1-(4-methoxyphenyl)-quinoxalin-2(1H)-one as a pale orange-colored powder.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52](Cl)=[O:53])[CH2:48][CH2:47]1>ClCCl.ClCCl.CO>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:52]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)=[O:53])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)N4CCN(C)CC4)CC3)nc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL) at 0° C., DIPEA (0.2 mL, 1.1 mmol), and 4-methylpiperazine-1-carbonyl chloride (17 mg, 0.09 mmol) were added. The mixture was then stirred at room temperature for 3 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 9/1) to 38 mg of the title compound (86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:30][Mg]Br.CCOC(C)=O>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)([OH:12])[CH3:30])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc2n1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)(c1ccc2nn(COCC[Si](C)(C)C)cc2c1)c1cnc2ccc(Cl)nn12
Reaction time: 0.5 h

Procedure:
To a solution of (6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-methanone (Stage 195.3, 539 mg, 1.259 mmol) in THF (50 mL) was added dropwise at rt a solution of methylmagnesium bromide in Et2O (3 M, 0.462 mL). After 30 min stirring, the RM was taken into EtOAc and washed with a 10% NaHCO3 solution and then with brine. The organic layer was dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=95:5->0:100) to afford after recrystallisation in pentane with a little EtOAc the title compound as a light yellowish powder (tR 5.6 min (conditions 3), MH+=444).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS[C:14]1[NH:19][C:18](=[O:20])[C:17]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][N:15]=1>N1C=CC=CC=1>[OH2:20].[OH2:20].[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:14]2[NH:19][C:18](=[O:20])[C:17]([CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCc1ccccc1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: O
Product: O=c1[nH]c(NCCCCc2ccccc2)ncc1Cc1cccnc1

Procedure:
A mixture of 4-phenylbutylamine (4.0 g), 2-methylthio-5-(3-pyridylmethyl)-4-pyrimidone (5.8 g) and dry pyridine (40 ml) was heated under reflux for 60 hours and evaporated to dryness. Water was added to the residue and the pH was adjusted to 7 with hydrochloric acid. The solid which separated out was recrystallised from aqueous ethanol to give 2-(4-phenylbutylamino)-5-(3-pyridylmethyl)-4-pyrimidone dihydrate m.p. about 70°.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][N:25]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Xe](F)[F:33].C(=O)([O-])O.[Na+]>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:24]([F:33])[N:25]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ncc(-c3ccccn3)[nH]2)cc1)C1CC1
Reactant: F[Xe]F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2nc(F)c(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1 %

Procedure:
To a solution of 2-(2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-imidazol-5-yl)pyridine (0.750 g) in acetonitrile (20 mL) was added xenon difluoride (434 mg), and the mixture was stirred at room temperature for 30 min, and at 0° C. for 63 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-100:0, volume ratio) and preparative thin layer chromatography to give the title compound (0.008 g, yield 1%) as a yellow oil. MS: 456 (MH+).