Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([CH3:24])[C:9]2[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=2[N:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[CH:27]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([CH3:24])[C:9]3[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=3[N:3]=2)[CH2:29][CH2:28]1
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(Cl)nc2c(F)ccc(O)c12
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Temperature: 90 °C
Yield: 23.1 %

Procedure:
A mixture of 2-chloro-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.26 g), cyclopropylboronic acid (0.12 g), caesium carbonate (0.92 g), dioxane (5.7 mL) and water (1.4 mL) was purged with argon, and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.058 g). The mixture was heated at 90° C. for 3 hours, cooled to room temperature, neutralised with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (5.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 3:2 by volume) gave title compound as a yellow oil (0.061 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:15][CH:16]([O:21][CH2:22][CH2:23][CH3:24])[O:17][CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>O>[CH2:18]([O:17][CH:16]([O:21][CH2:22][CH2:23][CH3:24])[CH2:15][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:19][CH3:20]
Reactant: CCCOC(CCl)OCCC
Reactant: Oc1ccc(S)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(CSc1ccc(O)cc1)OCCC
Temperature: 90 °C

Procedure:
The S-monosodium salt of 4-mercaptophenol (0.05 mole) and dimethylformamide (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-dipropoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is blanketed with nitrogen gas and is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 4-(2,2-dipropoxyethylthio)phenol.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:11]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][NH2:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(OCc2cccc(F)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cccc(OCc2cccc(F)c2)c1

Procedure:
A solution of 10.36 g (30 mmol) of [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-carbamic acid tert-butyl ester in 100 ml of dichloromethane and 15 ml of trifluoroacetic acid was stirred at room temperature overnight. The solvent was removed, a 5% K2CO3 solution in water was added and the product was extracted with ethyl acetate to obtain the title compound in quantitative yield as a sticky oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:63][N:64]1[CH:68]=[C:67]([C:69]2[CH:70]=[CH:71][C:72]3[N:73]([C:75]([SH:78])=[N:76][N:77]=3)[N:74]=2)[CH:66]=[N:65]1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:63][N:64]1[CH:68]=[C:67]([C:69]2[CH:70]=[CH:71][C:72]3[N:73]([C:75]([S:78][C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[N:8]=[CH:7][CH:6]=[CH:5]5)=[N:76][N:77]=3)[N:74]=2)[CH:66]=[N:65]1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Temperature: 100 °C
Reaction time: 23 h
Yield: 58.2 %

Procedure:
A solution of 6-bromoquinoline (45 mg, 0.215 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol) in DMF (1 mL) under nitrogen was degassed by bubbling in nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium (11 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol), and 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (50 mg, 0.215 mmol) were added, and the mixture was degassed for another 5 min. The reaction mixture was stirred at 100° C. for 23 h. More palladium catalyst (11 mg) and ligand (13 mg) were added after 6 h. The reaction mixture was cooled to room temperature, filtered through a 0.45 um filter, and the crude mixture was purified directly by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 45 mg of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline as a yellow solid (58% yield).
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27]C(O)=O)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1CCCCC1>O>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Solvent: O
Solvent: C1CCNCC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: -30 °C

Procedure:
A mixture of 5.00 g (21 mmol) of 4-dibutylaminobenzaldehyde, 4.27 g (24 mmol) of 4-nitrophenylacetic acid, 1.80 g (21 mmol) of piperidine, and 50 mL of xylenes was heated with stirring at reflux of 20 hours with continuous removal of water using a Dean-Stark apparatus. The mixture turned dark red. Approximately half the xylenes was distilled, 20 mL of heptane was added, and the residue was cooled to -30° C. Red crystals separated which were collected and then recrystallized from toluene/heptane. Yield: 2.81 g (37%), mp 117-119 (lit2 182°-182.5° C.).
Reaction SMILES: C(N1[CH2:9][CH2:8][N:7]([C:10](=[O:39])[CH:11]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[CH2:6]C1)(=O)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1.[CH3:78][OH:79]>CN(C=O)C.C(Cl)(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:11]([CH2:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26](=[O:28])[NH:77][O:76][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)[C:10]([N:7]1[CH2:6][CH2:78][O:79][CH2:9][CH2:8]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Reactant: CO
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)C(=O)N1CCOCC1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
The compound 19 (1.95 g, 3.61 mmol) was dissolved in dry DMF (30 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.54 g, 4.0 mmol), EDCI (0.7 g, 3.61 mmol), and triethylamine (1.5 mL, 11.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.64 g, 4.0 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (60 mL). The organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×40 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Silica gel flash chromatography (CHCl3:MeOH—49:1) yielded the desired benzyl hydroxamate 15 (1.0 g, 44%). 1H NMR (400 MHz, DMSO-d6): 10.93 (s, 1H), 8.23 (s, 1H), 7.28-7.33 (m, 5H), 7.20 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.84 (d, J=7.2 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 4.69 (s, 2H), 4.02 (m, 1H), 3.07-3.42 (m, 8H), 2.60-2.85 (m, 4H), 2.21 (t, J=7.6 Hz, 2H), 1.97 (s, 3H), 1.28 (s, 9H).
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[OH:32][C:33]1[CH:47]=[CH:46][C:36]([O:37][C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:48])[CH:34]=1.[C:49]1([CH:55]([C:57]2[CH:61]=[C:60]([C:62]3[CH:67]=[CH:66][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:64][CH:63]=3)[S:59][CH:58]=2)O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:44][C:38]([O:37][C:36]1[CH:46]=[CH:47][C:33]([O:32][CH:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:57]2[CH:61]=[C:60]([C:62]3[CH:63]=[CH:64][C:65]([C:68]([F:69])([F:70])[F:71])=[CH:66][CH:67]=3)[S:59][CH:58]=2)=[CH:34][C:35]=1[CH3:48])([CH3:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OC(c1ccccc1)c1csc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(c2ccccc2)c2csc(-c3ccc(C(F)(F)F)cc3)c2)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate (intermediate 10) and phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol (intermediate 127).
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[C:23]([Cl:25])[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[C:12]([CH:21]=2)[C:13]([N:15]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[CH3:16])=[O:14])=[C:5]([Cl:26])[CH:4]=1.C[N+]1([O-])CC[O:31]CC1>C(#N)C>[CH:17]1([N:15]([CH3:16])[C:13](=[O:14])[C:12]2[CH:21]=[C:8]([O:7][C:6]3[C:23]([Cl:25])=[CH:24][C:3]([CH:2]=[O:31])=[CH:4][C:5]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[OH:22])[CH2:20][CH2:19][CH2:18]1
Reactant: CN(C(=O)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O)C1CCC1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(C=O)cc2Cl)ccc1O)C1CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of the title compound of Step G (130 mg, 0.28 mmol) in dry acetonitrile (6 ml) at room temperature under nitrogen was added molecular seives (4 A°, 50 mg). After stirring for about 15 minutes at room temperature, N-methylmorpholine N-oxide (66 mg, 0.57 mmol) was added. The resulting mixture was stirred at room temperature for about 18 hours, then filtered through a short pad of silica gel with an acetonitrile wash. The filtrate was concentrated to afford the title compound (88 mg) as an off-white foam which was used in the next step without further purification. MS (APCl−) Calc: 393.1, found: 392.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[F:16][CH2:17][C:18]([C:22]1[O:26][N:25]=[C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:23]=1)([CH3:21])[CH2:19][F:20].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[F:20][CH2:19][C:18]([C:22]1[O:26][N:25]=[C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:23]=1)([CH3:21])[CH2:17][F:16]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)Nc2cc(C(C)(CF)CF)on2)cc1
Temperature: 65 °C
Yield: 100.3 %

Procedure:
To a stirred solution of tert-butyl 4-aminophenylcarbamate (176 mg, 0.85 mmol) in 5 mL of THF was added phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (250 mg, 0.85 mmol), DIEA (147 mL, 0.85 mmol), and DMAP (5.2 mg, 0.043 mmol). The resulting mixture was heated at 65° C. for 90 min. LC-MS indicated that the reaction was complete. The organic solvent was removed under reduced pressure and the residue was purified with silica gel column chromatography, eluting with 0-50% EtOAc in hexanes, to give tert-butyl 4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenylcarbamate (350 mg, 95%). LC-MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [O:1]1C[CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17]>>[OH:1][CH:2]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N+:16]([O-:18])=[O:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Product: O=C1c2ccccc2C(=O)N1CC(O)n1ccnc1[N+](=O)[O-]

Procedure:
According to the General Reaction Scheme, N-(2,3-epoxypropyl)phthalimide (1) is reacted with 2-nitro-imidazole (2) to obtain 2-[2-Hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3). This product is then reacted with N -hydroxyphthalimide, preferably in the presence of a tertiary amine such as triphenylphosphine, to obtain the intermediate of Formula II, 2-{2-(1,3-dioxoisoindolin -2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione (4). This intermediate is then reacted with hydrazine to obtain 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H -imidazole dihydrochloride (5), which is then reacted with the compound of Formula III to yield the compound of Formula I. A preferred compound of Formula III is 3-chloro-3-methyl-2-nitrosobutane, which, when used contacted with 1-[3-amino-2-(aminooxy)propyl]-2-nitro -1H-imidazole dihydrochloride (5), yields 3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime (7).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-:24].C[NH3+].[C:27]([BH3-])#[N:28].[Na+]>CO>[ClH:24].[CH3:27][NH:28][CH2:22][C:3]1[C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:4]=1
Reactant: [BH3-]C#N
Reactant: [Cl-]
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: C[NH3+]
Agent: [Na+]
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A solution (20 mL) of methyl 4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (920 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution (6.3 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (20 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (110 mg), N-methylmorpholine N-oxide (554 mg) and molecular sieves 4A powder (2.0 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give 4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde as a brown oil (yield 461 mg, 55%). 4-Methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (460 mg) was dissolved in methanol (25 mL), and methylammonium chloride (952 mg) and sodium cyanoborohydride (266 mg) were added. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the solution was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→ethyl acetate). The obtained oil was dissolved in ethyl acetate (5 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added. The precipitated crystal was collected by filtration, and vacuum-dried to give the title compound as a colorless solid (yield 196 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[F:9].[Li]CCCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.[CH3:28][Si:29](Cl)([CH3:31])[CH3:30].[NH4+].[Cl-]>C1COCC1>[F:9][C:3]1[CH:4]=[C:5]([Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:6]=[CH:7][C:2]=1[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(Br)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc([Si](C)(C)C)cc2F)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a −78° C. solution of 1,4-dibromo-2-fluorobenzene (4 g, 15.75 mmol) in THF (52.5 mL) was added a solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol). The reaction mixture was stirred at −78° C. for 30 min 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.21 mL, 15.75 mmol) was then added, and the mixture was stirred at −78° C. for an additional 1 h. A solution of n-BuLi (2.5 M in hexanes; 6.3 mL, 15.75 mmol) was then added, followed after 30 min by TMSCl (4.03 mL, 31.5 mmol). The reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. The mixture was then poured into a half saturated NH4Cl solution (300 mL), and the crude product was extracted with Et2O (3×). The combined organic layers were dried over MgSO4, filtered, concentrated and dried in vacuo to afford the title compound as a yellow oil (4.87 g, 11.92 mmol, 76% yield based on a 72% purity): 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J=7.2, 6.0 Hz, 1H), 7.26 (dt, J=7.2, 1.2 Hz, 1H), 7.16 (dd, J=9.6, 0.4 Hz, 1H), 1.36 (s, 12H), 0.26 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −104.02; EIMS m/z 294.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Cl.[Cl:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[ClH:11].[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[N:4]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Nc1cc(F)ccc1F
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: Fc1ccc(F)c(N2CCNCC2)c1
Temperature: 130 °C

Procedure:
0.03 Mol of 2,5-difluoroaniline and 0.03 mol of bis-(2-chloroethyl)amine hydrochloride are suspended in 50 mL of xylene and 15 mL of NMP. The mixture is heated at 130° C. for 25 h while stirring, then cooled to RT and the solvents are evaporated. The residue is dissolved in water and 1 equivalent of 2N aqueous sodium hydroxide (NaOH) is added. The mixture is extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous MgSO4, filtered and evaporated to dryness in vacuo. The residue is dissolved in acetone and 1 equivalent of HCL in diethyl ether (Et2O) is added. The precipitated product is collected by filtration and recrystallized from isopropanol to afford 1-(2,5-difluorophenyl)piperazine hydrochloride: m.p. 195° C. LC/MS (M+1=199.1). 1H NMR (DMSO-d6, 400 MHz) δ 3.22 (m, 4H), 3.28 (m, 4H), 6.83 (m, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 9.46 (br s, NH).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:22][CH2:21][CH2:20][CH2:19][N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN1CCN(CCCN)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(CCCNc2ccc3ncc(Br)n3n2)CC1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-(4-methylpiperazin-1-yl)propan-1-amine according to general procedure 1 providing the intermediate (200 mg, 85%) as a clear oil: Rf=0.25 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.67 (d, J=9.7 Hz, 1H), 3.42 (t, J=7.0 Hz, 2H), 2.53-2.50 (m, 10H), 2.29 (s, 3H), 1.91 (quin, J=6.6 Hz, 2H)
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[N:8]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(CC)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 15 %

Procedure:
A solution of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (20 g), 1-bromo-3,3-dimethylbutan-2-one (8.7 mL) and cesium carbonate (21 g) in N,N-dimethylformamide (200 mL) was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (3.8 g, 15%) as a colorless liquid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>[Pd].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C[SiH](Cl)Cl
Agent: [Pd]
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCCCCCC
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 319.8 %

Procedure:
As described in Example 2, 2.92 g (0.0221 mol) of dicyclopentadiene, 3.79 g (0.0331 mol) of methyldichlorosilane, 0.0602 g 1% Pd on Charcoal, 86 μL (0.000267 mol) of tributylphosphine and 4 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 180° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (12.8 g) of (2-cyclopentenyl)methyldichlorosilane (3.8 g, 63%), other unreacted reactants, toluene, hexadecane, and unidentified compounds. Besides, tetrakis(triphenylphosphine)palladium also showed catalyst effect.