Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[O:29]CCO4)=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[N:20]=[CH:21][C:22]([CH:25]=[O:29])=[CH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(C2OCCO2)cn1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (4.40 g) in acetic acid (35 mL) was added ammonium acetate (10.3 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.22 g, yield 83%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 465 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[CH:3]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:24]([O:23][C:21]([CH:20]([O:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[CH:3]=1)[CH3:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Temperature: 80 °C
Yield: 181.3 %

Procedure:
A mixture of 40 g of 7-hydroxy-3-phenyl-4H-1-benzopyran-4-one, 46 g of ethyl 2-bromopropionate, 250 ml of dimethylformamide and 46.5 g of potassium carbonate was stirred well with heating at 80° C. for 2 hours and poured into 270 ml of ice water. The resulting crystalline precipitate was collected by filtration and recrystallized from ethyl acetate-ethanol to give 103 g of 7-(1-ethoxycarbonylethyl)oxy-3-phenyl-4H-1-benzopyran-4-one as white crystals. m.p. 165°-166° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.[F-].[K+]>C1(C)C=CC=CC=1>[N:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2n1CCCC2
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2n1CCCC2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
142 mg of the 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-2] was dissolved in 2.5 mL of toluene, 81.6 mg of tetrakis triphenylphosphine palladium (0) and 477 μL of tributyl(1-ethoxyvinyl)tin were added, and the mixture was stirred overnight at 120° C. The reaction mixture was cooled back to room temperature to add 10% aqueous solution of potassium fluoride, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of potassium fluoride and with saturated brine in the subsequent order, and then was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the purification by silica gel column chromatography was carried out. The obtained compound was dissolved in 2 mL of chloroform, 200 μL of 10% hydrochloric acid-methanol solution was added, and the mixture was stirred for 40 minutes. The liquid was basified by adding a saturated aqueous solution of sodium hydrogen carbonate, and was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography to obtain 62.2 mg of 1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)ethanone [44-3] as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Cc1ccccc1N
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1ccccc1Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 23.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and o-toluidine (0.07 mL, 0.65 mmol) to provide 240 (31 mg, 21% yield) as a yellow/green powder. LC-MS (M+H (parent)=302, obsd.=302). 1H NMR (400 MHz, d6-DMSO): δ 11.63 (s, 1H), 8.44 (dd, 1H), 8.37 (s, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.55 (d, 1H), 7.33 (m, 2H), 7.25 (m, 2H), 7.11 (m, 1H), 7.07 (dd, 1H), 2.24 (s, 3H).
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:8])[CH2:7][CH2:6]1.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]1([NH:8][C:11](=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[N:22][O:23][C:24]=3[CH3:25])=[N:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of cyclopropylamine (69 mg, 84 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 3 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (100 mg, 91%) which was obtained as a white solid. MS: m/e=368.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6](N)=[O:7].C(O)(=O)C[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[NH2:1][C:2]([NH2:4])=[O:3].[C:6]([OH:7])(=[O:3])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCC(=O)O
Agent: NC(N)=O
Product: O=C(O)CCC(=O)O
Reaction time: 4 h

Procedure:
50 g. of urea was further added to the mother liquor with the glutaric acid adduct removed and dissolved at 60° C. The resulting solution was cooled to and allowed to stand at 15° C. for 4 hours to precipitate a urea-succinic acid adduct. By filtration, 51 g. of urea-succinic acid adduct (including 23 g. of succinic acid) was obtained. The obtained urea-succinic acid adduct was then dissolved in 300 g. of water at 30° C. and the solution was treated with the same strongly acidic ion exchange resin as mentioned above to remove urea. 200 g. of water was removed from the treated solution and on subsequent cooling to and allowing to stand at 10° C. for 3 hours, succinic acid crystallized out of the solution. By filtration, 20 g. of succinic acid having a purity of 99% was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:31](=[O:32])[CH:5]2[CH:6](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25]C=C(C(F)(F)F)[CH:22]=4)=[CH:17][N:16]=3)[N:7]3[CH:12]([CH:4]2[C:3]1=[O:33])[CH2:11][CH2:10][CH2:9][CH2:8]3.BrC1C=CC(/C=C/C2N3C(CCCC3)C3C(=O)N(C)C(=O)C23)=NC=1.[S:58]1C=CC(B(O)O)=C1>>[CH3:1][N:2]1[C:31](=[O:32])[CH:5]2[CH:6](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][S:58][CH:22]=4)=[CH:17][N:16]=3)[N:7]3[CH:12]([CH:4]2[C:3]1=[O:33])[CH2:11][CH2:10][CH2:9][CH2:8]3
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: OB(O)c1ccsc1
Agent: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1
Product: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2ccsc2)cn1

Procedure:
The title compound is prepared analogously to the compound from Example 17 from 42 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-2-methyloctahydropyrrolo[3,4-a]-indolizine-1,3-dione (from Example 6, racemic mixture 3) and 15 mg of 3-thiophene-boronic acid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH2:22][O:23]C(=O)CC)[O:9][CH2:8][C:7]2([CH2:14][O:13][C:12]([CH3:21])([CH2:15][O:16]C(=O)CC)[O:11][CH2:10]2)[CH2:6][O:5]1>O.CO>[CH3:21][C:12]1([CH2:15][OH:16])[O:11][CH2:10][C:7]2([CH2:6][O:5][C:4]([CH3:3])([CH2:22][OH:23])[O:9][CH2:8]2)[CH2:14][O:13]1
Reactant: CCC(=O)OCC1(C)OCC2(CO1)COC(C)(COC(=O)CC)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CO)OCC2(CO1)COC(C)(CO)OC2
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 76.1 %

Procedure:
To a solution of sodium hydroxide (3 g, 0.075 mol) in water (25 ml) and methanol (25 ml), 3,9-dimethyl-3,9-bis(propionyloxymethyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (6.5 g, 18 mmol) was slowly added, followed by stirring for 40 minutes at 60° C. After the solvent was distilled off under reduced pressure, the resultant concentrate residue was dissolved in acetonitrile/brine. The separated-off organic layer was concentrated under reduced pressure, and then ethyl acetate was added thereto. After the insoluble material was filtered out, the resultant filtrate was concentrated again under reduced pressure. The resultant concentrate residue was recrystallized from ethyl acetate/hexane, to give 3,9-dimethyl-3,9-bis(hydroxymethyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (3.4 g, 13.7 mmol, yield 76%).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([Cl:20])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOC(=O)NCC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOC(=O)NCC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(allyloxycarbonyl)glycine (described in Chem. Pharm. Bull., 48, 716 (2000); 600 mg, 3.77 mmol) in dichloromethane (15 ml) was cooled to 0° C., and N,N-dimethylformamide (0.03 ml) and oxalyl chloride (0.6 g, 4.7 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, then toluene was added thereto, and the solvent was distilled off under reduced pressure to give crude 2-(allyloxycarbonylamino)acetyl chloride.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6](Cl)[N:5]=1.[CH3:21][CH2:22][CH:23]([OH:25])[CH3:24]>>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6]([O:25][C@@H:23]([CH2:22][CH3:21])[CH3:24])[N:5]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CCC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC[C@@H](C)Oc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A flask was charged with sodium hydride (60% oil dispersion, 300 mg, 7.5 mmol) which was washed with hexanes before the addition of (±)-cis-4-(2-amino-6-chloro-9H--purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (800 mg, 3 mmol) in ~10 mL of R-(-)-2-butanol. The solution was stirred at room temperature for 3 hours then at 60° C. (oil bath) for 1 hour. The solution was allowed to cool to room temperature before neutralization with 1 H HC1. The solution was concentrated and the residue chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform (0.81 g, 89%). Crystallization of such a sample from ethanol-acetonitrile yielded an off-white powder, m.p. 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]([OH:16])=[CH:14][C:5]2[O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:4]=2[CH:3]=1.[C:17]([C:23](OC)=[O:24])#[C:18][C:19]([O:21]C)=[O:20].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCOCC1.O>[C:19]([C:18]1[O:16][C:15]2[C:2]([Cl:1])=[CH:3][C:4]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH2:7][O:6][C:5]=3[C:14]=2[C:23](=[O:24])[CH:17]=1)([OH:21])=[O:20]
Reactant: Oc1cc2c(cc1Cl)-c1ccccc1CO2
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccccc1CO3
Temperature: 75 °C

Procedure:
The starting compound was obtained in the following way: A solution of 9.8 gm (0.04 mol) of 2-chloro-3-hydroxy6H-dibenzo-[b,d]-pyran and 9.0 gm (0.06 mol) of dimethyl acetylene-dicarboxylate in 20 ml of dioxane was admixed with 0.85 ml of a 40% solution of benzyl trimethylammonium hydroxide in water. The resulting solution was heated for 10 minutes at 75° C, then cooled, admixed with 5 N sodium hydroxide, and heated for one hour more. Then, the reaction mixture was cooled, acidified with concentrated hydrochloric acid, and the precipitate formed thereby was filtered off, washed with water, dried and recrystallized from a mixture of acetic acid and chloroform (1:9). The compound named in the heading, m.p. 242°-243° C, was obtained with a yield of 10.5 gm (99%) of theory).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][N:12]2C(OC)=O)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br>>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][NH:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(C)(C)C)c1
Agent: Br
Product: CC(C)(C)c1cccc([C@H]2C[C@@H](c3cc(=O)[nH]o3)CCN2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
(2R,4S)-Methyl 2-(3-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.340 g, 0.95 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 5.49 mL, 31.35 mmol) and the solution stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-tert-butylphenyl)piperidin-4-yl)isoxazol-3(2H)-one (107 mg, 37%). 1H NMR (400 MHz, dmso) δ 1.26 (s, 9H), 1.32-1.43 (m, 1H), 1.43-1.54 (m, 1H), 1.81-1.90 (m, 1H), 1.90-1.99 (m, 1H), 2.68-2.78 (m, 1H), 2.80-2.91 (m, 1H), 3.08-3.16 (m, 1H), 3.59-3.66 (m, 1H), 5.72 (s, 1H), 7.13-7.29 (m, 3H), 7.37 (s, 1H). HRMS Calcd for [C18H24N2O2+H]+: 301.1916. Found: 301.1909.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:21]>C(O)C.[Pd]>[ClH:21].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[CH3:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCC(Oc2ccc(N)cc2C)CC1
Reaction time: 2 h

Procedure:
To a solution of 1-Acetyl-4-(4-nitro-2methylphenyoxy)piperidine (4.5 g) obtained in Example 23, (1) in ethanol (70 ml) was added conc. hydrochloric acid (1.4 ml) and, by using 10% palladium/carbon (containing 48% water, 0.5 g) as a catalyst, catalytic reduction was conducted under normal pressure for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 1-acetyl-4-(4-amino-2methylphenyloxy)piperidine hydrochloride (5.1 g) as a light brown amorphous material.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:14][CH2:13]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(CCc4ccccc4)CC3)nn12
Yield: 71 %

Procedure:
A mixture of 1-phenethylpiperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(2-phenylethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 71% yield.
Reaction SMILES: [C:1]([N:5]([CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:18]([CH3:20])[CH3:19])[O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:27].[Na+]>CC(C)=O>[C:1]([N:5]([CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:18]([CH3:20])[CH3:19])[O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][I:27])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(ON(C(c1ccccc1)C(C)C)C(C)(C)C)c1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(ON(C(c1ccccc1)C(C)C)C(C)(C)C)c1ccc(CI)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 50-mL round-bottom flask equipped with a magnetic stirbar was added chloromethyl alkoxyamine 3 (1.789 g, 4.784 mmol) and acetone (20 mL). To the resulting solution was added sodium iodide (2.869 g, 19.14 mmol, 4 equiv) and the reaction mixture was capped with a rubber septum and allowed to stir for 24 hours at room temperature. The sodium chloride side product was remove by gravity filtration, and the filtrate was concentrated on a rotary evaporator. The crude oily product was purified by flash chromatography, eluting with hexanes. The desired iodomethyl akoxyamine 4 was obtained as a colorless oil (1.968 g, 88.3% yield). ESI-MS: m/z=466.0, observed; 465.41, calculated. 1H NMR (500 MHz, CDCl3, both diastereomers) δ 7.5-7.1 (m, 18H), 5.35 (t, 2H) 4.90 (q+q, 2H, both diastereomers), 4.55 (s, 4H), 3.55 (m, 2H), 3.40 (d, 1H, minor diastereomer), 3.30 (d, 1H, major diastereomer), 2.40 (m, 2H, both diastereomer), 2.30 (d, 2H), 1.65 (d, 3H, minor diastereomer), 1.58 (d, 3H, major diastereomer), 1.33 (d, 3H, minor diastereomer), 1.05 (s, 9H, major diastereomer), 0.98 (s, 6H), 0.95 (d, 3H, major diastereomer), 0.89 (d, 12H), 0.85 (d, 6H), 0.82 (s, 9H, minor diastereomer), 0.68 (s, 2H), 0.59 (d, 3H, minor diastereomer), 0.28 (d, 3H, major diastereomer).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].[K+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: C=CCCCBr
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCOc1ccc(C(C)=O)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
Under dry condition, 3.58 g (18.41 mmol) of 5-acetylsalicylic acid, methyl ester is dissolved in 25 mL of dry N,N-dimethylformamide. To this solution is added 3.07 g (20.58 mmol) of 5-bromo-1-pentene, 6.83 (20.58 mmol) of potassium carbonate, and 0.246 g (1.65 mmol) of potassium iodide, and the reaction mixture is stirred for 24 hours at ambient temperature. Another portion of 5-bromopentene is added to the reaction, followed by one-half portions of the other two reagents above, and stirring is continued for 72 hours. The mixture is then evaporated under high vacuum at 70° C. The residue is partitioned between ether/water and the organic phase is separated, dried with magnesium sulfate, filtered, and evaporated under vacuum to leave 4.60 g (95%) of 5-acetyl-2-(4-pentenyloxy)benzoic acid, methyl ester as a yellow liquid: IR (neat) 1735, 1710, 1680 cm-1 ; 1HNMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 263 (M+ +H). Analysis calculated for C15H18O4 : C, 68.69; H, 6.92; O, 24.40. Found: C, 68.60; H, 6.92; O, 24.46.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.[NH2:36][C:37]1[CH:52]=[CH:51][C:40]2[N:41]([CH2:49][CH3:50])[CH2:42][C:43]([CH2:47][OH:48])([OH:46])[CH2:44][O:45][C:39]=2[CH:38]=1>C(O)(C)C>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:36][C:37]2[CH:52]=[CH:51][C:40]3[N:41]([CH2:49][CH3:50])[CH2:42][C:43]([OH:46])([CH2:47][OH:48])[CH2:44][O:45][C:39]=3[CH:38]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(O)(CO)COc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CC(O)(CO)COc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21

Procedure:
10-Camphorsulfonic acid (107 mg, 0.462 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (132 mg, 0.420 mmol), and 3-Amino-9-ethyl-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.100 g, 0.420 mmol) in Isopropyl alcohol (3.0 mL) and the mixture was irradiated in a CEM microwave (120° C., 40 min). The reaction mixture was then purified by HPLC and lyophilized to afford 2-[5-Chloro-2-(9-ethyl-7-hydroxy-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a black lyophilate (2 mg, 1%). LCMS: 517.32 (M+H); HNMR (CD3CN): 9.70 (s, 1H), 8.03 (s, 1H), 7.43 (m, 3H), 7.10 (s, 1H), 7.00 (s, 1H), 6.84 (d, J=8.84 Hz, 1H), 6.66 (d, J=8.60 Hz, 1H), 4.02 (q, J=6.80 Hz, 2H), 3.87 (s, 1H), 3.51 (s, 1H), 3.32 (m, 4H), 3.13 (s, 2H), 2.81 (s, 5H), 1.12 (t, J=7.08 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].Cl[CH:29]([F:31])[F:30].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH:29]([F:31])[F:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)cc1OC
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: COCCOC
Product: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)cc1OC

Procedure:
Five hundred milligrams (500 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide (1.33 mmol), 2.00 g (3.56 mmol) of 10% aqueous potassium hydroxide solution, 87 mg (0.266 mmol) of tetrabutylammonium bromide and 10 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature. After a sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatograph analysis, 5% hydrochloric acid was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=2:1) and the obtained residue was washed with hexane to give 360 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-difluoromethoxy-2-(4-chlorophenyl)acrylamide.