Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][C@@H:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C@H:9]([CH3:20])S[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br-:21].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:54]([O-:58])([O-])(=[O:56])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[Br:21][C:17]1[CH:18]=[C:13]([C@H:10]2[C@H:9]([CH3:20])[S:54](=[O:58])(=[O:56])[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=3[O:11]2)[CH:14]=[CH:15][C:16]=1[OH:19]
Reactant: [Br-]
Reactant: COc1cccc2c1O[C@@H](c1ccc(O)cc1)[C@H](C)S2
Reactant: O=S([O-])([O-])=S
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc2c1O[C@@H](c1ccc(O)c(Br)c1)[C@H](C)S2(=O)=O
Reaction time: 1.5 h
Yield: 52 %

Procedure:
4-[(2S*,3S*)-8-methoxy-3-methyl-2,3-dihydro-1,4-benzoxathiin-2-yl]phenol synthesized in Reference Example 14 was dissolved in a mixed solvent of methanol (12 mL) and chloroform (6 mL), and with cooling with ice, a methanol (6 mL) solution of phenyltrimethylammonium tribromide (304 mg) was dropwise added over 5 minutes, and thereafter with cooling with ice, this was stirred for 1.5 hours. Aqueous saturated sodium thiosulfate solution (4 mL) and aqueous saturated sodium hydrogencarbonate solution (4 mL) were added, and then immediately back-extracted twice with chloroform. The organic layer was collected, washed with saturated saline, dried with magnesium sulfate, and the solvent was evaporated off under reduced pressure. The obtained residue was purified by reversed-phase HPLC (0.1% TFA acetonitrile/H2O=10% to 95%, gradient) to obtain the entitled compound (146 mg, 52%) as a white solid.
Reaction SMILES: [C:1]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:2]([CH2:4][C:5]([O:7]CCCC)=[O:6])[SH:3].[CH2:18](O)[CH2:19]O>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[C:1]([OH:13])(=[O:12])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[SH:3].[CH2:15]([CH:16]=[CH2:17])[CH2:14][CH2:18][CH3:19]
Reactant: CCCCOC(=O)CC(S)C(=O)OCCCC
Reactant: OCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: C=CCCCC
Product: O=C(O)CC(S)C(=O)O
Temperature: 125 °C

Procedure:
Two moles dibutyl thiomalate, 1 mole ethylene glycol, and 3 g tetrabutyl titanate catalyst were stirred and heated for 3 hours at 125° C. Vacuum was then applied, and volatiles stripped off to 135° C and 18 mm, to give butyl ethylene thiomalate having the following properties:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C([Li])CCC.Cl[C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[NH2:30][C:31]1[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:35][CH:36]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:6][C:18]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=1)=[O:19])=[O:5]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cccc(C(F)(F)F)c1
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
A solution of 0.912 grams of 2,6-dichlorobenzamide in 75 ml. of dry tetrahydrofuran was placed in a 3-necked, 250 ml. round bottomed flask. The solution was cooled to about -72° C. with a dry ice/acetone bath. To the mixture was added 1.8 ml. of n-butyllithium solution over a 5-minute period. The mixture was allowed to stand for 30 minutes at -75° C. to -70° C. A solution of 0.804 grams of 4-nitrophenyl chloroformate in 24 ml. of dry tetrahydrofuran was added over a period of 30 minutes at about -72° C. The mixture was allowed to stand an additional 30 minutes in the cold at which time it became colorless. The solution was warmed to -40° C. and held at that temperature for 2.75 hours. The mixture was cooled again to about -72° C. and a solution of 0.64 grams of 3-aminobenzotrifluoride in 25 ml. of dry tetrahydrofuran was added over 10 minutes. The solution was allowed to warm to room temperature and was then heated at 50° C. for 16 hours. The solvent was removed and the residue was dissolved in 10 ml. of ether. The solution was washed with 1 N sodium carbonate solution, dried over magnesium sulfate and the solvent again removed. The residue was triturated under ether to give 0.6 grams of a white crystalline solid melting above 200° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1c(CBr)nc2ccccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2nc3ccccn3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine (1.07 g, 5.87 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.539 g, 3.82 mmol) in anhydrous ethanol (30 mL) at 0° C. was added triethylamine (2.08 g, 2.86 mL, 20.57 mmol), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and water was added to precipitate the product. The crude product was purified by column chromatography using dichloromethane and methanol (0-10%) to provide 2-[({3-chloroimidazo[1,2-a]pyridin-2-yl}methyl)sulfanyl]-6-methylpyrimidin-4-ol; 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.52 (s, 2H), 6.03 (bs, 1H), 7.07 (t, 1H), 7.35 (t, 1H), 7.59 (d, 1H), 8.30 (d, 1H); M+1 279.3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1([CH3:19])[CH2:18][O:17][CH2:16]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FB(F)F.C(OCC)C.C(N(CC)CC)C.C(OCC)C>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]12[O:12][CH2:16][C:15]([CH3:19])([CH2:14][O:13]1)[CH2:18][O:17]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(COC(=O)CCOCc2ccccc2)COC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC12COC(CCOCc3ccccc3)(OC1)OC2
Temperature: -15 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
3-Methyl-3-oxetanylmethyl 3-benzyloxypropionate (521 mg) was dissolved in dichloromethane under an argon atmosphere, and trifluoroborane-diethylether was added thereto at -15° C. The mixture was stirred for 5 hours at -15° C. Triethylamine (280 μl) was added to the reaction mixture, and stirring was continued for 15 minutes. Subsequently, diethylether (3 ml) was added. The precipitating crystals were removed from the reaction mixture by filtration, then the mother liquid was concentrated under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetatehexane 1:3), to give 385 mg of 1-(2-benzyloxyethyl)-4-methyl-2,6,7-trioxabicyclo-[2.2.2]octane as a colorless solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:25][CH:26]1[C:48](=[O:49])[N:28]2[C:29]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])=[C:30]([O:33][CH3:34])[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:25][CH:26]2[C:48](=[O:49])[N:28]3[C:29]([C:35]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:36])=[C:30]([O:33][CH3:34])[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CCCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Yield: 77.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetic acid (syn isomer, 1.09 g.), N,N-dimethylformamide (322 mg.) and phosphoryl chloride (675 mg.) in ethyl acetate (9.2 ml.) and a solution of 4-nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate hydrochloride (1.5 g.), trimethylsilylacetamide (5 g.) and bis(trimethylsilyl)acetamide (2 ml.) in ethyl acetate (30 ml.) were treated in a similar manner to that of Example 3-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 1.8 g.).
Reaction SMILES: C(OCC(C[O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CCOC(=O)C)(=O)C.O>C(O)(=O)C>[C:15]([OH:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)OCCC(COC(C)=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
2-Trityloxymethyl-1,4-butanediol diacetate (60.90 g, 0.136 mol) was dissolved in acetic acid (320 ml) at 100° C. and water, (80 ml) was added. The solution was kept at 100° C. for 15 min, evaporated in vacuum to small volume and cooled to 0° C. The precipitate was filtered off and washed with cold ethyl acetate to give 26.44 g (theory 35.51 g) of tritylalcohol. The combined filtrate was evaporated to small volume. The compound was purified on a silica gel column (500 g SiO2); eluent 0-2700 ml ethyl acetate+n-hexane (1+1), 2700-3740 ml ethyl acetate+n-hexane (2+1), then neat ethyl acetate. The fractions 2540-4800 ml were evaporated to give 14.20 g (51%) of pure 4-acetoxy-2-hydroxy-methylbutyl acetate. TLC on silica (ethyl acetate+n-hexane 1+1): Rf 0.30.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]([CH3:21])=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].[Cl-].C[N+]1C=CC=CC=1Cl.[Cl-].[NH2:32][C:33]([NH2:35])=[NH2+:34].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[NH2:34][C:33]([NH2:35])=[N:32][C:8](=[O:9])[C:7]1[C:11]([CH3:21])=[CH:12][C:13]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: NC(N)=[NH2+]
Reactant: Cc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 0.25 h

Procedure:
1.0 g of 3-methylsulfonyl-4-(3-pyridyloxy)-6-methylbenzoic acid [obtainable by reacting 3-methylsulfonyl-4-chloro-6-methylbenzoic acid with 3-hydroxypyridine] is dissolved in 15 ml of 1-methylpyrrolidone, and 0.67 g of 1-methyl-2-chloropyridinium chloride is added to this solution, which is stirred for 15 min. 0.9 g of guanidinium chloride and 2.6 ml of N-ethyldiisopropylamine are then added, and the mixture is stirred at room temperature for one hour. Following customary working-up, N-diaminomethylene-3-methylsulfonyl-4-(3-pyridyloxy)-6-methylbenzamide is obtained, m.p. 221-224°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH2:12]([CH:14]1O[CH2:15]1)[Cl:13].C(P(=[O:30])(CCCC)CCCC)CCC.[Br-].[Li+]>C1(C)C(C)=CC=CC=1>[Cl:13][CH2:12][CH:14]1[O:11][C:10](=[O:30])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15]1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: CCCCP(=O)(CCCC)CCCC
Reactant: ClCC1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1C
Product: CSc1ccc(N2CC(CCl)OC2=O)cc1
Yield: 192 %

Procedure:
To a hot (130° C.) solution of 105 g (0.64 mole) of 4-methylthiophenyl isocyanate and 93 g (1 mole) of epichlorohydrin in 600 ml of xylene was added 200 ml of tri-n-butylphosphine oxide-lithium bromide complex. (The complex was prepared by heating a mixture of 45 g of tri-n-butylphosphine oxide, 12.7 g of lithium bromide and 550 ml of xylene to reflux until a clear solution was obtained by removing water.) An exothermic reaction took place. After all of the catalyst had been added, the mixture was heated under reflux for 1 hour and cooled. The solution was decanted into a flask and concentrated to one-half the volume. An equal volume of petroleum ether was added to the residue. The solid that formed was collected by filtration and recrystallized from acetonitrile to give 102 g (62% yield) of the title compound; m.p. 106.5°-107.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].CCCCCC.C([Li])CCC.[F:24][C:25]1[C:26]([CH:31]=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>C(OCC)C.C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][O:11][CH3:12])=[C:2]([CH:7]=1)[CH:31]([C:26]1[C:25]([F:24])=[CH:30][CH:29]=[CH:28][N:27]=1)[OH:32]
Reactant: O=Cc1ncccc1F
Reactant: COCOc1ccc(Br)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1ccc(Br)cc1C(O)c1ncccc1F
Reaction time: 0.33 h
Yield: 40.5 %

Procedure:
To a solution of 2,4-dibromo-1-methoxymethoxybenzene (3.50 g) in diethyl ether (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (8.1 ml). The mixture was stirred for 20 minutes at the same temperature, to which was added a solution of 3-fluoro-2-formyl-pyridine (1.48 g) in THF (10 ml), followed by stirring for one hour at temperatures ranging from -78° to 60° C. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-hydroxy-2-methoxymethoxybenzyl)-3-fluoropyridine (1.64 g) (Compound D-6). The physical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=1)=[O:6].[CH3:26]I.O>CN(C)C=O>[CH3:26][N:7]([CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:11]=1)[C:5](=[O:6])[C:4]([F:24])([F:3])[F:25]
Reactant: O=C(NCCc1ccn(S(=O)(=O)c2ccccc2)c1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCc1ccn(S(=O)(=O)c2ccccc2)c1)C(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
50% Sodium hydride oil dispersion (0.62 g) was added to an ice-cooled solution of N-trifluoroacetyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (3.59 g) in dimethylformamide (20 ml) after 20 minutes, methyl iodide (1.76 g) was added and the mixture was heated at 70° C. overnight. After cooling, water was added and the mixture was extracted with ether 3 times. The ether was washed with water, dried and evaporated to give N-methyl-N-trifluoroacetyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine as an oil. The oil was dissolved in methanol (40 ml), 0.880 ammonia added and the solution was stirred for 6 hours. After evaporation, the residue was dissolved in 5M hydrochloric acid and extracted with ether. The aqueous part was basified with 0.880 ammonia and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give the title product as a pure oil.
Reaction SMILES: F[P:2]123[N:12]4[CH2:13][CH2:14][N:3]1[CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][N:9]3[CH2:10][CH2:11]4.[OH-:15].[Na+]>>[O:15]=[P:2]12[N:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:3]1[CH2:4][CH2:5][N:6]2[CH2:7][CH2:8]3
Reactant: FP123N4CCN1CCN2CCN3CC4
Reactant: [OH-]
Agent: [Na+]
Product: O=P12N3CCNCCN1CCN2CC3

Procedure:
A 100 mg sample of 13-fluoro-1,4,7,10-tetraaza-13-phosphatetracyclo[5.5.1.04,13.010,13 ]tridecane was dissolved in 0.5 ml of 1N sodium hydroxide by heating to near boiling. This mixture was cooled, filtered and evaporated. The white residue was then sublimed at 150°-180° and 0.1 mm pressure to give 90 mg of 13-oxo-1,4,7,10-tetraaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane and leaving 10- 20 mg of residue. The sublimate was kept under dry nitrogen and melted at 215°-217° to a clear colorless melt. On exposure to moist air this solid picked up water of hydration without softening. The hydrated sample softened at 90° and slowly lost water up to 160° where the sample frothed and then darkened and totally melted in the range of 200°-210°. The anhydrous sample was used for nmr and mass spectra.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Br)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of N-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide (1.80 g, 4.54 mmol) in acetone (50 mL) and water (5 mL) was added potassium carbonate (1.50 g, 10.8 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo, and the residue was washed with water and t-butyl methyl ether to yield the title compound in 78% yield (1.12 g): mp 222-224° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.60 (t, J=6.0 Hz, 1H), 7.33-7.16 (m, 5H), 4.35 (d, J=6.0 Hz, 2H), 3.97 (t, J=7.2 Hz, 2H), 2.59 (t, J=7.8 Hz, 2H), 2.46 (s, 3H), 2.14-1.94 (m, 2H); MS (ES+) m/z 316.4 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].C(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH:18]([O:17][CH:10]([CH3:9])[CH3:11])([CH3:19])[CH3:22].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[O:23][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OC(C)C
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 155.9 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.8 g, 2.5 mmol) and 2-methoxyaniline (0.45 g, 3.7 mmol) in toluene (12 ml) was heated to 90° C. and stirred 3.0 h. After cooling to room temperature, methylene chloride and water were added. The mixture was neutralized with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. Trituration with isopropyl ether gave 0.80 g (77%) of the desired product.
Reaction SMILES: I[C:2]([F:5])([F:4])[F:3].Br[C:7]1[C:12]([O:13][CH2:14][C:15]2[N:16]([CH3:20])[N:17]=[CH:18][N:19]=2)=[N:11][N:10]2[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:22][N:23]=[C:9]2[CH:8]=1>CN(C=O)C.ClCCl.[Cu]>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[N:10]2[N:11]=[C:12]([O:13][CH2:14][C:15]3[N:16]([CH3:20])[N:17]=[CH:18][N:19]=3)[C:7]([C:2]([F:5])([F:4])[F:3])=[CH:8][C:9]2=[N:23][N:22]=1
Reactant: FC(F)(F)I
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1Br
Agent: [Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
Iodotrifluoromethane (2.0 g, 10 mmol) was bubbled through a solution of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.10 g, 0.25 mmol) in dry DMF (2 ml) at room temperature until the required quantity of gas had dissolved. Copper powder (0.16 g, 2.5 mmol) was added and the mixture was stirred in a sealed tube at 80° C. for 18 h. The mixture was cooled, diluted with dichloromethane (50 ml) and filtered. The filtrate was washed with water (50 ml), then dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography, eluting with 3% methanol-dichloromethane, gave 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-trifluoromethyl-1,2,4-triazolo[4,3-b]pyridazine (0.0061 g, 6%) as a pale yellow solid; m.p. 123-126° C.; 1H NMR (360 MHz, CDCl3) δ 3.92 (3H, s), 5.60 (2H, s), 7.31 (1H, dd, J=8 and 8 Hz), 7.40 (1H, dd, J=8 and 8 Hz), 7.56-7.64 (1H, m), 7.86-7.94 (2H, m), 8.50 (1H, s); MS (ES+) m/e 393 [MH]+.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[CH:11]1[C:16]([CH:17]=O)=[CH:15][C:14]2[O:19][CH2:20][O:21][C:13]=2[CH:12]=1.N1CCOCC1.Cl>O.CS(C)=O>[CH2:20]1[O:21][C:13]2[CH:12]=[CH:11][C:16]([CH:17]=[CH:2][C:1]([CH:4]3[C:8](=[O:9])[CH2:7][CH2:6][C:5]3=[O:10])=[O:3])=[CH:15][C:14]=2[O:19]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: O=C(C=Cc1ccc2c(c1)OCO2)C1C(=O)CCC1=O
Yield: 49 %

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.39 g.) was treated with piperonal (4.79 g.) in 60 ml. of dimethylsulfoxide in the presence of 5 ml. of morpholine at 85° C for 45 minutes. After cooling, the reaction mixture was poured into 150 ml. of water containing 7 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration and washed with water, and dried. 2-(3,4-Methylenedioxycinnamoyl)-1,3-cyclopentanedione (3.23 g.) was obtained in a yellow crystalline form, which showed mp. 181° - 182° C. after recrystallization from a mixed solvent of dioxane and ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=O)[CH2:8][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[CH2:29]Cl)=[N:21]2)=[CH:16][CH:15]=1.CN(C=[O:38])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[CH2:29][O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][C:8](=[O:38])[NH:9]4)=[CH:4][CH:3]=3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: O=C1CNc2cc(O)ccc2C1
Reactant: ClCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=C1CCc2ccc(OCc3cccc(OCc4ccc5ccc(Cl)cc5n4)c3)cc2N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.326 g (2 mmol) of 7-hydroxy-1,2,3,4-tetrahydroquinolin-3-one, 0.609 g (5 mmol) of K2 CO3, 0.075 g (0.25 mmol) of tetra-n-butylammonium bromide, 40 ml of DMF and 0.636 g (2 mmol) of 3-(7-chloro-2-quinolinylmethoxy)benzyl chloride was stirred at room temperature for 3 days. Insoluble matter was removed and the solvent was then distilled off. The residue was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from acetone, whereby 0.245 g of the title compound was obtained as pale yellow powder (yield: 27.6%).