Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)[NH2:3].C([O-])(=O)C.[Na+].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O.C(O)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[N:3][NH:2][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: C1=COCCC1
Reactant: CS(=O)(=O)NCc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NCc1ccc(NN=CCCCCO)cc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of 23.9 g of crude N-[(4-hydrazinylphenyl)methyl]methanesulfonamide hydrochloride in 175 mL of water and 300 mL of ethanol was added sufficient sodium acetate to bring the pH to 4. To the resulting suspension was added 10.4 mL (114 mmol, 1.3 equiv.) of 3,4- dihydro-2H-pyran. The mixture was then stirred for twenty hours at room temperature. The ethanol was removed in vacuo. The pH was raised to 10 by adding solid potassium carbonate and the mixture was extracted three times with 50 mL portions of methylene chloride. The combined organic layers were washed with 25 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and filtered to give an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to yield 11.1 g (39%, two steps) of pure N-[[4-[2-(5-hydroxypentylidene)hydrazinyl]phenyl]methyl]methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17]3[CH2:18][CH2:19][CH2:20][N:16]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: O=C1CCCN1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)N(C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-chlorophenoxazine, 2-pyrrolidinone, and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-CHLORO-10-(1-PYRROLIN-2-YL)PHENOXAZINE as a distillable oil, b.p. 150°-165° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 209.5°-213.5° C. (corr.), in a 40% overall yield.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C=C/CBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C=CCOc1ccccc1Br
Temperature: 22 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
To an acetone solution containing pulverized anhydrous K2CO3 (5.58 g, 40.5 mmol) and 2-bromophenol (5.0 g, 28.9 mmol) was added ethyl 4-bromocrotonate (6.69 g, 34.7 mmol). The mixture was stirred at 22° C. for 5 h and filtered. The filtrate was concentrated in vacuo and treated with 5% NaHCO3 (~10 mL). The residue and aqueous phase were extracted with CH2Cl2 (3×). The combined organic extracts were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound (6.10 g, 74%) as a solid material which was used without further purification.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A reaction vessel was charged with 3.75 g of 4-octanoyl-2'-fluoro-4'-bromobiphenyl and 20 ml of trifluoroacetic acid. To the mixture was added dropwise 2.4 g of triethylsilane with stirring at room temperature. After stirring for 6 hours, the reaction liquid was poured into water and the mixture was extracted with benzene. The benzene extract was washed successively with water, an aqueous solution of sodium hydrogen carbonate and water, and then dried over Glauber's salt. The solvents were distilled off and the residue was distilled in a glass tube oven (GTO) to obtain 2.56 g (71.1%) of 4-octyl-2'-fluoro-4'-bromobiphenyl. GTO-set temperature: 150° C./0.2 mmHg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[OH-].[Li+]>C1COCC1.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cccc(-c2nccs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Preparation H11, Step 4: A solution of 0.6 g (0.0027 mol) of methyl 3-(thiazol-2-yl)benzoate in 6 ml of THF and 1.2 ml of water was charged with 0.11 g (0.0046 mol) of lithium hydroxide. The reaction mixture was stirred at RT overnight. THF was removed and the aqueous layer was washed with ether and acidified with 1.5 N HCl. The solid product was extracted with ethyl acetate. The organic layer was washed with brine and concentrated to afford 3-(thiazol-2-yl)benzoic acid (0.4 g) as an off white solid obtained. 1H NMR (400 MHz, CDCl3): 7.45 (d, 1H), 7.63 (m, 1H), 8.0 (d, 1H), 8.22 (d, 1H), 8.30 (d, 1H), 8.79 (s, 1H). MS found: (M−H)−=204.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:20](=[O:40])[C:19]=3[C:18]=2[O:41][CH3:42])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].C(O)C.Cl>C1COCC1.O>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32](=[O:39])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:20](=[O:40])[C:19]=3[C:18]=2[O:41][CH3:42])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 51.2 %

Procedure:
A mixed solution of the compound of Example 123 (125 mg, 0.218 mmol) and 8N aqueous sodium hydroxide solution (1 mL) in THF (2 mL)-ethanol (7 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, acidified with 6N hydrochloric acid (1.5 mL), and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-THF to give the title compound (59.2 mg, 51%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH:12]1([CH2:17]Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:12]1([CH2:17][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CCCC1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
A stirred solution of 3-hydroxy-4-methoxy-benzaldehyde (5.74 g) in dry dimethylformamide (50 mL) is treated with cyclopentylmethyl bromide (7.34 g) and potassium carbonate (15 g), and the solution is heated at 60° C. for 24 hours. After cooling and filtration, the solution is evaporated to low bulk and dissolved in ethyl acetate (100 mL). The organic solution is washed with aqueous sodium hydroxide solution (4×50 mL; 2 N) and water (2×50 mL), dried over magnesium sulfate, and evaporated to give 3-cyclopentylmethoxy-4-methoxybenzaldehyde (6.5 g) in the form of a light brown oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.CO.O1CCCC1.[BH4-].[Na+]>O>[OH:14][CH:4]1[C:5]2[CH:6]=[C:7]3[O:13][CH2:12][O:11][C:8]3=[CH:9][C:10]=2[C:2](=[O:1])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2=O)OCO4)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2O)OCO4)CC1
Reaction time: 0.42 h
Yield: 69.6 %

Procedure:
To a reaction vessel, 92 g (0.23 mol) compound XI, 250 ml methanol and 250 ml tetrahydrofuran were added while stirring, the mixture was cooled to 0˜10° C., 10 g (0.26 mol) sodium borohydride was added, the reaction was kept at 0˜10° C. for 20-30 min, 100 ml water was added, the reaction mixture was concentrated to dry under reduced pressure (at 45° C.), The residue was added 500 ml ethyl acetate and 300 ml water, and extracted, the organic layer was collected, dried over sodium sulfate, concentrated to a minor amount, 300 ml petroleum ether was added, a solid was precipitated out, filtered, the filter cake was washed wth petroleum ether, dried, and 64.7 g compound VII-1 was obtained, with yield of 70%. 1H NMR (DMSO-d6): δ 0.95-1.04 (m, 2H), 1.39 (s, 10H), 1.51 (m, 2H), 1.70 (dd, 2H, J=25.0, 12.4 Hz), 2.65 (br s, 2H), 3.23-3.30 (m, 1H), 3.54-3.61 (m, 1H), 3.90 (d, 2H, J=10.0 Hz), 5.67 (d, 1H, J=8.9 Hz), 6.12 (s, 1H), 6.13 (s, 1H), 6.50 (d, 1H, J=9.0 Hz), 7.08 (s, 1H), 7.09 (s, 1H); MS (ESI): m/z 427 [M+Na]+.
Reaction SMILES: [I:1][C:2]1[C:7](I)=[CH:6][C:5]([O:9][CH3:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(I)c(I)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(I)c([N+](=O)[O-])cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4,5-Diiodo-1,2-dimethoxybenzene (8.8 g, 23 mmol) was added into acetic acid (300 mL), and the mixture was heated to 100° C. to dissolve the solid. The clear mixture was then cooled to room temperature followed by dropwise addition of nitric acid (68-70%, 120 mL). The reaction mixture was stirred at room temperature overnight and then poured into ice-water (200 mL). The mixture was extracted by CH2Cl2 (100 mL) three times. The combined organic phase was washed with saturated NaHCO3 solution (200 mL), brine (100 mL), and dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 4-iodo-5-nitro-1,2-dimethoxybenzene (5.25 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H, Ph-H), 7.38 (s, 1H, Ph-H), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3).
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>C1(C)C(C)=CC=CC=1>[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[NH2:1][C:25]1[C:24]([OH:23])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: [NH2-]
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Oc1cccnc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Nc1ncccc1O
Temperature: 25 °C

Procedure:
A mixture of 89.7 g (2.3 moles) of sodamide, 500 cc of xylene containing 0.1 cc of oleic acid and 95 g (1 mole) of 3-hydroxypyridine was placed in a Magne Drive as described in Example 2. The autoclave was closed and purged of air with ammonia, pressurized with ammonia to 40 psig and to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated (158°-186° ) for almost 5 hours, during which time hydrogen was evolved. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 250 cc of water. The temperature during the hydrolysis was 60° C. The aqueous phase was separated and neutralized to pH 7.0 with concentrated hydrochloric acid. It was extracted 3 times with 4-picoline. The picoline extracts were combined and distilled to give 39.3 g of recovered 3-hydroxypyridine and 40.6 g of 2-amino-3 -hydroxypyridine boiling 223°-228° C. at 29 mm. The melting point of the 2-amino-3-hydroxypyridine. recrystallized from methanol-xylene, was 162°-163° C. The structure was confirmed by NMR and the IR spectrum was identical to the spectrum of 2-amino-3-hydroxypyridine found in Aldrich Library of Infrared Spectra. 2nd ed., p. 1157E. The yield of 2-amino-3-hydroXypyridine, based on 3-hydroxypyridine recovered, was 62.9%. This result significantly differed from the literature report by Levitt and Levitt, Chemistry and Industry, 1621 (1963) which reports the amination of 3-hydroxypyridine gave 2.6-diaminopyridine in good yield while also pointing out that 2-amino-3-hydroxypyridine should, in fact, not be obtained. This is not true of applicants' discovery. The recovered 2-amino-3-hydroxypyridine was found useful, for example, in preparing prostaglandin synthetase inhibitors as reported in Belg. Patent 830,786 (1975), in preparing anti-inflammatory agents, analgesics and antipyretics as reported in Shen, et al., Ger. Offen. 2,330,109 (1974), and in preparing antibacterials as reported in Meszaros et al., Hung Telies, 10,957 (1975). The 2-amino-3-hydroxypyridine was also found useful in the preparation of metallized azo dyes for dyeing wool, polyamide, and acrylic fibers as reported in Back and Buehler, Ger. Offen. 2,236,299 (1973) and Ger. Offen. 2,236,269 (1973).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.O>[Br:24][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH2:9][CH2:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(N2CCc3ccccc32)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(N2CCc3cc(Br)ccc32)CC1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of compound 2 (1.12 g, 5.176 mmol) in dry DMF (10 mL) was treated with NBS (0.92 g, 5.176 mmol) in dry DMF (5 mL) at 0° C. over a period of 5 min. and stirring was continued at same temperature for 3 h. The reaction was diluted with water (100 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 3:97) to obtain compound 3 (1.15 g, 76%) as a syrup. 1H NMR (DMSO-d6) δ 7.14-7.06 (m, 2H), 6.37 (d, 1H, J=8.4 Hz), 3.35-3.24 (m, 3H, merged with water peak), 2.93-2.80 (m, 4H), 2.16 (s, 3H), 2.00-1.88 (m, 2H), 1.64-1.55 (m, 4H); EI-MS (m/z, %): 293, 295 (M+, bromine isotope, 47), 98 (59), 97 (100), 71 (47).
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:2]1[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: Cn1cc([N+](=O)[O-])cc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc([N+](=O)[O-])cn(C)c2=O)c(C)c1
Temperature: 90 °C
Yield: 83.3 %

Procedure:
A mixture containing 0.40 g (1.72 mmol) of 3-bromo-1-methyl-5-nitropyridin-2(1H)-one, 0.39 g (2.60 mmol) of 2,4-dimethylphenyl boronic acid, 0.70 g (5.06 mmol) of potassium carbonate, 0.31 ml (17.22 mmol) of water, and 0.99 g (0.86 mmol) of tetrakis(triphenylphosphine)palladium(0) in 80 ml of dioxane was heated to 90° C. under a nitrogen atm. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 60% ethyl acetate/hexanes gave 0.37 g (82.55%) of product.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([CH:29]=O)[C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[C:23]=2[O:22][CH2:21]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5c4OCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-benzodioxole-4-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-benzodioxol-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Cl)cc1O

Procedure:
A solution of 4-chloro-2-hydroxybenzoic acid (100 g, 0.58 mol), methanol (500 mL) and concentrated sulfuric acid (50 mL) was refluxed for 20 hr. Benzene (100 mL) was added and the solvent was slowly distilled off from the mixture until 300 mL of distillate was collected. The residue was taken up in diethyl ether, the aqueous phase was separated, the organic phase was washed with sodium bicarbonate solution, dried and evaporated to give 100 g of the title compound as an oil which crystallized on cooling; mp 27°-30° C., and IR (mineral oil) 3150, 1660 and 1600 cm-1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[C:15](Cl)(=[O:17])[CH3:16]>CN(C=O)C>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
AlCl3 (303 g, 2.27 mol) is placed in a 3-necked flask fitted with a thermometer and a dropping funnel. While stirring DMF (50 ml) is added dropwise and the temperature rises to about 60°. The mixture is cooled down to 45°, and oxindole (33 g, 0.25 mol) is added in 3 portions. After an additional 10 minutes, acetyl chloride (36 ml, 0.5 mol) is added. The mixture is stirred for an additional 30 minutes at room temperature. The mixture is poured onto ice (3000 g). This results in the formation of a solid which is filtered off, washed first with water and then with cold methanol (1000 ml), and then dried to give 5-acetyloxindole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:18]>C(Cl)Cl>[ClH:18].[ClH:18].[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[C:8]1([NH2:7])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ncccn2)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1(c2ncccn2)CC1
Reaction time: 3 h
Yield: 79.2 %

Procedure:
(1-Pyrimidin-2-yl-cyclopropyl)-carbamic acid tert-butyl ester (1.60 g, 6.80 mmol) was dissolved in CH2Cl2 (10 mL). HCl solution (4M in 1,4-dioxane, 17 mL, 68 mmol) was added via in one portion via syringe and the solution immediately became cloudy. The reaction was allowed to stir for 3 h. Solvents were removed in vacuo yielding a solid mass that was dried under vacuum to give 1.12 g of the title compound as a light yellow solid, m/z 136.32 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH2:4][OH:5].[ClH:14].[NH2:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21]>>[ClH:14].[NH2:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:5][CH2:4][C:3]1[C:2]([F:1])=[C:9]([F:10])[C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13])=[O:21]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1c(F)c(F)c(F)c(F)c1F
Reaction time: 144 h

Procedure:
From 2,3,4,5,6-pentafluorobenzyl alcohol (5.1 g; 26 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 6 days at 100° C. The yield was 0.25 g (13%). Mp 146–148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[OH-].[K+].Cl.Cl[CH2:38][CH2:39][N:40]([CH3:42])[CH3:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Combine a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (25.00 g; 1.00 equiv; 60.47 mmol) in DMSO (200.00 mL; 2.82 mol) with KOH (powder) (9.98 g; 151.18 mmol) and heat the mixture to 45° C. To this solution, add 2-chloro-N,N-dimethylethanamine hydrochloride (10.45 g; 1.20 equiv; 72.57 mmol). Stir the mixture at 45° C. for 3 h. Pour the mixture into ice-water, stir at RT and extract with EA. Wash the organic layer with water (3×) and brine; dry over MgSO4, filter and concentrate in vacuo to give the title compound (28.00 g; 57.79 mmol; 95.56%) as a yellow oil and use without further purification. 1H NMR (300 MHz, DMSO): 8.04-8.00 (m, 2H), 7.74 (s, 1H), 7.46 (t, J=9.9 Hz, 1H), 4.06-3.99 (m, 4H), 3.03-2.93 (m, 3H), 2.57 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.81-1.77 (m, 2H), 1.70-1.55 (m, 2H), 1.42 (s, 9H).