Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[C:8](=[O:25])[O:7][C:6]1([CH3:27])[CH3:26])(=O)C.[BH4-].[Li+]>O1CCCC1>[OH:4][CH:5]([C:9]1([CH2:8][OH:25])[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)[C:6]([OH:7])([CH3:27])[CH3:26]
Reactant: CC(=O)OC1C(C)(C)OC(=O)C12CCN(C(=O)OCc1ccccc1)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)C(O)C1(CO)CCN(C(=O)OCc2ccccc2)CC1
Yield: 27 %

Procedure:
Benzyl 4-(acetyloxy)-3,3-dimethyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (i) above; 1.4 g) was dissolved in tetrahydrofuran and lithium borohydride (81 mg) was added. The mixture was heated under reflux for 2 h, cooled and quenched carefully with water and HCl (30 mL, 5N). The mixture was extracted with ethyl acetate and dried (MgSO4), and concentrated in vacuo. The crude product was purified by chromatography on silica using 2-5% methanol in dichloromethane as eluant to afford the product (340 mg).
Reaction SMILES: CC([O-:5])(C)C.[K+].[OH2:7].[ClH:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C:34]([CH2:43][O:44][C:45](NCC)=[O:46])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=[CH:14][C:15]=1[Cl:16].O.O.[Cl:52][C:53]1[CH:54]=[C:55]([CH:60]([CH2:72][CH2:73][N:74]2[CH2:79][CH2:78][C:77]([C:87]3[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=3)([CH2:80][O:81][C:82](NCC)=[O:83])[CH2:76][CH2:75]2)[CH2:61][N:62]([CH3:71])[C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:56]=[CH:57][C:58]=1[Cl:59].Cl.Cl>CN(C=O)C>[OH2:5].[ClH:9].[C:45]([CH2:80][C:77]1([C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH2:78][CH2:79][N:74]([CH2:73][CH2:72][CH:60]([C:55]2[CH:56]=[CH:57][C:58]([Cl:59])=[C:53]([Cl:52])[CH:54]=2)[CH2:61][N:62]([CH3:71])[C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:75][CH2:76]1)([OH:46])=[O:44].[OH2:27].[OH2:7].[C:82]([CH2:43][C:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:36][CH2:35]1)([OH:83])=[O:81].[ClH:8]
Reactant: CC(C)(C)[O-]
Reactant: CCNC(=O)OCC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(CCN1CCC(CC(=O)O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: 80 °C
Yield: 136.9 %

Procedure:
1.8 g of potassium tert-butylate and then 1.5 g of the compound obtained in step C of EXAMPLE 15 are added to a solution of 2.3 g of the compound obtained in PREPARATION 1.22 in 20 ml of DMF, and the reaction mixture is heated to 80° C. for 2 hours. It is concentrated under vacuum, the residue is taken up in water, the mixture is neutralized to pH 7 by adding concentrated HCl solution, the product is extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/MeOH (95:5; v/v) mixture. The product obtained is taken up with ethereal hydrogen chloride and the solvent is evaporated off under vacuum. 0.96 g of the expected product is obtained after crystallization in iso ether.
Reaction SMILES: [K].CC(C)([O-])C.[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1ccccc1SCc1ccccc1
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1Cc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.35 g of potassium-tertbutoxide in 25 mL of dimethylformamide, cooled to 0° C., was added 0.92 mL of 2-pyrrolidinone. As a white precipitate formed, the mixture was stirred for 10 minutes, and 3.0 g of 2-phenylmethylthio chloromethyl benzene was added in one portion. The resulting solution was allowed to warm to room temperature, stirred for 1 hour, poured into water, and extracted with methylene chloride. The organic layer was washed well with water, dried over magnesium sulfate, filtered, and the filtrate evaporated to leave 3.0 g of a yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:15][C:16]#[C:17][CH2:18]Cl>C(OCC)C>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][C:16]#[C:17][CH2:18][N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClCC#CCCl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: CCOCC
Product: C(#CCN(c1ccccc1)c1ccccc1)CN(c1ccccc1)c1ccccc1
Temperature: 85 °C
Yield: 28.4 %

Procedure:
A vigorously stirred mixture of diphenylamine (174 g, 1.03 mol) and 1,4-dichlorobut-2-yne (23 g, 0.19 mol) is heated at 85° C. for 72 hours. The black mixture is allowed to cool to room temperature and is then taken up in diethyl ether. Diphenylamine hydrochloride is removed by filtration and the solvent is removed in vacuo leaving a black oil. The oil is extracted with several 200 ml portions of hot hexane. The extracts are allowed to stand whereupon a solid crystallizes. The solid is collected and is then recrystallized from hexane to give 21 g (29% yield) of the title compound as a tan solid melting at 84°-86° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:25])[NH:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:25])[N:14]([CH2:31][CH3:32])[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)Nc2ccc(C(F)(F)F)nc2)COC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(C(F)(F)F)nc1
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a stirred solution of (R)-2,2-dimethyl-4-(6-trifluoromethyl-pyridin-3-ylcarbamoyl)-oxazolidine-3-carboxylic acid tert-butyl ester (0.20 g, 0.51 mmol) in dimethylsulfoxide (4 ml) under an argon atmosphere was added sodium hydride (0.028 g, 0.59 mmol) and the mixture was stirred for 20 min. Iodoethane (0.05 ml, 0.61 mmol) was added and the mixture was stirred overnight at room temperature. Water (20 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. After removal of the solvent the residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1) to yield a light yellow oil (0.15 g, 70%), MS (ISP): 418.2 ([M+H]+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C=CC=CC=1.Cl[C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>COCCOCCOC.[Cu].O>[O:7]([C:22]1[CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:19]=[CH:18][CH:23]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(-c4cccc(Oc5ccccc5)c4)c3)c2)cc1
Temperature: 100 °C

Procedure:
A 500 ml. reaction flask equipped with stirrer, condenser and Dean-Stark trap was charged with 250 g. (2.66 moles) of phenol. This was heated with stirring at 100°C. while 56 g. (1.0 mole) of potassium hydroxide was added in increments. Toluene (50 ml.) was then added to the fluld mass and water azeotroped from the system. After all toluene and water had been removed, 150 ml. of diglyme was added together with 5.0 g. (0.05 mole) of cuprous chloride and 1.0 g. of copper powder. To this mixture 20 g. (0.053 mole) of 3-chloro-3'-(m-phenoxyphenoxy)biphenyl in diglyme was added over a 30 minute period. Diglyme was distilled from the mixture which was then heated at 240° for 18 hrs. On cooling the mixture was slurried in 200 ml. of ether and salts were filtered off. The ethereal solution was washed with 25% potassium hydroxide solution, water until neutral and then dried over magnesium sulfate. The ether was removed under vacuum and the resulting oil distilled to give 13.1 g. of the desired product, bp 248°-253° /0.06 mm., nD25 1.6474.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1([C:9]2[CH:10]=[C:11]([C:19]([O:21]C)=O)[C:12](=[CH:17][CH:18]=2)[C:13](OC)=[O:14])[CH:8]=[CH:7][CH:6]=[N:5]1>C(O)C>[N:4]1([C:9]2[CH:10]=[C:11]3[C:12](=[CH:17][CH:18]=2)[C:13](=[O:14])[N:3]=[N:2][C:19]3=[O:21])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1C(=O)OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2cc(-n3cccn3)ccc21

Procedure:
22 ml hydrazine monohydrate was added to a mixture of 77 g dimethyl 4-(1H-1-pyrazolyl)phthalate and 500 ml ethanol, and heated under reflux for 6 hr. After cooling, the resulting precipitates were collected by filtration to give 36 g of 6-(1H-1-pyrazolyl)-1,4-phthalazine dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C@H:15]([OH:28])[CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C@H:15]1[CH2:16][O:28]1
Reactant: CCOC(=O)CCc1ccc(Cl)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)c([C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
To a solution of ethyl 3-[4-chloro-3-((1S)-1-hydroxy-2-{[(4-methylphenyl) sulfonyl]oxy}ethyl)phenyl]propanoate (1.77 g, 4.1 mmol) in absolute ethanol (12 mL) was added potassium carbonate (0.63 g, 4.6 mmol) and the reaction was stirred at rt for 3 days. The reaction was concentrated and diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with H2O, brine, dried (Na2SO4), and concentrated to afford 810 mg of product as a white solid (78%). The product was pure enough to use in the subsequent step. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27 (d, J=8.59 Hz, 1 H) 7.07-7.10 (m, J=2.72, 2.72, 2.72, 2.72 Hz, 2 H) 4.19 (dd, J=4.04, 2.53 Hz, 1 H) 4.13 (q, J=7.07 Hz, 2 H) 3.19 (dd, J=5.68, 4.17 Hz, 1 H) 2.91 (t, J=7.71 Hz, 2 H) 2.65 (dd, J=5.56, 2.53 Hz, 1 H) 2.59 (t, J=7.58 Hz, 2 H) 1.24 (t, J=7.20 Hz, 3 H)
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:23])([F:22])[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=1>C(N(CC)CC)C>[F:47][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:35][NH:34][C:17](=[O:19])[CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([C:8]([CH3:9])([CH3:10])[C:7]([F:6])([F:23])[F:22])=[CH:21][CH:20]=1
Reactant: CC(C)(c1ccc(OCC(=O)O)cc1)C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a tetrahydrofuran (THF) (3.0 ml) solution of [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetic acid (157 mg, 0.6 mmol) was added 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (97 mg, 0.6 mmol) at room temperature and the mixture was stirred for 2 hours, followed by additional stirring for 10 hours with triethylamine (0.33 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (122 mg, 0.48 mmol). The reaction was partitioned with water and methylene dichloride and the organic layer was separated, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of methylene dichloride and methanol (5/1 to 5/2) to furnish 62.9 mg (28% yield) of the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 20 °C

Procedure:
To a cooled (−5-0° C.) solution of ethyl 2,4-difluorobenzoate (3.4 g; 18.3 mmol) in conc. sulphuric acid (6 ml) was added potassium nitrate (1.94 g; 19.2 mmol) in small portions over one hour −5° C. Following the addition the temperature was allowed to raise to 20° C. over 4.5 hours. The mixture was poured into ice-water with vigorous stirring. The product was filtered off, washed with water and air-dried. Yield: 3.2 g (76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8](NCCOC)=[C:7]([N+:16]([O-])=O)[CH:6]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:2][CH2:1][O:3][CH3:4])=[C:7]([NH2:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NCCOC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(CCOC)c(N)c1

Procedure:
Prepared analogously to example 1b by hydrogenation of 4-(2-methoxy-ethylamino)-3-nitro-benzoic acid ethyl ester using palladium/charcoal 10% in ethanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]=2[N+:14]([O-:16])=[O:15])=[CH:28][CH:27]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Product: COC(=O)Cn1c(C)cc(Cc2ccc(F)cc2)c([N+](=O)[O-])c1=O

Procedure:
This compound is prepared from 11 g (29.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 10 g (52.9 mmol) of (4-fluorophenyl)-methyl bromide according to the method described in 1.5.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>C(O)C>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(Br)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(Br)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (106 mg, 0.59 mmol) was reacted in ethanol (2 mL) with the product from Example 106b (200 mg, 0.59 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (53 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3 H) 2.77 (s, 3H), 6.41 (d, J=6.99 Hz, 1 H), 7.02 (d, J=8.82 Hz, 1 H), 7.33 (d, J=8.46 Hz, 2 H), 7.58 (d, J=8.82 Hz, 2H), 7.65 (dd, J=8.46, 2.21 Hz, 1 H) 7.77 (d, J=2.21 Hz, 1 H), 7.81 (d, J=8.82 Hz, 1 H), 8.48 (d, J=6.99 Hz, 1 H), 8.96 (d, J=8.82 Hz, 1 H), 10.11 (s, 1 H), 11.06 (s, 1 H), 14.53 (s, 1 H); MS (DCI/NH3) m/z 479 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][CH3:19])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: COCc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxymethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:22][C:32]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: Cc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)cc1

Procedure:
The title compound, light yellow solid (13 mg, 10%), MS (ISP) m/z=388.2 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][C@H:13]([CH3:16])[CH2:12][N:11]1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:9][C@H:10]1[CH2:15][N:14]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C@H:13]([CH3:16])[CH2:12][N:11]1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1
Reactant: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1
Reactant: O=Cc1cccnc1
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1Cc1cccnc1
Yield: 84 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(2S,5R)-2,5-dimethyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 84% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)[CH3:32]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:31][CH3:32])[CH:34]=1)=[O:9]
Reactant: CCc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 3-ethylbenzenamine (79 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 80 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[C:14]=1Cl)([O-:12])=[O:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14]2[C:15]([C:22]([F:24])([F:25])[F:23])=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(N)nc1
Product: COc1ccc(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)nc1

Procedure:
In accordance with the process of Preparation 8 except using 1.2 g. of 2-amino-5-methoxypyridine and 2.8 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene, the reaction was carried out for 5 hours. The reaction mixture was treated as the process of Preparation 6 to obtain 1.2 g. of the object compound having the melting point of 102° to 105° C.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][S:2]([O:5][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[OH:10])=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:4])=[O:3]
Reactant: [O-][n+]1ccc(O)c2ccc(OC(F)(F)F)cc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cnc2cc(OC(F)(F)F)ccc2c1O
Reaction time: 2.5 h

Procedure:
Methanesulphonic anhydride (1.55 g) was added to a stirred mixture of 4-hydroxy-7-trifluoromethoxy-quinoline-1-oxide (2.0 g), potassium carbonate (1.2 g) and dichloromethane (100 ml) at 0°. After stirring at 0° for a further 2.5 hours, the reaction mixture was washed with saturated aqueous sodium carbonate (60 ml) and the dichloromethane phase separated. The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined dichloromethane phase and extracts were dried over magnesium sulphate. The solvent was removed by evaporation and water (100 ml) followed by saturated aqueous sodium bicarbonate (5 ml) at 10° was added. The solid was collected by filtration to give the novel compound 4-hydroxy-7-trifluoromethoxyquinol-3-yl methanesulphonate, m.p. 125°-127°.
Reaction SMILES: C=O.O.[C:4]([NH:8][CH:9]=[N:10][C:11]([NH2:13])=[O:12])(=[O:7])[CH:5]=[CH2:6].[CH3:14][O:15]C1C=CC(O)=CC=1>C(N(CC)CC)C>[CH2:14]([CH:6]=[CH:5][C:4]([NH:8][CH:9]=[N:10][C:11]([NH2:13])=[O:12])=[O:7])[OH:15]
Reactant: C=CC(=O)NC=NC(N)=O
Reactant: COc1ccc(O)cc1
Agent: C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)N=CNC(=O)C=CCO

Procedure:
11.34 g of a 37% strength aqueous solution of formaldehyde, 40 g of water, 20 g of acrylamidomethyleneurea, 50 mg of hydroquinone methyl ether and 0.2 g of triethylamine are introduced into a 250-ml reactor. The reaction mixture is heated for 1 hour to 60° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH2:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=2)=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][C:5]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=1.COC(=O)C1CC(NC2C=CC=CC=2)=C(C(OC)=O)CC=1NC1C=CC=CC=1>>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]([C:3]([O:2][CH3:1])=[O:30])=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1=C(Nc2ccc(Cl)cc2)CC(C(=O)OC)=C(Nc2ccc(Cl)cc2)C1
Agent: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Product: COC(=O)c1cc(Nc2ccccc2)c(C(=O)OC)cc1Nc1ccccc1

Procedure:
Example 13 was repeated except that the 2,5-di(p-chloroanilino)-3,6-dihydroterephthalic acid dimethyl ester used in Example 13 was replaced with 7.56 parts of 2,5-dianilino-3,6-dihydroterephthalic acid dimethyl ester, to give 6.88 parts (98.9% of the theoretical yield) of 2,5-dianilinoterephthalic acid dimethyl ester.