Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[CH3:5][O:6][C:7]([C:9]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([OH:23])[C:12]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:11][N:10]=1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[N:10]([CH2:4][CH:3]=[CH2:2])[CH:11]=[C:12]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: COC(=O)c1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1cc(C(=O)NCc2ccc(F)cc2)c(=O)c(OCc2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.7 %

Procedure:
After 3-bromopropene (2.15 ml, 24.8 mmol) was added to a solution of the compound 14 (6.79 g, 16.5 mmol), and cesium carbonate (8.09 g, 24.8 mmol) in dimethylformamide (54 ml), the mixture was stirred at room temperature for 4.5 hours. To the reaction solution was added an aqueous ammonium chloride solution, and this was extracted with ethyl acetate, washed with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 1-allyl-3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 15 (6.15 g, 83%) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:33])=[C:21]([CH3:34])[CH:20]=2)=[N:12][C:13]([O:15]CC)=O)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:15])[C:24]3[C:19](=[CH:20][C:21]([CH3:34])=[C:22]([O:25][C:26]4[C:27]([CH3:33])=[CH:28][CH:29]=[CH:30][C:31]=4[CH3:32])[CH:23]=3)[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C(Nc1ccc(Oc2c(C)cccc2C)c(C)c1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Titanium (IV) chloride (0.25 mL, 2.3 mmol) was added to a solution of 1-{[4-(2,6-dimethyl-phenoxy)-3-methyl-phenylamino]-ethoxycarbonylimino-methyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.97 g, 2.1 mmol) and DCE (10 mL), and the resulting mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to room temperature and poured into 50 mL EtOH. The mixture was stirred for 30 min and concentrated to dryness. The solid was and purified by FCC (CH3CN/DCM, gradient 0:100 to 20:80) to provide the titled compound (0.28 g, 32%). MS (ESI): mass calcd. for C23H22N4O4, 418.4; m/z found, 419.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.77 (s, 1H), 8.96 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.25 (d, J=7.4 Hz, 2H), 7.18 (dd, J=8.3, 6.7 Hz, 1H), 6.78 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 2.08 (s, 6H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:20]2[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)CCC>[N:29]1([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=3)[N:5]=[C:4]([C:20]3[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=3)[N:3]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CC(=O)c1cccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: C1COCCN1
Solvent: CCCCO
Product: CC(=O)c1cccc(-c2nc(Nc3ccc(OC(F)(F)F)cc3)cc(N3CCOCC3)n2)c1
Temperature: 30 °C
Yield: 75 %

Procedure:
A mixture of compound 1-{3-[4-chloro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-2-yl]-phenyl}-ethanone (0.13 g, 0.32 mmol) and morpholine (0.22 g, 2.55 mmol) in n-butanol (10 mL) was refluxed for 24 hours under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C. and concentrated under vacuum. The crude compound was purified by column chromatography using 18-20% ethylacetate in petroleum ether to afford the desired compound (0.11 g, 75%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:22])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 17.3 g (66.2 mmol) of 1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester and 100 ml of phosphorous oxychloride was stirred at ambient temperature for 1 h, and then heated slowly with stirring in the course of 2 h to reflux temperature. The mixture was refluxed gently with stirring for 30 min. After cooling to room temperature the excess phosphorous oxychloride was evaporated in vacuo, and the residue was dissolved in 100 ml of ethyl acetate. The solution was poured into 300 ml of a saturated aqueous sodium bicarbonate solution with stirring. The precipitate formed was removed by vacuum filtration. The organic phase was separated, and the aqueous phase was extracted with 3×100 ml of ethyl acetate. The combined aqueous phases were dried over sodium sulfate, filtered through a pad of silica gel and evaporated in vacuo to give a brown oil that solidified later. 11.37 g of the title compound were obtained; 1H NMR (CDCl3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: CC(C)[O-].[Na+:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH2:19][O:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[C:16]([CH3:18])[N:17]=2)=[CH:9][CH:8]=1>C(O)(C)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH2:19][O:20][C:21]([CH3:26])([CH3:25])[C:22]([O-:24])=[O:23])=[C:16]([CH3:18])[N:17]=2)=[CH:9][CH:8]=1.[Na+:5]
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)[O-]
Yield: 90 %

Procedure:
10.0 ml of 1M sodium isopropoxide solution in isopropanol were added to a warm stirred solution of 3.09 g (10 mmol) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid in 30 ml of isopropanol and the mixture was allowed to cool slowly to give 3.0 g (90%) of sodium 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionate in the form of a colourless crystalline solid of melting point 277°-278° C.
Reaction SMILES: C(C(C1C=CC2C(=CC=CC=2)C=1)C#N)(CC)C.C(C(C1C=CC2C(=CC=CC=2)C=1)C#N)(C)C.C(C(C1C=CC2C(=CC=CC=2)C=1)C(O)=O)C(C)C.[CH:52]([CH:56]([C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[C:57]([OH:59])=[O:58])([CH2:54]C)[CH3:53]>>[CH:52]([CH:56]([C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[C:57]([OH:59])=[O:58])([CH3:54])[CH3:53]
Reactant: CCC(C)C(C(=O)O)c1ccc2ccccc2c1
Agent: CC(C)C(C#N)c1ccc2ccccc2c1
Agent: CC(C)CC(C(=O)O)c1ccc2ccccc2c1
Agent: CCC(C)C(C#N)c1ccc2ccccc2c1
Product: CC(C)C(C(=O)O)c1ccc2ccccc2c1

Procedure:
Following the above-procedure but substituting α-isobutyl-2-naphthaleneacetonitrile or α-sec-butyl-2-naphthaleneacetonitrile for α-isopropyl-2-naphthaleneacetonitrile yields respectively, α-isobutyl-2-naphthaleneacetic acid melting point 115° C. to 119° C. and α-sec-butyl-2-naphthaleneacetic acid, melting point 112° C. to 115° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12](/[C:14](=[C:8]1/[CH2:7][CH2:6][C:5]2[C:9]/1=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)/[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]
Reactant: O=C1CCc2ccc(F)cc21
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(C#N)=C1\CCc2ccc(F)cc21

Procedure:
The mixture of compound 6-Fluoro-indan-1-one (5 g, 0.03 mol), and ethyl cyanoacetate (5 g, 0.05 mol), ammonium acetate (25 g, 0.33 mol) and glacial acetic acid (50 ml) in toluene (205 ml) was refluxed with a Dean Stark water trap for 4 h. The mixture was concentrated in vacuo, the residue washed by water and EtOH three times to afford the the compound (8.00 g, y=97.96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:10][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C)[n+]([O-])c1
Product: COc1ccc(COC(C)=O)nc1

Procedure:
The crude N-oxide product obtained above (13.5 g.) was then placed in acetic anhydride (100 ml.) and heated on a steam bath for a period of three hours. The excess anhydride was thereafter removed by means of distillation and the liquid residue so obtained was fractionally distilled to give pure 2-acetoxymethyl-5-methoxypyridine (yield, 6.6 g.), b.p. 148°-150° C./12 mm. Hg. This particular product was then hydrolyzed by heating same on a steam bath while in concentrated hydrochloric acid for a period of four hours. Evaporation of the resulting reaction solution then gave crude 2-hydroxymethyl-5-methoxypyridine as the residue.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].[CH3:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[C:14]=1[CH:20]=[CH:21][C:22]#[C:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])=[CH:26][CH:25]=1.[BH4-].[Na+]>C(O)C>[OH:19][CH:15]1[C:14](/[CH:20]=[CH:21]/[C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])=[O:29])=[CH:37][CH:38]=2)=[C:13]([CH3:12])[CH2:18][CH2:17][CH2:16]1
Reactant: CC1=C(C=CC#Cc2ccc(C(=O)OCC[Si](C)(C)C)cc2)C(=O)CCC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1=C(/C=C/C#Cc2ccc(C(=O)OCC[Si](C)(C)C)cc2)C(O)CCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cerium trichloride heptahydrate (4.88 g, 13.1 mmol) and (trimethylsilyl)ethyl 4-(4-(2-methyl-6-oxocyclohexen-1-yl)but-3-en-1-ynyl)benzoate (Compound D, 500 mg, 1.31 mmol) were dissolved in ethanol (80 mL), cooled to 0° C. and treated with sodium borohydride (495 mg, 13.1 mmol) in three equal portions. The resulting solution was stirred in the dark for 20 minutes at 0° C. The excess hydride was quenched by the addition of saturated aqueous NH4Cl and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water, and brine, dried (MgSO4), filtered and the solvents were removed in vacuo. The residue was purified by silica gel chromatography using a solution of hexane and ethyl acetate in a 5 to 1 ratio, respectively, to give the racemic title compound as a yellow oil.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28](OC)[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC1C2C(=CC=C(C)C=2)N(CCC)C1=O)(=O)C1C=CC=CC=1.BrCC1C=CC(OC)=C(OC)C=1>>[C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:36])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: COc1ccc(CBr)cc1OC
Product: CCCN1C(=O)C(Cc2ccc(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-methyl-2-oxo-1-propylindolin-3-yl benzoate and 4-(bromomethyl)-1,2-dimethoxybenzene. 1H-NMR δ 8.06 (d, 2H), 7.57 (t, 1H), 7.43 (t, 2H), 7.07 (d, 1H), 6.90 (s, 1H), 6.68 (d, 1H) 6.62 (m, 2H), 6.39 (s, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 3.56 (m, 1H) 3.47 (m, 2H), 3.25 (d, 1H), 2.27 (s, 3H), 1.52 (m, 2H), 0.84 (t, 3H). Calculated mass for C28H29NO5, 459.53. Observed 482.2 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:9]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(F)ccc1Oc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)benzoic acid (Anales de la Asociacion Quimica Argentina 1985, 73, 509) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 7.99 (4H, m), 7.30 (2H, d, J=7.6 Hz), 7.14–7.03 (3H, m), 6.96–6.92 (2H, m), 6.80 (1H, dd, J=9.2, 4.4 Hz), 4.70 (2H, d, J=5.9 Hz), 3.91 (3H, s); MS (ESI) m/z 398 (M+H)+, 396 (M−H)−.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH2:9]P(OCC)(=O)OCC)[O:6][N:5]=1)([CH3:3])[CH3:2].COC([O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O)C>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[OH:22])[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: COC(C)Oc1ccccc1C=O
Reactant: CCOP(=O)(Cc1cc(C(C)C)no1)OCC
Product: CC(C)c1cc(C=Cc2ccccc2O)on1

Procedure:
Using the method described in Example I, 32 g (0.12 mole) of diethyl (3-isopropyl-isoxazol-5-yl)methanephosphonate and 22 g (0.12 mole) of o-(1-methoxy-ethoxy)-benzaldehyde are reacted and the product is recrystallized from toluene. 20 g (73% of theory) of colorless crystals, of melting point 129°-133° C., are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: ClCc1ccco1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccco2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 40 %

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloromethylfuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound (40%) as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H), 7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85 (dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 155.9, 149.0, 148.9, 142.6, 142.3, 141.8, 132.2, 128.9, 123.8, 123.5, 119.5, 110.6, 109.3, 108.7, 103.1, 101.5, 93.6, 80.4, 58.2, 37.1; MS (ES+) m/z 362.5 (M+1).
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.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[C:29]([CH2:30][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)[CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(-c2ccc(F)cc2)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1ccc(-c2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-fluorophenyl)benzaldehyde 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, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-fluorophenyl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1c(S(=O)(=O)Cl)oc2ccc(C(C)C)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)oc2ccc(C(C)C)cc12
Yield: 21.5 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-isopropyl-3-methylbenzofuran-2-sulfonyl chloride (Intermediate 16) (24 mg, 0.09 mmol) and 5-(3-amino-phenyl)tetrazole (28 mg, 0.17 mmol) giving 7.7 mg (21%) of the title compound. MS (ESI+) calcd for C19H19N5O3S 397.12086, found 397.12046.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:32][CH:31]([NH:33][C:34](=[NH:49])[CH2:35][C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)=[O:37])[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:32][CH:31]([NH:33][C:34](=[NH:49])[CH2:35][C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])[CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=N)CC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
0.99 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(N-4-nitrobenzyloxycarbonylacetimidoylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] was dissolved in 1.49 ml of anisole, and 10 ml of trifluoroacetic acid and 0.24 ml of trifluoromethanesulfonic acid were added dropwise to the resulting solution. The resulting mixture was stirred at the same temperature for 40 minutes and then at room temperature for 50 minutes, after which 1,2-dichloroethane was added to the reaction mixture. The mixture was then concentrated by evaporation under reduced pressure. The resulting residue was washed by repeated decantation, in turn, with hexane and diethyl ether, and the mixture was then diluted with ethyl acetate, and made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 0.82 g of the title compound, in the form of an amorphous powder.
Reaction SMILES: C(O)(=O)C.Br.C(OP([N:14]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23][CH2:22][CH:21]([F:40])[CH2:20][CH2:19][CH2:18][N:17]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N+:50]([O-:52])=[O:51])(=[O:43])=[O:42])[CH2:16][CH2:15]1)(=O)OCC)C>C(OCC)C>[F:40][CH:21]1[CH2:22][CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:29])=[O:30])[CH2:26][CH2:27][NH:14][CH2:15][CH2:16][N:17]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N+:50]([O-:52])=[O:51])(=[O:42])=[O:43])[CH2:18][CH2:19][CH2:20]1
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCC(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
Acetic acid (15 ml), saturated with anhydrous hydrogen bromide (gas) was added to [11-fluoro-1,7-bis(2-nitro-benzenesulfonyl)-1,4,7-triaza-cyclotetradec-4-yl]-phosphonic acid diethyl ester (560 mg, 0.77 mmol) contained in round-bottomed flask closed by glass stopper. The resulting mixture was allowed to stir for 18 hours at room temperature and then diethyl ether (50 ml) was added. The white precipitate which formed was allowed to settle to the bottom of the flask and the diethyl ether solution was decanted off. This white solid was re-dissolved in methanol, stirred with K2CO3 (solid) for 30 mins then diluted with 100-ml ethyl acetate, and the solids were removed by filtration. Evaporation of the filtrates gave the title compound (454 mg, 100%) as white foam. 1H NMR (CDCl3) δ 1.75–1.99 (m, 8H), 2.90 (t, 4H, J=5.0 Hz), 3.26–3.39 (m, 8H), 4.61–4.77 (m, 1H), 7.60–7.65 (m, 2H), 7.68–7.72 (m, 4H), 7.94–7.97 (m, 2H); ES-MS m/z 588.3 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1)[CH3:2].[I:14]N1C(=O)CCC1=O.C(#N)C>C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[I:14])[CH3:2]
Reactant: CCc1ccnn1-c1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1c(I)cnn1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-ethyl-1-phenyl-1H-pyrazole (21 mg, 0.12 mmol) and N-iodosuccinimide (41 mg, 0.18 mmol) were added to acetonitrile (5 ml). The reaction mixture was heated to 60° C. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 5-ethyl-4-iodo-1-phenyl-1H-pyrazole.
Reaction SMILES: O[C:2]1C=CC=C[C:3]=1N1C=CC=C1.ClC1C=CC(O)=C(N2C=CC=C2)C=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[O:35][C:34](C)([CH2:36][C:37]([OH:39])=[O:38])[C:33]3=[CH:41][CH:42]=[CH:43][N:32]3[C:31]=2[CH:44]=1>>[CH2:2]([O:39][C:37](=[O:38])[CH2:36][C:34]1[O:35][C:30]2[CH:29]=[CH:28][CH:27]=[CH:44][C:31]=2[N:32]2[CH2:43][CH:42]=[CH:41][C:33]=12)[CH3:3]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CC1(CC(=O)O)Oc2ccc(Cl)cc2-n2cccc21
Agent: Oc1ccc(Cl)cc1-n1cccc1
Product: CCOC(=O)CC1=C2C=CCN2c2ccccc2O1

Procedure:
In the same manner but replacing N-(2-hydroxyphenyl)pyrrole with an equivalent amount of N-(5-chloro-2-hydroxyphenyl)pyrrole, described in Example 1, 8-chloro-4-methyl-4H-pyrrolo[2,1-c][1,4]-benzoxazine-4-acetic acid, νmaxCHCl3 2,900 - 2,500, 1,728, 1,498, 1,445 cm-1, is obtained via the intermediate ester, 8-chloro-4-methyl-4H-, pyrrolo[2,1-c][1,4]benzoxazine-4-acetic acid ethyl ester, νmaxCHCl3 1,732 cm-1.