Azzindani/Open_Reaction_Data huggingface dataset:
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.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:21]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccnc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccnc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1sc(C(=O)O)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (238 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (209 mg, 0.54 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (293 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL, 2.62 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (silica) (3:1 hex/EtOAc) affording the title compound (229 mg, 60%): LC-MS (ES) m/z=695 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si]([O:15][CH2:16][C@H:17]([CH3:47])[O:18][C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:35]=1)[C:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][O:31][CH3:32])[N:29]=1)=[O:23])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[OH:15][CH2:16][C@H:17]([CH3:47])[O:18][C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([O:36][C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH:35]=1)[C:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][O:31][CH3:32])[N:29]=1)=[O:23]
Reactant: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO)c2)n1
Reaction time: 1 h
Yield: 55.7 %

Procedure:
TFA (2 mL) was added to a solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-[4-(methoxymethyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenoxy]benzamide (325 mg, 0.536 mmol) in DCM (4 mL) and water (1 mL) and the reaction was stirred for 1 h. The reaction was basified to pH7-8 with saturated aqueous sodium hydrogencarbonate and then extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated and purified by column chromatography, eluting with 50% to 100% ethyl acetate in hexanes, to afford the title compound as a white foam (147 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[N:16][N:15]4[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CN.C1C[N:35]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:34]C1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([NH:35][CH3:34])=[O:22])=[N:16][N:15]4[C:23]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 55 %

Procedure:
To a solution of 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid that was prepared in a manner analgous to that described for Example 8 (0.15 g, 0.39 mmol) and methylamine (2 M in THF, 1.43 mL, 2.93 mmol, 7.5 equiv) in DMF (1 mL) was added PYBOP (0.22 g, 0.43 mmol 1.10 equiv) and N,N-diisopropylethylamine (0.27 mL, 1.56 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 25 h, then was treated with water (10 mL). The resulting aqueous mixture was extracted with EtOAc (4×15 mL). The combined organic phases were washed with water (2×15 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was triturated with MeOH to give 2-[4-(1-aminocyclobutyl)phenyl]-N-methyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide (0.085 g, 55%):
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].Cl.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1(N)CCCCC1>C(O)C>[CH:8]1([NH:14][CH:3]=[CH:4][C:5]#[N:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: N#CC=CO
Reactant: NC1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC=CNC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.5 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) is added to a suspension of cyclohexylamine hydrochloride (composed of 29.8 g (0.3 mol) of cyclohexylamine and gaseous hydrochloric acid) in 150 ml of ethanol and the mixture is stirred for 24 h at 25° C. After removal of the solid by filtration, and withdrawal of the solvent followed by recrystallization from carbon tetrachloride, 32.1 g (85.6%) of 3-cyclohexylaminoacrylonitrile was obtained.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.[CH3:40][C:41]([NH:43][S:44]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[CH:48]=1)(=[O:46])=[O:45])=[O:42]>CN(C)C=O>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([S:44]([NH:43][C:41]([CH3:40])=[O:42])(=[O:46])=[O:45])[CH:48]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CC(=O)NS(=O)(=O)c1cccc(N)c1
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1cccc(NC(=O)NC2(C3CCCCC3)N=Cc3ccccc3N(C)C2=O)c1
Yield: 65.2 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-l,3-dihydro-1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino ]-2H-1,4-benzodiazepin-2-one (0.5 g, 1.2 mmol), triethylamine (0.16 ml, 1.2 mmol), dimethylformamide (10 ml) and 1-(methylcarbonylaminosulphonyl)-3-aminobenzene (0.26 g, 1.2 mmol).After recrystallisation from methanol, the title compound (0.2 g, 34%) was afforded as a colourless solid. mp 195°-198° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.87-0.99 (1H, m), 1.10-1.66 (7H, m), 1.78 (1H, m), 1.94 (1H, m), 1.91 (3H, s), 2.95 (1H, m), 3.30 (3H, s), 5.07 (1H, d, J=8.3 Hz), 7.39 (4H, m), 7.54 (2H, m), 7.64 (1H, dd, J=7.9 and 7.9 Hz), 7.76 (1H, d, J=7.9 Hz), 8.07 (1H, s), 9.42 (1H, s), 11.99 (1H, brs).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)[S:10][C:3]=12
Reactant: Cn1ccnc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of the tin derivative 6 (24.79 g, 54.05 mmol) and 2-bromo-1-methyl-1H-imidazole (10.4 g, 64.86 mmol) [McCallum, P. W.; Weavers, R. T.; Grimmet, M. R.; Blackman, A. G.; Aust. J. Chem.; 52; 3; 1999; 159-166.] in toluene (180 mL) Pd[PPh3]4 (5 g, 4.32 mmol) was added and the mixture was refluxed under nitrogen for 2 days, cooled to room temperature. A precipitate was formed which was collected by filtration, washed with Et2O and dried, to afford the title compound 7 as a grey solid (12.72 g, 94% yield). MS (m/z): 250.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:18](=[O:22])[C:19]([OH:21])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10]CC1C=CC=CC=1)([O-:3])=[O:2].Cl>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:18](=[O:22])[C:19]([OH:21])=[O:20])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2]
Reactant: O=C(O)C(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of 2-(3-nitro-4-benzyloxyphenyl)glyoxylic acid (30 g.), conc. hydrochloric acid (90 ml.) and acetic acid (120 ml.) was stirred for 3 hours at 100° C. To the reaction mixture was added under cooling ice-water (600 ml.) and the mixture was extracted with ethyl acetate. The extract was washed with ice-water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from a mixture of benzene:ether:petroleum ether (2:1:4). The crystals were collected by filtration, washed with benzene and dried under reduced pressure to give 2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (19.0 g.), mp 139° to 140.5° C.
Reaction SMILES: N1([O:10][C:11]2[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]4[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]4)[N:23]=3)=[O:20])[C:15](=[O:17])[CH:16]=2)C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55]O>C(#N)C>[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][O:10][C:11]1[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]3[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]3)[N:23]=2)=[O:20])[C:15](=[O:17])[CH:16]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(On4nnc5ccccc54)cc3=O)n2)O1
Reactant: OCCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(OCCc4ccccc4Cl)cc3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (0.30 g, 0.54 mmol) in acetonitrile (10 mL, 0.055M) was treated with cesium carbonate (0.36 g, 1.10 mmol) and 2-(2-chloro-phenyl)-ethanol (86 μL, 0.65 mmol). The resulting reaction mixture was stirred at 25° C. overnight. The reaction mixture was then heated at 75° C. for 5.5-6 h. At this time, the reaction was partitioned between water and methylene chloride. The organics were dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 12 g, 50-75% ethyl acetate/hexanes) afforded 2-{4-[2-(2-chloro-phenyl)-ethoxy]-6-oxo-6H-pyridazin-1-yl}-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (114.1 mg, 37%) as a light yellow solid as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]([F:63])([F:62])[C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:56][C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([C:52]([F:51])([F:62])[F:63])[CH:54]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCc4cccc(C(F)(F)F)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 59.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethylphenethyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 56%).
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([O:19][CH3:20])[C:11]([NH:15]C(=O)C)=[CH:12]2)=[CH:7][CH:6]=1)#N.[OH2:21]>C(O)CO>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[CH:6][C:5]([C:3]([OH:21])=[O:1])=[CH:14]2)=[CH:9][C:10]=1[O:19][CH3:20]
Reactant: COc1cc2ccc(C#N)cc2cc1NC(C)=O
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: OCCO
Product: COc1cc2ccc(C(=O)O)cc2cc1N
Temperature: 195 °C

Procedure:
Sodium hydroxide (0.17 g, 4.17 mmol) was added to a suspension of N-(7-cyano-3-methoxy-naphthalen-2-yl)-acetamide (0.2 g, 0.83 mmol) in ethylene glycol (2 mL) and the resulting mixture was heated at reflux (195° C.) overnight. The reaction mixture was then cooled, water was added and the pH was adjusted to 4. The precipitate was collected by filtration and dried to give 0.156 g of 7-amino-6-methoxy-naphthalene-2-carboxylic acid as a brown solid. MS=218 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH3:24][C:25]1([CH3:39])[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][P:28]([OH:38])(=[O:29])[O:27][CH2:26]1.C(O)C>C(Cl)Cl>[OH:38][P:28]1(=[O:29])[O:30][C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]([CH3:24])([CH3:39])[CH2:26][O:27]1.[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC1(C)COP(=O)(O)O[C@@H]1c1ccccc1
Agent: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3c(F)cccc3[C@@H]12
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)COP(=O)(O)O[C@H]1c1ccccc1

Procedure:
Preparation analogous to Example 5, step i, from (±)-(cis)-7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (30.5 mmol) and (+)-phencyphos (3.7 g, 15.29 mmol) in CH2Cl2 (160 mL), and ethanol (100 mL). Recrystallization gave the title compound (2.55 g, 17%).
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C:9]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[ClH:1].[OH:8][C:9]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4 mol/L hydrogen chloride-dioxane solution (3.0 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.025 g), followed by stirring at room temperature for 3 hours and then at 50 to 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.020 g of 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: CN(CCCCN1CCCCC1)Cc1ccc(CN)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36.7 %

Procedure:
The compound (248.5 mg) obtained in Example 44-5 was dissolved in methanol (12.4 ml) and added with 2-imidazole carboxaldehyde (123.7 mg) and trimethyl orthoformate (0.282 ml) and the whole was stirred at room temperature for 2.5 hours. Subsequently, sodium borohydride (97.4 mg) was added thereto under ice-cooling and the whole was stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (116.3 mg) as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:17](OC)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][NH2:39])[CH2:28][CH2:27]1.CCCC(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:39][CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:21]=[CH:22][C:23]=3[CH3:24])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CN1CCN(c2ccccc2CN)CC1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnc2cc(Br)ccn12
Temperature: 100 °C

Procedure:
Methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (Intermediate 1B) (400 mg, 1.030 mmol) and TBD (143 mg, 1.030 mmol) in toluene (10 ml) was treated with (2-(4-methylpiperazin-1-yl)phenyl)methanamine (212 mg, 1.030 mmol) and heated at 100° C. under nitrogen overnight. Further TBD (106 mg, 0.82 mmol) was added the mixture was heated at 100° C. for a further 24 hrs. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 ml) and sodium bicarbonate solution (50 ml). The organic portion was separated and washed with sodium bicarbonate (2×25 ml), dried (MgSO4), filtered and evaporated to dryness to give a yellow solid. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM afforded a colourless oil. The oil was dissolved in minimum volume of EtOAc and titurated iso-hexane to afford the title compound as a white solid;
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=O)[CH:16]([CH3:21])[CH2:17][O:18]2)=[CH:13][CH:12]=1.Cl.[NH2:24][OH:25]>CO>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[N:24][OH:25])[CH:16]([CH3:21])[CH2:17][O:18]2)=[CH:13][CH:12]=1
Reactant: NO
Reactant: CC1COc2cc(-c3ccco3)ccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1COc2cc(-c3ccco3)ccc2C1=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (395 mg, 4.82 mmol) was added portionwise to a solution of 7-furyl-3-methyl-4-chromanone (60) (500 mg, 2.19 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol) in methanol (5 mL), and stirred overnight at room temperature. The reaction was quenched with H2O and extracted with ether (2×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give 7-furyl-3-methyl-4-chromanone oxime (61) as a white solid, m.p. 175-177° C.
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29].CC(C)([O-])C.[K+]>O1CCCC1>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[CH:2]=[C:7]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]3=[O:29])[C:6]=2[CH:8]=1)[C:13]([F:14])([F:15])[F:16]
Reactant: O=C1CCCCN1
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 3 %

Procedure:
To a mixture of 0.54 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.24 g of 2-piperidinone and 10 ml of tetrahydrofuran was added 0.27 g of potassium tert-butoxide with stirring under ice-cooling. The mixture was stirred for 6 hours under ice-cooling and then stirred at room temperature for 16 hours. Ice water was added to the mixture, which was then extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.02 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-oxo-1-piperidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 149-150° C.