Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:18]=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC[OH:22]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:22])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2ccccc2c(-c2cccc(I)c2)n1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-iodophenyl)-3-methylisoquinoline (5.733 g, 16.62 mmol), N-bromosuccinimide (NBS) (7.399 g, 41.57 mmol), and benzoyl peroxide (BPO) (0.48 g) in CCl4 (100 mL) was heated to reflux while being illuminated by a flood lamp for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with saturated NaHCO3 aqueous solution (40 mL), dried (Na2SO4), then filtered. The filtrate was concentrated in vacuo, thereby affording crude 1-(3-iodophenyl)-3-dibromomethylisoquinoline (8.327 g) as a yellow oil. It was used directly in next step without any purifications. To a refluxing solution of crude dibromide (8.327 g) in EtOH (110 mL) and THF (60 mL) was added dropwise a solution of AgNO3 (7.994 g) in H2O (10 mL). The mixture was refluxed for 1 h and filtered while hot. The filter cake was washed with hot THF (2×30 mL). The combined filtrate was concentrated in vacuo to give crude 1-(3 -Iodophenyl)-3-isoquinoline-carboxaldehyde as an dark yellow oil (11.62 g, containing H2O). This oil was used without further purification. To a solution of crude aldehyde (11.62 g) in absolute EtOH (80 mL)was slowly added a solution of AgNO3 (7.28 g) in H2O (10 mL). To this stirred solution was added dropwise a solution of NaOH (5.80 g) in H2O (100 mL). The resulting black slurry was stirred at room temperature for 2 h. Then the mixture was filtered through a small Celite column. The filter cake was washed with ether. The ether was evaporated and the aqueous solution was made slightly acidic with concentrated HCl. The precipitate was collected by filtration, then washed with H2O. It was recrystallized from CH3CN, thereby affording 1-(3-iodophenyl)-3-isoquinolinecarboxylic acid as a yellow crystalline (2.22 g, 36%). mp 145-146° C. 1H NMR (DMSO-d6) d 7.37 (t, J=6.0 Hz, 1 H, aromatic), 7.65-7.71(m, 2 H, aromatic), 7.80 (t, J=4.8 Hz, 1 H, aromatic), 7.91 (d, J=6.6 Hz, 1 H, aromatic), 7.95 (d, J=6.3 Hz, 1 H, aromatic), 8.01 (s, 1 H, aromatic), 8.14 (d, J=6.0 Hz, 1 H, aromatic), 8.44 (s, 1 H, aromatic). HRMS Calcd for C16H10INO2 : 374.9756. Found: 374.9741.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:29]=[C:28]([C:30]2[CH:31]=[N:32][C:33]3[N:34]([C:36]([CH2:39][C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[N:46]=[CH:45][CH:44]=[CH:43]5)=[CH:37][N:38]=3)[N:35]=2)[CH:27]=[CH:26][C:10]=1[C:11]([NH:13][C@@H:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:12]>C(Cl)Cl>[F:8][C:9]1[CH:29]=[C:28]([C:30]2[CH:31]=[N:32][C:33]3[N:34]([C:36]([CH2:39][C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[N:46]=[CH:45][CH:44]=[CH:43]5)=[CH:37][N:38]=3)[N:35]=2)[CH:27]=[CH:26][C:10]=1[C:11]([NH:13][C@@H:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([OH:17])=[O:16])=[O:12].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution of tert-butyl (2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)-3,3-dimethylbutanoate (0.092 g, 0.16 mmol) in methylene chloride (1.0 mL) and stirred at RT for 2 h. The volatiles were removed under reduced pressure to give the desired product as a TFA salt. LCMS: (M+H)=513.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[CH:18]=[C:17]([Cl:19])[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]=1[Cl:20])=O.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[CH:18]=[C:17]([Cl:19])[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]=1[Cl:20])=[N:25][OH:26]
Reactant: O=C(c1cccc(Cl)c1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2c(Cl)c(C(=NO)c3cccc(Cl)c3)cc(Cl)c2O1
Yield: 100.3 %

Procedure:
A mixture of 5-(3-chlorobenzoyl)-4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid (11.5 g), hydroxylamine hydrochloride (21.5 g) and pyridine (110 ml) was refluxed for 14 hours. After distilling off the solvent, water was added to the mixture which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water an.d dried. By distilling off the solvent, 12 g of 5-(3-chloro-α-hydroxyiminobenzyl)4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid was obtained. This compound (12 g) was dissolved in anhydrous dimethylformamide (150 ml), and to the ice-cooled solution, 3.9 g of 60% sodium hydride was added in small amounts under agitation. After stirring for 8 hours at room temperature, the mixture was left to stand overnight. After adding water, the mixture was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 5.6 g of 5-chloro- 3-(3-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 168°-169° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 349.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:33])([F:32])[CH2:21][O:22][C:23]1[C:24]([C:29](O)=[O:30])=[N:25][CH:26]=[CH:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:24]3[C:23]([O:22][CH2:21][C:20]([F:33])([F:32])[F:19])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncccc1OCC(F)(F)F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3OCC(F)(F)F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound. MS (ISP): m/z=463.1 [M+H]+. The 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was prepared as follows:
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([NH2:17])[CH:19]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Nc1cccc(Oc2ccc(C(=O)c3ccc(Oc4cccc(N)c4)cc3)cc2)c1

Procedure:
4,4'-bis(m-aminophenoxy)benzophenone was prepared in accordance with the method of Example 1 employing 4,4'-dichlorobenzophenone and m-aminophenol as the starting materials. 26% yield of product having a melting point of about 138°-140° C. was obtained.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:10][C:9](=[O:11])[CH:8]2[CH2:12][CH:5]1[CH2:6][CH2:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>CCCCCC.O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:10]2[C:4](=[O:3])[CH:5]3[CH2:12][CH:8]([CH2:7][CH2:6]3)[C:9]2=[O:11])=[O:22])=[CH:16][C:15]=1[C:23]([F:24])([F:25])[F:26]
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.064 g, 1.59 mmol) was washed with dry hexane under a nitrogen atmosphere to remove mineral oil. It was then suspended in dry tetrahydrofuran (3 mL). To the suspension was added a solution of 2,4-dioxobicyclo[3.2.1]octane (0.20 g, 1.45 mmol) in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. It was then treated with 4-fluoro-3-(trifluoromethyl)phenyl isocynate (0.31 mL, 2.17 mmol) via syringe. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was partitioned between dichloromethane (150 mL) and 1N aqueous HCl (100 mL). The aqueous layer was extracted twice with additional portions of dichloromethane ((25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatrography on silica gel (2% methanol/dichloromethane) to yield the title compound as a light yellow solid (0.36 g, 73% yield), mp=97–100° C.; MS (−) ESI m/z=342 (M−H)−.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC(=O)Cl
Reactant: COc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(=O)c1cc(C)ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
4-Methoxytoluene (100 ml, 0.793 mol) and methylene chloride (300 ml) were mixed, and this solution was cooled to 0° C. To this solution was added aluminum chloride (190.3 g, 1.44 mol), and then heptanoyl chloride (123 ml, 0.8 mol) was added dropwise to this solution over 2 hours. The reaction mixture was heated to room temperature, and stirred for 2 hours. The reaction mixture was poured onto ice (400 g) to stop the reaction. The aqueous layer was extracted with chloroform (300 ml). The organic layers were combined, washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 ml each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by distillation (120 pa, 125-140° C.) to give 1-(2-hydroxy-5-methylphenyl)heptan-1-one (127.8 g, 77%/) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Mg+2:40].[OH-]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Mg+2:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Mg+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.050 g, 0.091 mmol) in ethanol (5 mL) was added magnesium hydroxide (7.97 mg, 0.137 mmol) in 1 mL of water. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was washed with ethyl acetate (2×5 mL), acetone (2×10 mL) and acetonitrile (2×10 mL) to afford magnesium(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (8) (0.040 g, 0.069 mmol, 76% yield) as a yellow solid. 1H NMR was not taken because of poor solubility. LCMS Method I: retention time 1.66 min, [M−1]=547. HPLC Method B: Purity 98.1%, retention time 6.18 min, HPLC Method C: Purity 95.6%, retention time 5.98 min. Elemental analysis: MF C25H20N6SPO5.Mg H2O, Calculated C, 46.15; H, 4.41; N, 12.92; Mg, 4.15; H2O, 11.70. Found C, 40.66; H, 4.12; N, 11.23; Mg, 4.14; H2O, 11.70; C and N are not in agreement.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)#[N:13]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Reaction time: 72 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.355 g, 2.06 mmol) was diluted with THF (12 mL), treated with 4-cyano-benzoyl chloride (0.377 g, 2.23 mmol) and stirred for 72 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.6 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([NH:8][NH2:9])=[O:7])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:7])[NH:8][NH:9][C:11](=[O:14])[CH2:12][CH3:13])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(=O)NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)NNC(=O)CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of hydrazinocarbonylacetic acid ethyl ester (1.0 g, 6.84 mmol) and diisopropypethylamine (1.77 g, 13.69 mmol) in THF (7 mL) is added a solution of propionyl chloride (633 mg, 6.84 mmol) in THF (2 mL) dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to furnish 3-oxo-3-(N′-propionylhydrazino)-propionic acid ethyl ester. 1H-NMR (400 MHz, CDCl3); δ ppm 1.21 (t, 3H), 1.30 (t, 3H), 2.31 (q, 2H), 3.43 (s, 2H), 4.23 (q, 2H), 8.27 (s, 1H), 9.63 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:1][C:16](=[O:17])[NH:15][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: O=C(CO)c1ccc(Cl)cc1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)NC(=O)OCC(=O)c1ccc(Cl)cc1
Yield: 49.1 %

Procedure:
A mixture of 2-hydroxy-1-(4-chloro-phenyl)-ethanone (4.7914 g, 28 mmol), prepared in the previous step, isopropyl isocyanate (4.1 ml, 42 mmol) and triethylamine (2.83 ml, 28 mmol) in 100 ml of benzene was refluxed under nitrogen for approximately 24 hours. The solid formed was collected by filtration and dried under high vacuum to give 3.5184 g (49%) of isopropyl-carbamic acid 2-(4-chloro-phenyl)-2-oxo-ethyl ester as an off-white solid. Recrystallization of a portion of this solid from isopropyl alcohol gave an analytically pure sample, mp 163-164° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH:9]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)C=CC=CC=1.[ClH:39]>CC(C)=O>[ClH:39].[O:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[NH2:8])=[N:17]1
Reactant: Fc1ccc(CC(N=C(c2ccccc2)c2ccccc2)c2ccccc2-c2noc3ccccc23)cc1
Agent: Cl
Solvent: CC(C)=O
Product: NC(Cc1ccc(F)cc1)c1ccccc1-c1noc2ccccc12
Reaction time: 8 h

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to -65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1 M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystalised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][C:5]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:29][N:28]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)nc1C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12

Procedure:
2-Benzoyl-6-benzyloxynicotinic acid methyl ester (1.14 g) and hydrazine monohydrate (0.40 ml) were stirred together in ethanol (50 ml) at reflux overnight. The reaction was cooled (ice bath) precipitating a solid, which was separated by filtration and washed with diethyl ether. This was 2-benzyloxy-8-phenyl-6H-pyrido[2,3-d]pridazin-5-one (0.845 g). 1H NMR (400 MHz, DMSO) δ5.42 (2H, s), 7.33 (6H, m), 7.50 (3H, m), 7.86 (2H, m), 8.51 (1H, d, J=9.7 Hz), 13.04 (1H, s); MS (ES+) m/e 330 [MH]+.
Reaction SMILES: O.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCCl>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=CC(=O)O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)C=Cc1ccc(Oc2c(-c3ccc(O)cc3)ccc3cc(O)ccc23)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution was prepared of 658 mg (1.54 mmol) of 3-[4-((2-(4-methoxyphenyl)-6-methoxynaphth-1-yl)oxy)phenyl]propenoic acid hydrate in 10 mL of dichloromethane. The solution was cooled to 5° C. and 0.44 mL (4.7 mmol) of BBr3 was added. The reaction was allowed to proceed for one hour at 0° C. under a nitrogen atmosphere. The reaction was quenched by pouring into water and extracting three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, brine, dried with Na2SO4, and evaporated to an oily, red solid. The product was purified by chromatography on a silica gel column eluted with MeOH--CHCl3 (1:99) (v/v). This yielded 489 mg of the title compound as a yellow, amorphous solid, mp 150-153° C.
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH:9](O)[CH3:10])(C)(C)C.[H-].[Na+]>O>[F:19][C:14]1[CH:13]=[C:12]([CH:8]2[CH:9]([CH3:10])[O:20][C:6](=[O:5])[NH:7]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1OC(=O)NC1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a well stirred solution of [1-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.11 g, Rf =0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf =0.5, 3:1 hexane-EtOAc). NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[CH:11]=1>C(#N)C.ClCCl>[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[C:11]=1[I:1]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1I

Procedure:
N-Iodosuccinimide (17.67 g) was added portionwise to a stirred solution of 5-amino-3-cyano-1-(2,4,6-trichlorophenyl)pyrazole (U.S. Pat. No. 5,232,940; 22.5 g) in acetonitrile (300 ml) and the resulting mixture stirred at room temperature for 1 hour, then evaporated under reduced pressure. The residue was partially purified by chromatography on silica gel (800 g), using an elution gradient of dichloromethane:ethyl acetate (100:0 to 0:100), to produce a pale brown solid which was further purified as follows. Trituration with hexane (25 ml ) provided a residue which was dissolved in dichloromethane (500 ml). This solution was washed with water (500 ml), the aqueous washing back-washed with ethyl acetate (500 ml) and the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure to furnish the title compound as a pale brown solid. δ(DMSOd6): 6.28 (br.s,2H), 7.98 (s,2H). MS (thermospray): M/Z [M+H] 413.0; C10H4Cl3IN4+H requires 412.9.
Reaction SMILES: F[C:2]([F:7])(F)[C:3](O)=O.[NH2:8][C:9]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[S:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)=[O:12]>>[NH2:8][C:9]1[N:30]=[C:29]([NH:8][CH2:9][C:10]2[CH:27]=[CH:28][C:2]([F:7])=[CH:3][CH:11]=2)[CH:28]=[CH:27][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[S:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Product: Nc1nc(NCc2ccc(F)cc2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Yield: 16 %

Procedure:
The title compound (10.6 mg, 0.0188 mmol, 16%) was obtained as a trifluoroacetic acid salt from 2-amino-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (41 mg, 0.12 mmol) and 4-fluorobenzylamine (200 μl, 1.75 mmol) according to an analogous method to Example A-94.