Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg+2:1].[Cl-].[Cl-].C(O)C.[C:7]([O:22]CC(C)C)(=[O:21])[C:8]1[C:9](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([O:12]CC(C)C)=[O:11]>CCCCCCC>[Mg:1].[C:7]([O-:22])(=[O:21])[C:8]1[C:9](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([O-:12])=[O:11]
Reactant: [Mg+2]
Reactant: CC(C)COC(=O)c1ccccc1C(=O)OCC(C)C
Agent: [Cl-]
Solvent: CCO
Solvent: CCCCCCC
Product: O=C([O-])c1ccccc1C(=O)[O-]
Product: [Mg]
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
Into a stirred reactor 28.4 g of MgCl2, 49.5 g of anhydrous ethanol, 10 ml of vaseline oil ROL OB/30, 100 ml of silicone oil having a viscosity of 350 cs were added. The mixture was heated at 120° C. until MgCl2 was dissolved. The hot reaction mixture was then transferred to a 1.5 l reactor equipped with a Ultra Turrax T-45 N stirrer, containing 150 cm3 of vaseline oil and 150 cm3 of silicone oil. The temperature was maintained at 120° C. whilst stirring for 3 minutes at 3000 RPM. The mixture was then discharged in a 2 liter stirred tank containing 1 l of anhydrous n-heptane cooled to 0° C. whilst stirring at a speed of 6 m/sec for about 20 minutes, maintaining the temperature at 0° C. The particles so obtained, after washing with n-hexane, were subjected to a thermal treatment in a nitrogen stream, at temperatures ranging from 50° to 150° C. until spherical particles were obtained having a residual alcohol content of about 35% by weight. 25 g of this product were charged into a stirred reactor containing 625 ml of TlCl4 at 0° C. and under stirring. The mixture was then heated to 100° C. for one hour and then left to cool. When the temperature of 40° C. was reached, diisobutyl phthalate was added in quantities such to give a molar ratio of magnesium to phthalate of 8. The mixture was heated to 100° C. for 2 hours under stirring and then the solid was left to settle. The hot liquid was removed by syphoning. Then 500 ml of TiCl4 was added and the mixture was heated to 120° C. for 1 hour whilst stirring. After settling, the hot liquid was removed by syphoning and the solid was washed with n-hexane.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[I:12])[CH:7]=[O:8].IC.[C:15]1([O-])C=CC=CC=1.[OH:22][CH2:23][C:24]([CH3:28])([CH2:26]O)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[I:12][C:11]1[CH:10]=[CH:9][C:6]([CH:7]2[O:22][CH2:23][C:24]([CH3:28])([CH3:26])[CH2:25][O:8]2)=[CH:5][C:4]=1[O:3][CH3:15]
Reactant: [O-]c1ccccc1
Reactant: CC(C)(CO)CO
Reactant: O=Cc1ccc(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C2OCC(C)(C)CO2)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (887 mg, 60% dispersion in mineral oil, 22.2 mmol) was added to an ice-cooled solution of 3-hydroxy-4-iodobenzaldehyde (5.00 g, 20.2 mmol) in DMF (20 ml) and stirred at 0° C. for 60 min. Iodomethane (3.15 ml, 22.2 mmol) was added dropwise to the solution of the phenolate, and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate and washed with ice-water and saturated sodium chloride solution. After drying over magnesium sulfate, the organic phase was concentrated under reduced pressure. The residue (6.32 g) was dissolved in toluene (150 ml) and, after addition of neopentyl glycol (2.76 g, 26.5 mmol) and Amberlyst-15 (400 mg), the reaction mixture was heated under reflux with a water trap for 3 h. After filtration, the reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase gradient 10-25% ethyl acetate in dichloromethane). Yield: 6.83 g (77%) of a yellowish oil. MS (API-ES, pos) m/z=349 [M+H]+
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[OH:5][CH:6]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[NH2:8]>>[C:1](=[O:2])([OH:4])[O-:3].[C:1](=[O:2])([OH:4])[OH:3].[OH:5][CH:6]1[O:14][C@H:13]([CH2:15][OH:16])[C@H:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[NH2:8]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])O
Product: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Product: O=C(O)O

Procedure:
Carbonating agents are prepared by reacting bicarbonate ions with the amino moiety of glucosamine or galatosamine in aqueous solution to form glucoasamine bicarbonate or galactosamine bicarbonate. The bicarbonate is then isolated by drying. The resulting dry 2-amino sugar bicarbonate is stable at room temperature and can be used as a carbonating agent. It may be used with other constituents to form a dry beverage mix. Upon rehydration, the 2-amino sugar bicarbonate releases carbon dioxide and additionally imparts a mild sweet taste to the carbonated beverage.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][CH3:11])[C@H:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@H](OC)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of (2S,3R)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (150 mg, 0.578 mmol) in THF (4 mL) and water (2.0 mL) was added LiOH (69.3 mg, 2.89 mmol) and the reaction mixture was stirred at RT for 40 h. Another aliquot of LiOH was added (69.3 mg, 2.89 mmol). Stirring was continued at RT for 60 h and subsequently at 50° C. for 16 h to complete the reaction. Water was added and volatiles were removed under reduced pressure. The aqueous phase was adjusted to pH 2 to 3 by addition of 1N aqueous HCl, followed by extraction with EtOAC (3×). The combined organics were dried (Phase separator) and concentrated in vacuo to give the title compound as a white solid. MS (LC/MS): 262 [M+Na]+, 190 [MH−tBu]+, 146 [MH−Boc]+, tR (HPLC conditions b): 3.51 min.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=2[O:2]1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1>O.C(O)CC>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CCCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc2c(c1)OCO2
Temperature: 4 °C
Yield: 39.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3,4-methylenedioxybenzoic acid (16.6 g), N,N'-carbonyldiimidazole (16.2 g) and 2-amino-7-chloro-1,8-naphthyridine (11.7 g). The product produced by precipitation in water (15.7 g; m.p. 256° C.) is dissolved in 1-propanol (1000 cc). After 16 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 1-propanol (3×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3,4-methylenedioxybenzamide (8.4 g) is produced, m.p. 256° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](N(OC)C)=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:28]([Mg]Br)=[CH:29][CH3:30]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:23])[CH:28]=[CH:29][CH3:30])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:11]=[CH2:12])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: CC=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 5, 32.5 g, 80.73 mmol) in THF (400 mL) under nitrogen at 0° C. was added prop-1-enylmagnesium bromide (323 ml, 161.45 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then quenched with 400 mL 10% citric acid, diluted further with 100 mL water and extracted with ether. The organics were concentrated and the resulting oil was dissolved in ether and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (5%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oil (27 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.C(O)(=O)C.O[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O.C(O)C>C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:3]3[N:4]=[CH:5][C:6]([C:7]#[N:8])=[C:2]3[N:1]=[CH:14][CH:15]=2)[CH:19]=1
Reactant: O=C(C=CO)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A solution of 0.54 g. of 3-aminopyrazole-4-carbonitrile and 1.29 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone acetate in 25 ml. of absolute ethanol is refluxed for 15 hours. The mixture is cooled and filtered giving a solid which is dissolved in methylene chloride and treated as described in Example 1, giving the desired product, m.p. 141°-142.5° C.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:13]([N:15]([CH2:18][CH2:19][N:20]=[C:21]=[S:22])[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH2:19][NH:20][C:21]([NH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[S:22])[CH3:14]
Reactant: CCN(CC)CCN=C=S
Reactant: Cc1cnc2c(c1)CCCC2N
Product: CCN(CC)CCNC(=S)NC1CCCc2cc(C)cnc21

Procedure:
8-amino-3-methyl-5,6,7,8-tetrahydroquinoline may be treated with diethylaminoethyl isothiocyanate according to the procedure of Example 4 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[S:15](Cl)(=[O:18])(=[O:17])[NH2:16].[Cl-].[Na+]>CN(C)C(=O)C>[S:15](=[O:18])(=[O:17])([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:15](=[O:18])(=[O:17])[NH2:16])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[NH2:16]
Reactant: Nc1ccc(-c2ccc(O)cc2)cc1
Reactant: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)Nc1ccc(-c2ccc(OS(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.4 h
Yield: 52.7 %

Procedure:
43 mg of 4′-aminobiphenyl-4-ol was dissolved in 0.7 ml of N,N-dimethylacetamide, and 107 mg of sulfamoyl chloride was added thereto under cooling with ice, followed by stirring at room temperature for 2.4 hours. After the reaction mixture was poured into a saturated aqueous solution of sodium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 17:10 mixture of chloroform and tetrahydrofuran as the developing solvent) to obtain 42 mg of 4′-(sulfamoylamino)biphenyl-4-yl sulfamate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].C(Cl)(Cl)Cl>C(O)C.N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nn(-c2ccc(Br)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Bromophenylhydrazine hydrochloride (10 mmol, 2.5 g) was added to 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) in ethanol (10 mL) and pyridine (10 mL). The mixture was stirred overnight at room temperature. Thin layer chromatographic (TLC) analysis using chloroform indicated the reaction was complete. The solvents were removed under vacuum. The residue was dissolved in 150 mL ether, then washed with 50 mL water to remove the pyridine. The ether was dried over sodium sulfate (NaSO4), the solids filtered, then the solvents were removed under vacuum. The resulting oil was purified on a silica column. The named product crystallized upon standing in the column effluent, m.p. 71° C.–73° C. Analysis by 1H-NMR and 13C-NMR verified synthesis the named product.
Reaction SMILES: [C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:37])[C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:9].[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]([CH3:37])[C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45][CH2:46]3)=[O:32])=[CH:29][CH:28]=2)[CH2:15][CH2:16]1)=[O:9]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
The compound (200 mg, 0.311 mmol) obtained in Example 15c was dissolved in 1,4-dioxane, a 4 N hydrochloric acid-dioxane solution (4.67 mL, 18.7 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, toluene was added, and then the solvent was evaporated under reduced pressure to give crude 4-({6-[(2-{4-[(biphenyl-2-ylcarbamoyl)oxy]piperidin-1-yl}ethyl)(methyl)amino]-6-oxohexyl}amino)benzoic acid. The resulting crude carboxylic acid compound and tert-butyl piperazine-1-carboxylate (58 mg, 0.311 mmol) were dissolved in methylene chloride, triethylamine (0.259 mL, 1.87 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg, 0.467 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in ethyl acetate, water and saturated aqueous sodium hydrogencarbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (98 mg; yield, 42%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of 4-bromo-2-fluoro-1-nitrobenzene (10.0 g, 45 mmol), diisopropanylethylamine (15.8 ml, 90 mmol) and aniline (5.0 ml, 54 mmol) in 100 ml 1-methylpyrrolidin-2-one (NMP) was heated at 100° C. for 16 hours. The solution was cooled to room temperature and added 1,000 ml water. The result red precipitate was filtered and washed with water (100 ml), dried under high vacuum to obtain 5-bromo-2-nitro-N-phenylbenzenamine (10.3 g, 77%). A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.50 g, 1.7 mmol) and piperidine (0.67 ml, 6.8 mmol) in 10 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperidin-1-yl)benzenamine (0.50 g, 100%) was obtained by flash column chromatograph (30% acetyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 1.66 (m, 6H), 3.33 (t, J=5.8 Hz, 4H), 6.34 (dd, J=2.6, 9.7 Hz, 1H), 6.42 (d, J=2.6 Hz, 1H), 7.23-7.46 (m, 5H), 8.14 (d, J=9.7 Hz, 1H), 9.93 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 24.8, 25.4, 48.7, 95.6, 106.4, 124.8, 125.6, 129.4, 130.1, 139.7, 146.0, 156.0.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22](O)=[O:23].O.[NH2:39][NH2:40]>CS(C)=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([NH:39][NH2:40])=[O:23]
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid (40 mg, 0.09 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Hydrazine hydrate (13 mg, 0.27 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (22 mg, 53%). LC-MS (M+H=467, obsd.=467).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]1[S:22][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cccc1Cl
Reactant: NC(N)=S
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Fc1cncc2sc(-c3c(Cl)cccc3Cl)nc12
Temperature: 85 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
A stirred suspension of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride (15.4 g, 47.8 mmol), thiourea (14.5 g, 0.191 mol) and pyridine (19.3 mL, 0.239 mol) in isopropanol (250 mL) was heated at 85° C. for 4 hours under argon. To the mixture was added Et3N (40 mL, 0.287 mol) and heating at 85° C. was continued for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc (500 mL) and water (500 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with water, then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in pentane to afford the title compound as a pale yellow solid (8.5 g, 59%). LCMS (Method D): RT=3.56 min, m/z: 299 [M+H+].
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=3)=[CH:20][CH:19]=2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCn3cncn3)cc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (0.296 g) in N,N-dimethylformamide (14 ml) was added 1,2,4-triazole (0.511 g) and 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g), and was stirred for 5 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 2.5 with conc. hydrochloric acid. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(1,2,4-Triazol-1-yl)octyloxy]phenyl]benzoic acid (0.81 g).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:53][C:54]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].CCCCCC>C(O)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:53][C:54]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 55 %

Procedure:
The product of Example 44 was deprotected in the manner described in Example 69. The product was purified by MPLC over a silica Lobar A column eluting with 40:59:1 EtOAc:hexane:acetic acid to give a 55% yield of a white solid. 1H-NMR (CDCl3, 300 MHz): 0.87 (t, 3H, J=7.4 Hz), 1.32 (m, 2H), 1.69 (m, 2H), 2.65 (3 line m, 2H, J=7.3 Hz), 5.15 (s, 2H), 5.29 (bs, 2H), 6.95 and 7.04 (AB, 4H, J=8.2 Hz), 7.30-7.42 (m, 5H), 7.49-7.59 (m, 3H), 7.72(bs, 1H), 7.98 (d, 1H), 8.06 (s, 1H), 8.12 (bd, 1H). FABMS m/e: 586 (M+ +1) calc. for C34H31N7O3