Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O.[CH2:36]([OH:38])[CH3:37]>>[OH:38][CH2:36][C:37]1[CH:34]=[CH:33][C:12](/[CH:13]=[CH:13]/[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:34][CH:33]=2)=[CH:11][CH:10]=1
Reactant: CCO
Reactant: CCCCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Product: CCCCCCOc1ccc(/C=C/c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
115 mg (16.5 mmole) of Li were dissolved in 75 ml of ethanol under a nitrogen atmosphere. Then 2.05 g (15 mmole) of aldehyde 4-hydroxymethylbenzaldehyde were added and the mixture was cooled in an ice bath. Then 5.148 g (15 mmole) of (4-hexyloxy-benzyl)-triphenylphosphonium bromide were added. The mixture was stirred in the ice bath under nitrogen for 0.5 hour, and then stirred at room temperature for 3 hours. 2.5 ml of water were added and the precipitate was collected on a filter and washed with 10 ml of ethanol. After drying over silica in a dessicator, 1.75 g of a white powder were obtained. Yield 37%.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[C-]#N.[Na+].[CH3:32][N:33](C=O)C>CCOCC>[F:9][C:8]([F:11])([F:10])[CH:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)[CH2:6][C:32]#[N:33]
Reactant: CS(=O)(=O)OCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Product: N#CCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
In a 20 mL round-bottomed flask, 3,3,3-trifluoro-2-((2-(3-(trifluoromethyl)phenyl)morpholino)-methyl)propyl methanesulfonate (850 mg, 1.95 mmol) and sodium cyanide (957 mg, 19.5 mmol) were combined with DMF (30 ml) to give a light yellow solution. The reaction mixture was heated at 60° C. and stirred for 2 h. The reaction mixture was diluted with ether (60 ml), washed with brine and H2O, dried over MgSO4, filtered and concentrated to give crude product as an oil. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 60% ethyl acetate in hexanes) to afford 400 mg (56%) of 4,4,4-trifluoro-3-[2-(3-trifluoromethylphenyl)-morpholin-4-ylmethyl]-butyronitrile as a colorless oil. MH+=367.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]=[CH2:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH:18]([C:20](C)=[O:21])=C>>[Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]/[CH:16]=[CH:17]/[C:20](=[O:21])[CH3:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: C=CCc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: C=CC(C)=O
Product: CC(=O)/C=C/Cc1ccccc1O[Si](C)(C)C(C)(C)C
Yield: 73.7 %

Procedure:
The representative procedure was followed using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), methyl vinyl ketone (106 mg, 1.50 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil (107 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[OH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3 mL) was added hydroxyl amine HCl (0.427 g, 6.19 mmol) and potassium carbonate (1.14 g, 8.26 mmol). The reaction mass was stirred at RT for 15-17 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water, acidified with dilute HCl and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m, 2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:9]2)[O:7][NH:30]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.888 g, 4.87 mmol) was dissolved in MeOH (18 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.195 g, 4.87 mmol) dissolved in water (1.800 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.299 mL, 4.87 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (24 mL, 144.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow oil. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. A mixture of cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate and trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)-piperidine-1-carboxylate (1.027 g, 59%) was obtained as white solid after freeze drying. MS m/z 357 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.N(CC)CC.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) Cul in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][CH2:20]/[C:19](=[CH:23]\[C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N+:32]([CH2:36][O:37][P:38]([OH:41])([OH:40])=[O:39])=[CH:31]4)=[C:26]([O:42][CH3:43])[CH:25]=3)/[C:18]2=[O:44])[CH3:16])=[CH:11][CH:10]=1.O>C(#N)C>[P:38]([O-:40])([O:37][CH2:36][N+:32]1[C:33]([CH3:35])=[CH:34][N:30]([C:27]2[CH:28]=[CH:29][C:24](/[CH:23]=[C:19]3/[C:18](=[O:44])[N:17]([C@H:15]([C:12]4[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=4)[CH3:16])[CH2:22][CH2:21][CH2:20]/3)=[CH:25][C:26]=2[O:42][CH3:43])[CH:31]=1)([OH:41])=[O:39]
Reactant: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COP(=O)(O)O)c1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COP(=O)([O-])O)c1
Yield: 90.7 %

Procedure:
An aqueous solution (4 mL) of 3-{4-{1-[(S)-1-(4-fluorophenyl)ethyl]-2-oxopiperidin-(3E)-ylidenemethyl}-2-methoxyphenyl}-5-methyl-1-(phosphonooxymethyl)-3H-imidazol-1-ium trifluoroacetate (150 mg) obtained in Example 1 was subjected to reversed phase C18 silica gel column chromatography (developing solvent: 100% water to 35% acetonitrile aqueous solution). The objective fraction was concentrated and then lyophilized to give 112 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]([CH:19]=[CH2:20])=O.S(=O)(=O)(O)O.N1CCCCC1>[Cl-].[Al+3].[Cl-].[Cl-].C(O)(=O)C>[C:13]([C:12]1[C:7]2[C:8](=[CH:17][CH:19]=[CH:20][CH:6]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:15])[C:14]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C(c1ccccc1)c1cccc2ccccc12

Procedure:
It has been known to produce benzanthrone by the following processes. (1) Anthraquinone is dissolved into sulfuric acid and a mixture of metallic powder and glycerin is added to the solution to reduce anthraquinone and simultaneously, the reaction product is further reacted with the compound resulted by dehydration of glycerin in an addition-reaction (B10S 987 and F1AT 1313). (2) Benzanthrone is produced by reacting an anthrahydroquinone ester such as acetate and sulfate which is obtained by reducing and esterifying anthraquinone, with acrolein in the presence of a dehydration catalyst such as sulfuric acid and piperidine in a solvent of acetic acid. (DRP 720,467). (3) Benzanthrone is produced by condensing α-benzoylnaphthalene at higher than 150° C. in the presence of aluminum chloride catalyst or at 120° C. in the presence of iron chloride catalyst. (DRP 239,761).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O:12]CC)=[O:11].[OH-].[Na+:16]>O1CCCC1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O-:12])=[O:11].[Na+:16]
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1nc2ccncc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (12 ml), ethyl thiazolo[5,4-c]pyridine-2-carboxylate (0.61 g) was dissolved, followed by the addition of a 1N aqueous sodium hydroxide solution (3 ml). After stirring at room temperature for 30 minutes, the insoluble matter was filtered off. Without purification, the filtrate was provided for the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)nc1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recolled to 0° C., and saturated aqueous K2CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2% MeOH/CH2Cl2) gave 7.5 g (59%) of a yellow solid, mp 49°-51° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])[CH:9]=2)=[CH:5][C:4]=1[N+:28]([O-])=O>CO.[Pd]>[NH2:28][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:16])[CH:9]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)NCCN3CCOCC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(NC(=O)NCCN3CCOCC3)c2)cc1N

Procedure:
To a flask containing N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide in methanol was added a catalytic amount of 10% Pd/C and hydrogenated to yield in quantitative amount N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide. MS: MH+=387.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[O:9][CH2:8]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH:14]=2)[O:9][CH2:8]1
Reactant: COc1cccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)c1
Reactant: ClCc1ccccn1
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2COc3ccc(OCc4ccccn4)cc3[C@@H]2O)c1

Procedure:
By the method of Example 13, using flash chromatography with 40:9:1 CH2Cl2 :hexane:isopropanol as eluant and recrystallization from 1:1 toluene:hexane, the title product of Example 25 (0.37 g, 0.00128 mol) and 2-picolyl chloride were converted to present title product, 0.15 g (30%), m.p. 105°-107° C. MS (m/e) calculated: 379.1424, found: 379.1394.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=N)C(c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.32 g (11 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide in methylene chloride is added, at room temperature, 1.78 g (12 mmol) of trimethyloxonium tetrafluoroborate. After stirring overnight under nitrogen, the resulting solution is poured onto an ice-cold mixture of ether and aqueous sodium bicarbonate. The aqueous layer is discarded, and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo affords methyl 2-(4-chlorophenyl)-3-methylbutanimidate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.12 mol) in DMF (100 mL) was added K2CO3 (26.3 g, 0.19 mol). The reaction mass was stirred at 80° C. for 1 h followed by addition of methyl iodide (12.3 mL, 0.19 mol). The reaction mass was further stirred at 80° C. for 5-6 h. The reaction mass was filtered and the obtained filtrate was concentrated. The residue was further diluted with water and obtained solid was filtered off to afford 20.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.83 (s, 3H), 3.97 (s, 3H), 7.38 (d, J=9.3 Hz, 1H), 8.41 (dd, J=2.4 Hz & 2.4 Hz, 1H), 8.47 (s, 1H); MS (m/z): 212.44 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:5]=1.Cl[Sn]Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Yield: 89.9 %

Procedure:
To a solution of 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester (4 g, 14.7 mmol) in methanol/ethyl acetate was added SnCl2 (11.15 g, 58.8 mmol) at room temperature. The reaction mixture was refluxed for 3 hours and then cooled. Solvent was removed under reduced pressure and the residue was dissolved in H2O and basified by addition of Na2CO3 to pH=9. The mixture was extracted with CH2Cl2, and the organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (3.2 g, 90%) as white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1.CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:13][C:14]([C:15]#[N:16])=[C:17]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:18]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a solution of imidazole (4.45 g, 65.4 mmol) in tetrahydrofuran (30 mL) and dimethylformamide (10 mL) was added potassium carbonate (9.95 g, 72 mmol) and the mixture was stirred for 30 min at room temp. To this was added 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and the mixture stirred at 90° C. for 3 h then at room temp for 2 days. The mixture was filtered and concentrated and the residue was purified by flash chromatography (SiO2) eluting with 20% to 70% ethyl acetate/hexane to give the title compound as white needles (1.1 g, 9% yield). 1H-NMR (500 MHz, CDCl3) δ ppm: 7.94 (1H, s), 7.84 (1H, dd, J=8.7, 5.6 Hz), 7.37 (1H, t, J=8.7, 5.6 Hz), 7.37 (1H, t, J=1.4 Hz), 7.29 (1H, t, J=1.1 Hz), 7.27-7.21 (2H, m). LCMS [M+H]+ calcd for C10H7N3F: 188.058; found: 188.12.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4](I)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)#[CH:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:16]#[C:15][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: COc1c(F)cc2c(c1I)OCC2=O
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1c(F)cc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
A solution of 5-fluoro-7-iodo-6-methoxybenzofuran-3(2H)-one (0.0582 g, 0.184 mmol) in triethylamine (3 mL) was added with tert-butyl 4-ethynylpiperidine-1-carboxylate (0.0389 g, 0.184 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0129 g, 0.0184 mmol) and copper(I) iodide (0.00350 g, 0.0184 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[(5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.0502 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Cl[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[N:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Cc1nc2c(Cl)nccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2c(C)nc3c(Cl)nccc32)nc1
Yield: 51 %

Procedure:
4-Chloro-2-methylimidazo[4,5-c]pyridine* (3.34 g, 20 mmol), and ethyl 6-chloronicotinate (3.71 g, 26.2 mmol) were dissolved in N,N-dimethylformamide (42 ml). Potassium carbonate (2.76 g, 20 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled, the solvent removed under reduced pressure and the crude product purified by flash chromatography eluting with ethyl acetate. Fractions containing product were evaporated and the resulting foam triturated with ether. The solid was filtered and dried under reduced pressure yielding the title compound as a yellow solid (3.2 g, 51%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)C.C(Cl)Cl>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH:10]([OH:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2c1OC(C)(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc2c1OC(C)(C)C2O

Procedure:
An aqueous solution of sodium borohydride (8.2 g, 50 ml) is added to a stirred solution of the product obtained in Step 3. (41.8 g) in ethanol (1 l) and the mixture refluxed for 3 hours and evaporated in vacuo. The residue is taken up in water and toluene, the layers are separated and the organic phase washed, dried and evaporated in vacuo affording an oil which is dissolved in methylene chloride, dried, filtered and evaporated in vacuo. The residue is dissolved in ethyl acetate and chromatographed on silica gel affording the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:37][O:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:7]
Reactant: NOCCO
Reactant: COCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 69 %

Procedure:
The title compound was prepared from reaction of the product of Example 25, Step C, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]amino]benzoic acid with CDI and 2-(aminooxy)ethanol, by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]-amino]-N-(2-hydroxyethoxy)benzamide as a cream solid (69%); m.p. (Et2O/hexanes) 136-137° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.77 (br s, 1 H), 7.43-7.36 (m, 1 H), 7.15-7.00 (m, 2 H), 6.95-6.77 (m, 2 H), 4.71 (br s, 1 H), 3.85 (t, J=4.8, 2 H), 3.56 (t, J=4.8, 2 H), 3.33 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 2.56 (t, J=7.7 Hz, 2 H), 1.80-1.71 (m, 2 H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Li+:9].C[C:11](C)=[O:12]>CO>[C:4]([O:12][CH3:11])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Li+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]

Procedure:
Twenty grams of maleic anhydride is dissolved in 200 mls methanol, 4.8 grams (0.2 moles) of lithium hydroxide is added. The mixture is stirred until all the lithium hydroxide dissolves (at this point the pH reads 7.0). To the solution is added acetone and the solid is filtered and dried. 23 grams product is obtained.