Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH2:2][CH3:3].Cl.[NH2:19][OH:20]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1)[CH2:2][CH3:3]
Reactant: CCCOCCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCOCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Propoxyhexyl)-4-piperidone oxime is prepared from 1-(6-propoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C(c2ccccc2)C2CCCNC2)cc1
Yield: 99.3 %

Procedure:
A solution of 3-diphenylmethylenepiperidine hydrochloride (200 mg, 0.7 mmol) in ethanol (40 ml) was stirred under one atmosphere of hydrogen at 40° C. in the presence of 10% palladium on charcoal (20 mg) for 24 hours and filtered. The filtrate was concentrated to give the title compound (200 mg) as a pale brown gum which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][CH:41]=1)[O:23][C:24]1[CH:38]=[CH:37][C:27]2[N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[S:30][C:26]=2[CH:25]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:19][C:20]2[CH:41]=[CH:40][CH:39]=[C:22]([O:23][C:24]3[CH:38]=[CH:37][C:27]4[N:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:35][CH2:36]5)=[O:33])[S:30][C:26]=4[CH:25]=3)[CH:21]=2)=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)sc5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a suspension of 3-(1-cyanocyclopropyl)benzoic acid (156.5 mg, 0.836 mmol) in toluene (5 mL) was added thionyl chloride (0.2 mL, 2.74 mmol) and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The obtained residue was used as 3-(1-cyanocyclopropyl)benzoyl chloride. 3-(1-Cyanocyclopropyl)benzoyl chloride prepared above was dissolved in pyridine (5 mL), N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (114.8 mg, 352.8 gmol) and N,N-dimethylpyridine-4-amine (23.9 mg, 195.6 μmol) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with dilute hydrochloric acid (50 ml), and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→80/20) to give the title compound (117 mg, 67%) as a pale-brown amorphous substance.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.[Li]CCCC.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][C:20]2=O.O>C1COCC1>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[C:20]1[C:19]2[C:24](=[CH:25][CH:26]=[C:17]([F:16])[CH:18]=2)[O:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: O=C1CCOc2ccc(F)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c(c1)C(=C1SCCCS1)CCO2
Temperature: 0 °C

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (5.10 g, 26.5 mmol) in 50 mL of anhydrous THF at −60° C. under N2 was added drop-wise n-BuLi (1.6 M solution in hexanes, 16.6 mL, 26.5 mmol). The mixture was left to warm slowly to 0° C. over 3 h and subsequently cooled to −60° C. A solution of 6-fluoro-2,3-dihydrochromen-4-one (4.40 g, 26.5 mmol) in 25 mL of THF was added drop-wise. The mixture was slowly warmed to ambient temperature overnight, then poured into water, and extracted with EtOAc. The combined organic portions were washed with brine, and conc. in vacuo. The crude product was purified by flash column chromatography (0 to 10% of EtOAc in hexanes). The title compound was obtained as a pale oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[CH:7]=1.[Cl:22][C:23]1[C:28]([CH2:29]Cl)=[C:27]([Cl:31])[CH:26]=[CH:25][C:24]=1[N:32]([CH3:51])[C:33](=[O:50])[CH2:34][NH:35][C:36](=[O:49])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:47][CH3:48])=[O:46])=[N:43][CH:44]=1>>[Cl:22][C:23]1[C:28]([CH2:29][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[C:8]([CH3:17])[CH:7]=[C:6]3[O:5][CH2:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[F:1])=[C:27]([Cl:31])[CH:26]=[CH:25][C:24]=1[N:32]([CH3:51])[C:33](=[O:50])[CH2:34][NH:35][C:36](=[O:49])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:47][CH3:48])=[O:46])=[N:43][CH:44]=1
Reactant: Cc1cc(OCc2ccccc2F)c2cccc(O)c2n1
Reactant: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(CCl)c2Cl)cn1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccc5F)cc(C)nc34)c2Cl)cn1
Yield: 53 %

Procedure:
4-((2-fluorobenzyl)oxy)-2-methylquinolin-8-ol from step 1 was reacted with 5-(3-((2-((2,4-dichloro-3-(chloromethyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide as described previously to give 5-(3-((2-((2,4-dichloro-3-(((4-((2-fluorobenzyl)oxy)-2-methylquinolin-8-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide in 53% yield. MS (+APCI) 718 (M+). 1H-NMR (CDCl3, δ ppm): 8.36 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.95 (bd, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.63 (m, 1H), 7.58 (m, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.25 (m, 4H), 7.15 (m, 1H), 7.05 (m, 1H), 6.77 (bs, 1H), 6.40 (bt, 1H), 5.62 (s, 2H), 5.38 (s, 2H), 3.76 (dd, J=5.2, 17.6 Hz, 1H), 3.46 (dd, J=3.6, 18 Hz, 1H), 3.22 (s, 3H), 3.00 (m, 6H), 2.69 (m, 2H), 2.56 (t, 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClC(Cl)C>[Cl:15][CH2:16][C:17]([C:7]1[C:2]([F:1])=[CH:3][C:4]([F:9])=[CH:5][C:6]=1[F:8])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Fc1cc(F)cc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1c(F)cc(F)cc1F
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a mechanically stirred solution of 1,3,5-trifluorobenzene (6.0 mL, 58 mmol) in dichloroethane (14.0 mL) was added gradually AlCl3 (15.5 g, 116 mmol) in a period of 15 min with caution. Violent bumping and HCl gas evolution was observed. The mixture was carefully heated to reflux, and chloroacetyl chloride (5.5 mL, 69 mmol) was added drop wisely in a period of 45 min. The reaction mixture was heated at reflux for an additional 6.0 h. The solution was cooled, carefully poured onto an ice/water slush (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ethereal layers were washed with 10% aqueous HCl (2×30 mL), 1.0 N aqueous NaOH (3×30 mL), and brine (25 mL). The solution was dried over MgSO4(s) and concentrated under reduced pressure to give 2-chloro-1-(2,4,6-trifluorophenyl)ethanone (5.28 g) as yellow solids in 51% yield: 1H NMR (500 MHz, CDCl3) δ 6.79-6.76 (m, 2 H), 4.50 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:46]4[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 40 mg, 0.077 mmol), K2CO3 (32 mg, 0.23 mmol) and 4-(methylsulfonyl)phenylboronic acid (23 mg, 0.12 mmol) were diluted with dioxane (1 mL)/water (300 μL) followed by the addition of Pd(PPh3)4 (8.9 mg, 0.0077 mmol). The reaction was purged with nitrogen and stirred at 55° C. for 12 hours. The reaction was cooled and concentrated. The residue was taken up in minimal DCM and purified by silica gel chromatography, eluting with hexanes:ethyl acetate (1:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 44% yield) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1Br
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O

Procedure:
28 g (68 mmol) of ethyl 2-(2-bromo-3,4,5,6-tetrafluoro-benzoyl)-3-cyclopropylamino-acrylate are heated under reflux in 88 ml of dimethylformamide with 6.9 g (164 mmol) of sodium fluoride for 6 hours. After cooling, the mixture is poured into water and the precipitate (red) which has separated out is filtered off with suction, washed with a large quantity of water and dried at 80° C. in a circulating air cabinet.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]#[N:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]#[N:16])[CH2:9][CH2:10][C:11]3([O:19][CH2:18][CH2:17][O:14]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
25 g of 1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (73) were dissolved in 850 mL of toluene. 9 mL of ethylene glycol and 1.5 g of p-toluene sulfonic acid were added and the mixture was refluxed at a Dean-Stark apparatus for 6 h. The mixture was allowed to cool down to room temperature and extracted twice with saturated sodium bicarbonate solution and once with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give 30.15 g of crude product, that was sufficiently pure for further conversion. Rt=1.47 min (Method C). Detected mass: 262.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Na+].C(O)C.S(O[CH:46]([CH3:52])[C:47]([O:49][CH2:50][CH3:51])=[O:48])(C1C=CC(C)=CC=1)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH3:52])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].CCOCC>O1CCCC1>[Br:18][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2Br)cc1
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a cold (0° C.) solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (5.0 g, 20.2 mmol) in tetrahydrofuran (81 mL) was added N-bromosuccinimide (3.79 g, 21.2 mmol) in two portions. The solution solidified after 5 minutes and additional tetrahydrofuran was added (20 mL). The resultant solution was stirred for 15 minutes. Saturated aqueous sodium bicarbonate and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by recrystallization from ethyl acetate-hexane-methanol provided 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (5.7 g, 87%) as a crystalline solid. 1H NMR (CDCl3) δ 8.07 (dd, 2H), 7.53 (d, 1H), 7.23–7.16 (m, 3H), 6.98 (d, 1H); 19F NMR (CDCl3) δ −112.60; MS m/z 325 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:33]([O:34][CH3:35])[CH3:32])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CNOC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 4-bromo-2-methyl-benzoic acid (1.00 g, 4.65 mmol) in methylene chloride (40 mL) at room temperature, were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.936 g, 4.88 mmol), triethylamine (1.49 mL, 1.07 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.544 g, 5.86 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL) and washed with 0.5 M aqueous sodium hydroxide solution (75 mL). The aqueous layer was separated, extracted with ethyl acetate (50 mL) and the organic extracts combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted between 0 and 50% v/v ethyl acetate in hexanes to give 4-bromo-N-methoxy-2,N-dimethyl-benzamide (886 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([O:27][CH3:28])=[C:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)[CH:6]=[C:7]([NH:9]C(=O)C(F)(F)F)[CH:8]=1.O>CO>[NH2:9][C:7]1[CH:6]=[C:5]([C:16]([O:27][CH3:28])=[C:17]2[CH:18]3[CH2:26][CH:22]4[CH2:21][CH:20]([CH2:25][CH:24]2[CH2:23]4)[CH2:19]3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=C1C2CC3CC(C2)CC1C3)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Solvent: CO
Solvent: O
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(N)cc(OC)c1

Procedure:
Trifluoroacetamide enol ether 31 is hydrolyzed at 60° C. with finely ground K2CO2 (3 eq) in MeOH containing trace water. Work up by partitioning the mixture with EtOAc/H2O, followed by silica gel chromatography provides enol ether aniline 32.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16].[H-].[Na+]>CN(C=O)C.CO>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C#N)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(C#N)cc21
Temperature: 180 °C

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (45 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (61.5 s15 mg) and NaH (9.0 mg) in DMF (1 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (11 mg) as white crystals.
Reaction SMILES: [CH2:1](N1C=C2C(C=C(Br)C=C2)=N1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[F:28]>>[CH2:1]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([Cl:18])[C:20]([F:28])=[CH:21]2)=[N:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2cn[nH]c2cc1Cl
Reactant: Brc1ccc2cn(Cc3ccccc3)nc2c1
Product: Fc1cc2cn(Cc3ccccc3)nc2cc1Cl

Procedure:
This compound was prepared in a manner similar to the procedure described for the preparation of 2-benzyl-6-bromo-2H-indazole, using 6-chloro-5-fluoro-1H-indazole in place of 6-bromoindazole. 1H-NMR (300 MHz, DMSO-d6) 8.54 (s, 1H), 7.90 (d, 1H), 7.71 (d, 1H), 7.36 to 7.29 (m, 5H), 5.64 (s, 2H); ES-MS m/z 261.0 [M+H]+, RT (min) 3.56.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.C(O)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH:26]([CH3:31])[CH3:27])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 81.7 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxy-benzoate (0.735 g, 2.1 mmol), triphenylphosphine (0.551 g, 2.1 mmol), and isopropanol (0.158 mL, 2 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (0.433 mL, 2.2 mmol) dropwise. The solution was sonicated for 30 minutes. The reaction mixture was purified without workup by RPLC (EtOAc/Hexane 3:7) to give 0.675 g (86%) of pure product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](S(C)=O)[CH:9]=[C:8]([CH3:18])[N:7]=1.[H-].[Na+].[F:21][C:22]([F:26])([F:25])[CH2:23][OH:24]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([O:24][CH2:23][C:22]([F:26])([F:25])[F:21])[CH:9]=[C:8]([CH3:18])[N:7]=1
Reactant: COCCOc1nc(C)cc(S(C)=O)c1[N+](=O)[O-]
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1[N+](=O)[O-]

Procedure:
2-[(2-Methoxyethyl)oxy]-6-methyl-4-methylsulfinyl-3-nitropyridine (1.73 g, 6.31 mmol) was dissolved in 2,2,2-trifluoroethanol (15 mL). Sodium hydride (55% in oil, 600 mg, 13.75 mmol) was added to the solution, followed by refluxing for one hour. The resultant solution was allowed to stand for cooling. Subsequently, the solution was extracted with chloroform-water. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1→n-hexane/ethyl acetate=3/1), to thereby yield 2-[(2-methoxyethyl)oxy]-6-methyl-3-nitro-4-[(2,2,2-trifluoroethyl)oxy]pyridine as a pale yellow solid (1.77 g, 91%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18].O.CCCCCCC>CN(C=O)C>[Br:8][C:14]1[C:13]([CH3:16])=[CH:12][C:11]([O:17][CH3:18])=[C:10]([CH3:9])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C
Solvent: CCCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A solution of NBS (306.9 g, 1.724 mol, 1.1 equiv) in DMF (850 mL) was treated dropwise with 2,5-dimethylanisole (4, 213.2 g, 220.9 mL, 1.567 mol) at 25° C. under N2. The reaction temperature was maintained under 60° C. during the addition of 2,5-dimethylanisole. The resulting reaction mixture was stirred at room temperature for an additional 1 h before being treated with H2O (2000 mL) and heptane (1000 mL). The two layers were separated and the aqueous layer was extracted with heptane (500 mL). The combined organic extracts were washed with H2O (4×800 mL), and saturated NaCl solution (500 mL), dried over MgSO4, and concentrated in vacuo. The crude product (5, 329.8 g, 336.9 g theoretical, 97.9%) was obtained as pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C)=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][OH:48])=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Yield: 85.8 %

Procedure:
A sol. of compound E1 (7.93 g, 9.45 mmol) and TBAF (1.0 M in THF, 14.5 mL, 14.5 mmol) in THF (115 mL) was stirred at 0° C. for 1 h. The mixture was diluted with EtOAc (115 mL) and was then washed with brine (4×115 mL). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→1:1→3:2→7:3) yielded the title compound (5.54 g, 76%). LC-MS: tR=1.08 min, ES+: 683.27.