Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]1=[O:27])=O)C1C=CC=CC=1>C(O)C>[NH2:11][C@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:13]1=[O:27]
Reactant: CC(C)(C)OC(=O)CN1CCCC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
tert-Butyl (3S)-3-benzyloxycarbonylamino-2-oxoperhydroazepine-1-acetate (15 g) was disolved in ethanol (150 ml) and purged with argon. 10% palladium or carbon (1.5 g) was added and the flask evacuated and filled with hydrogen from a balloon. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then purged with argon and filtered through diatomaceous earth. The filtrate was evaporated to give tert-butyl (3S)-3-amino-2-oxoperhydroazepine-1-acetate (7.7 g) as a viscous oil; NMR (CDCl3): 1.45 (s, 9H), 1.55-2.05 (m, 6H), 3.2-3.3 (d, 1H), 3.55-3.75 (two overlapping doublets, 2H), 3.95-4.25 (q, 2H); mass spectroscopy, m/e (ES+) 243.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[CH:14]=[O:15])([O-:3])=[O:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[CH3:24]N(C=O)C>>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:13]/[C:8]1[N:9]([CH3:24])[C:10]2[C:6]([C:7]=1[CH:14]=[O:15])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2
Reactant: CN(C)C=O
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C=O
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/c1c(C=O)c2cc([N+](=O)[O-])ccc2n1C
Temperature: 100 °C

Procedure:
5-nitro-2-methyl-1H-indole-3-carbaldehyde (200 mg, 0.98 mmol) was dissolved in 5 mL dry DMF, followed by the addition of N,N-dimethylformamide dimethyl acetal (467 mg, 521 □L, 3.92 mmol). The reaction mixture was heated to 100° C. for 2 h and turned from light yellow to dark red over the course of the reaction. The crude reaction was concentrated in vacuo to obtain a red solid. The crude solid was washed with 5:1 EtOAc/hexane (6×10 mL), followed by hexane (2×10 mL) to obtain 2-((E)-2-(dimethylamino)vinyl)-1-methyl-5-nitro-1H-indole-3-carbaldehyde as a brick red solid (215 mg, 85% yield). Mass and purity were confirmed by LC/MS using an acetonitrile gradient with 5 mM ammonium formate pH 6.5. Theoretical (M+H)+ m/z for C14H15N3O3=273.11; Found 274.00. 1H NMR (400 mHz, DMSO-d6) δ 9.80 (s, 1H), 8.03 (dd, J=8.9, 2.4 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.58 (m, 2H), 5.25 (d, J=13.0 Hz, 1H), 3.72 (s, 3H), 3.03 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([C:12]([O-])=[O:13])[CH2:7][CH2:6][CH:5]([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.[BH4-].[Li+].CO>>[CH3:1][C:2]1([CH2:12][OH:13])[CH2:7][CH2:6][CH:5]([C:8]([F:9])([F:10])[F:11])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)[O-])CCC(C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CC1(CO)CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 1-methyl-4-(trifluoromethyl)cyclohexanecarboxylate (11.0 g, 49.00 mmol) in tetrahydrafuran (600 mL) was slowly added lithium borohydride solution (4.0 M in tetrahydrofuran, 37.0 mL, 147.00 mmol) and methanol (6.0 mL, 147.00 mmol) at 0° C. After stirring at 0° C. for 15 minutes, the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0° C. and quenched with 25% aqueous ammonium chloride solution (100 mL), and extracted with ethyl acetate. The combined organic layers were washed with brine; dried over anhydrous magnesium sulfate; filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 5% gradient ethyl acetate in hexanes) afforded the title compound (6.80 g, 72%) as a colorless oil): 1H NMR (300 MHz, CDCl3) δ 3.51 (s, 2H), 2.02-1.91 (m, 1H), 1.75-1.72 (m, 4H), 1.49-1.35 (m, 3H), 1.19-1.09 (m, 2H), 0.94 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][C:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5](OCC)=[O:6])=[O:2].[H][H]>[Pd].C(O)C>[CH:1]([NH:3][C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:22][C:5]1=[O:6])=[O:2]
Reactant: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])(NC=O)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(NC=O)Cc2ccccc2NC1=O
Yield: 100.7 %

Procedure:
A mixture of diethyl (formylamino)((2-nitrophenyl)methyl)propanedioate (8.54 g, 0.025 mol) and 10% palladium on carbon (2.0 g) in absolute ethanol (200 mL) was hydrogenated (50 lb initial H2 pressure) until hydrogen uptake ceased. The mixture was filtered through celite and refluxed for 2 hours to achieve cyclization. The solvent was removed under reduced pressure to give 6.6 g of product which was crystallized from methanol to give 5.0 g of white crystals, mp 187°-190° C. Anal. Calc'd for C13H14N2O4 : C, 59.53; H, 5.38; N, 10.68. Found: C, 59.77; H, 5.36; N, 10.75.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1cnccn1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cnccn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A mixture consisting of 4.8 gm (0.015 mol) of 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, 2.1 gm (0.022 mol) of aminopyrazine and 200 ml of dry xylene was refluxed for 8 hours in a Soxhlet apparatus equipped with 4-A-molecular sieve. Then, another 0.5 gm of aminopyrazine was added, the mixture was refluxed for 8 hours more, and then allowed to cool and stand overnight. The precipitate formed thereby was suctionfiltered off, and thefiltrate was evaporated in vacuo. The combined precipitate and evaporation residue was recyrstallized from ethyl acetate, yielding 3.0 gm (52% of theory) of 4-hydroxy-2-methyl-N-pyrazinyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1dioxide, m.p. 245° C (decomp.).
Reaction SMILES: CS(O[CH:6]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH:7]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)=O.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[N:10]1([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12][CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1OS(C)(=O)=O
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=CCCN(C(=O)OC(C)(C)C)CC1
Yield: 95.5 %

Procedure:
A solution of example 42C (0.77 g, 2.1 mmol) in 30 mL of benzene was treated with DBU (0.9 ml ) at 60° C. for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by flash column chromatography (30% EtOAc in hexane) to give the title product (540 mg, 95% yield). MS (DCI/NH3) m/z 270 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.Cl.C[NH:18][OH:19].[C:20](=O)([O-])[O-].[K+].[K+]>>[CH3:20][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:9]([NH:18][OH:19])=[O:11]
Reactant: CNO
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CC(CCCCCCBr)C(=O)NO
Temperature: 50 °C

Procedure:
A mixture of 2.23 g (10 mmol) of 8-bromooctanoic acid (IV3) and 1 ml of thionyl chloride was heated for 1 hour at 50° C. and the remainder thionyl chloride was evaporated under reduced pressure. The resulting product was treated with 835 mg (10 mmol) of N-methyl hydroxylamine hydrochloride and 1.66 g (12 mmol) of potassium carbonate according to the procedure shown in Example 10 to give methyl-8-bromooctanohydroxamic acid (V4), which was recrystallized from a mixture of ether-n-hexane (1:1) to give 2.12 g of the compound (V4) as colorless prismatic crystals. mp. 39° C. to 40° C. To a solution of 2.12 g (8.4 mmol) of the compound (V4) and 2.15 g (9 mmol) of 2,6-di-tert-butyl-4-mercaptophenol in ethanol was added of 1.05 g (26.3 mmol) of sodium hydroxide and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into 50 ml of a 5% aqueous solution of hydrochloric acid and the mixture was extracted with 100 ml of ether. The ether layer was washed with 100 ml of water twice, dried over anhydrous sodium sulfte, and concentrated under reduced pressure to give an oily residue which was chromatographed on silica gel. The aimed compound (I11) which was obtained from the fraction eluted with a mixture of ether-ethyl acetate (2:1) was recrystallized from n-hexane containing small amount of ether to give 2.99 g of colorless needle-like crystals in 87% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([CH2:9]Cl)=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>O1CCCC1>[Cl:2][C:3]1[C:8]([CH2:9][NH:20][CH2:19][CH2:17][OH:18])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: NCCO
Reactant: ClCc1c(-c2ccccc2)ccnc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCNCc1c(-c2ccccc2)ccnc1Cl

Procedure:
To a suspension of 2-chloro-3-(chloromethyl)-4-phenylpyridine hydrochloride (12.6 g) obtained in Reference Example 2C in tetrahydrofuran (150 ml) was added ethanolamine (14 ml), and the mixture was heated under reflux for 6 hrs. After cooling the reaction solution, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (13.4 g) as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:10]#[N:11].[OH-:17].[NH4+]>>[Br:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:10]([NH2:11])=[O:17]
Reactant: N#Cc1c(Cl)ccc(Br)c1F
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1c(Cl)ccc(Br)c1F
Temperature: 55 °C

Procedure:
Concentrated sulfuric acid (15 mL) was placed in a 100 mL 3-neck flask equipped with an internal thermometer and heated to 55° C. 3-Bromo-2-fluoro-6-chlorobenzonitrile (11.0 g, 47 mmol) was added portion-wise to the acid with stirring maintaining the temperature above 50° C. The dark solution was heated at 65° C. for 24 hours, allowed to cool to room temperature, poured over ice, and cautiously neutralized with concentrated ammonium hydroxide. The mixture was extracted with two portions of ethyl acetate and the combined organic layers were dried and concentrated to give 3-bromo-2-fluoro-6-chlorobenzamide (11.5 g, 45.5 mmol) as a light orange solid: mp 157-158° C., 1H NMR (CDCl3): δ 7.54 (t, 1H), 7.14 (dd, 1H), 6.03 (br s, 1H) 5.81 (br s, 1H).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14](=[O:22])[NH:15]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Br:23]Br.[BrH:25]>C(O)(=O)C.CC(C)=O>[OH2:20].[BrH:23].[Br:25][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:22])[NH:15]2
Reactant: COc1ccc(-c2cn3ccccc3n2)c2ccc(=O)[nH]c12
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: COc1ccc(-c2nc3ccccn3c2Br)c2ccc(=O)[nH]c12
Product: O
Reaction time: 3 h

Procedure:
To a solution of 5-(imidazo[1,2-a]pyridine-2-yl)-8-methoxycarbostyril (4 g) in acetic acid (80 ml) was added dropwise at room temperature a solution of bromine (2.22 g) in acetic acid (5 ml). After completion of addition, the mixture was stirred for 3 hours. Crystals which precipitated were collected by filtration and washed with diethyl ether. The crystals thus obtained were dissolved in acetone and the solution was adjusted to pH of about 1 by the addition of 48% hydrobromic acid. Crystals which precipitated were collected by filtration and recrystallized from methanol-water to give 5 g of 5-(3-bromoimidazo[1,2-a]pyridine-2-yl)-8-methoxycarbostyril monohydrobromide monohydrate.
Reaction SMILES: Cl[C:2]1[C:3](=[O:28])[N:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:5]=[CH:6][C:7]=1[N:8]([CH3:17])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ClC1C(=O)N(C2C=CC=C(C(F)(F)F)C=2)N=CC=1N(C)N>>[F:27][C:24]([F:25])([F:26])[C:20]1[CH:19]=[C:18]([N:4]2[C:3](=[O:28])[CH:2]=[C:7]([N:8]([CH3:17])[NH:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:5]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(N=Cc1ccccc1)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Agent: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Product: CN(NCc1ccccc1)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1

Procedure:
Following the process of example 4 and using an equivalent amount of the 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methyl-2-benzylidenehydrazino)-pyridazin-3(2H)-one above in place of the 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3(2H)-one used therein there is obtained 2-(3-trifluoromethylphenyl)-5-(1-methyl-2-benzylhydrazino)-pyridazin-3(2H)-one, (m.p. 89° to 90° C).
Reaction SMILES: [CH2:1]([Si:5]([CH3:8])([CH3:7])[CH3:6])[CH2:2][CH:3]=[CH2:4].C[Si](C)(C)Cl.[Br:14]CCC=C.Br>>[Br:14][CH2:4][CH2:3][CH2:2][CH2:1][Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: C=CCCBr
Reactant: C=CCC[Si](C)(C)C
Agent: Br
Agent: C[Si](C)(C)Cl
Product: C[Si](C)(C)CCCCBr

Procedure:
Thus, 3-butenyltrimethylsilane, prepared from trimethylchlorosilane and the Grignard reagent of 4-bromo-1-butene, undergoes the free radical catalyzed addition of hydrogen bromide to give 4-bromobutyltrimethylsilane. The reaction of an alkyl bromide with sodium nitrite in dimethylsulfoxide gives a nitroalkane with alkyl nitrites as byproducts. This reaction proceeds smoothly with 4-bromobutyltrimethylsilane to give 4-nitrobutyltrimethylsilane. The oxidative nitration reaction of this compound gave 4,4-dinitrobutyltrimethylsilane, which, under standard aqueous fluorination conditions, gave 4-fluoro-4,4-dinitrobutyltrimethylsilane. The reaction sequence may be summarized by the following equations: ##STR2##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].O>CS(C)=O>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol) in DMSO (3.5 mL) was added with 1-methanesulfonylpiperazine (0.71 g, 3.5 mmol), followed by stirring at 100° C. for 1 hour. The reaction mixture was added with water and the organic layer was extracted with hexane/ethyl acetate (4/1) to remove impurities. The aqueous layer was extracted with ethyl acetate and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain 4-(4-methanesulfonylpiperazin-1-yl)-2-nitrobenzaldehyde (0.36 g,
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[S:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(Cc2cc(OC3CCCC3)cs2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2cc(OC3CCCC3)cs2)cc1
Temperature: 75 °C
Yield: 40.9 %

Procedure:
To a solution of 4-(4-cyclopentyloxythien-2-ylmethyl)-nitrobenzene (1.28 g, 4.2 mmol) in absolute ethanol (34 mL) was added tin dichloride hydrate (4.76 g, 21.2 mmol) at 20-25° C. under nitrogen. The mixture was heated at 75° C. for 2.5 hours and cooled to 0-5° C. Saturated sodium bicarbonate was added to pH 8. Ethyl acetate was added and the mixture was filtered. The layers were separated, and the aqueous phase was extracted with additional ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography (silica, hexane/ethylacetate) gave 4-(4-cyclopentyloxythien-2-ylmethyl)-phenylamine (0.47 g, 41%) as a pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.03 (d,J=8.5Hz, 2H), 6.63 (d,J=8.5Hz 2H), 6.41 (m,1 H), 5.96 (d,J=1.7Hz,1 H, 4.58 (quintet, J=4.3 Hz, 1 H), 3.91 (S,2H), 3.59 (bs,2H), 1.67-1.88 (m, 6H), 1.46-1.67 (m, 2N).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)=O.[CH2:14]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])P(=O)(OCC)OCC.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O>O1CCCC1.C(OCC)(=O)C>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33](/[CH:31]=[CH:14]/[P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:34][CH:35]=1)=[O:38]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccc(C(=O)OC)cc1)OCC
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (17 ml) is diluted with anhydrous tetrahydrofuran (81 ml) under a nitrogen atmosphere and dry ice cooling, and then a solution of tetraethyl methylenebis(phosphonate) (4.6 g) in anhydrous tetrahydrofuran (8 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 30 minutes, and then a solution of methyl 4-formylbenzoate (2.64 g) in anhydrous tetrahydrofuran (12 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 1.5 hours and further under ice cooling for 2.5 hours. Ethyl acetate is added to the reaction mixture. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting precipitate is filtered off to give 4.1 g (86%) of diethyl (E)-2-[4-(methoxycarbonyl)phenyl]vinylphosphonate as crystals.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:44][C:45](=O)[C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][C:47]=2[S:55]([OH:58])(=[O:57])=[O:56])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([C:45]([NH:4][C:5]2[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]3[C:14]=2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]3)=[O:44])=[C:47]([S:55]([OH:58])(=[O:56])=[O:57])[CH:48]=1)([O-:54])=[O:53]
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reaction time: 0.17 h
Yield: 296.2 %

Procedure:
To an ice bath cooled solution (5° C.) of 16.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 6.7 g of sodium acetate trihydrate in 100 ml of water is added 8.8 g of 4-nitro-2-sulfobenzoic acid anhydride. The mixture is stirred vigorously for 10 minutes and is filtered. The filtrate is cooled in an ice bath and diluted with 500 ml of cold ethanol. The mixture is filtered and the product is washed with ethanol and ether and then is dried. The product is dissolved in 50 ml of warm water and is stirred for 10 minutes after the addition of one ml of acetone. The mixture is treated with activated charcoal, filtered through diatomaceous earth and is washed with 20 ml of water. The filtrate is cooled in an ice bath and acidified with 1.5 ml of concentrated hydrochloric acid. The solution is diluted with 500 ml of cold ethanol and the precipitated material is filtered, washed with ethanol followed by ether and dried. The above purification process is repeated without acidification. The product obtained is dried overnight at 110° C. to give 18.5 g of 8-(4-nitro-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid tetrasodium salt.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+]>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:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([C:31]2[CH:32]=[N:33][C:28]([C:26]([N:25]([CH3:37])[CH3:24])=[O:27])=[CH:29][CH:30]=2)[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=1
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
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: O
Solvent: C1COCCO1
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 90 °C
Yield: 84.6 %

Procedure:
The tert-butyl [1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (0.05 g, 0.1 mmol, Example 179, peak 2) was combined with {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (0.034 g, 0.17 mmol, Example 179, Step 5) in 1,4-dioxane (3.0 mL) and potassium carbonate (0.034 g, 0.25 mmol) dissolved in water (1.0 mL) in a tube. The reaction was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added and degassed again. The tube was sealed and heated in an oil bath to 90° C. After heating for 18 h the reaction was complete. This was allowed to cool to room temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give tert-butyl [1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamate as a viscous oil (0.04 g, 66%). LCMS calculated for C24H30ClN4O4 (M+H)+: m/z=473.2. found: 473.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(N(CC)C(C)C)(C)C>C(#N)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:13][CH:11]([C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:12])[CH:20]=1
Reactant: COc1cc(OC)cc(C(C)N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Yield: 61 %

Procedure:
1-(3,5-Dimethoxyphenyl)ethanamine (670 mg, 4.2 mmol), 2,4-difluoronitrobenzene (764 mg, 4.2 mmol) and N,N-diisopropylethylamine (1.08 mg, 8.4 mmol) were stirred at room temperature in dry acetonitrile (50 mL) for 6 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated to collect the title compound (820 mg, 61% yield). 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.19 (m, 1H), 6.45 (s, 2H), 6.30 (m, 3H), 4.48 (m, 1H), 3.76 (s, 6H), 1.62 (d, 3H); MS (ESI) m/z: Calculated for C16H17FN2O4: 320.12; Observed: 343.2 (M++1).