Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].CC(C[AlH]CC(C)C)C>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH2:7][OH:8])[CH:12]=1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-bromo-2-chlorobenzoate (1 eq.) in THF (0.03 M) was added, at −78° C., DIBAL (2.5 eq). The reaction was stirred at −78° C. for 1 h and then warmed slowly to RT over 1 h. The reaction mixture was then diluted with ether and carefully quenched with aq. 6 M HCl. The organic layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a white semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][CH:10]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][CH:10]=1)[NH2:21]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Yield: 91.6 %

Procedure:
Into a solution containing 13.8 grams (38.1 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2.5-dimethyl-1-nitrobenzene prepared in Part A in 400 milliliters of toluene was added 2.0 grams of a 5% platinum on carbon catalyst. The resulting mixture was placed in a one liter rocking Parr hydrogenation vessel. Hydrogen was introduced into the vessel to a pressure of 120 psi. The hydrogen pressure was maintained between 100-120 psi until hydrogen uptake ceased. The contents of the reactor vessel were then removed and filtered. Removal of the solvents from the filtrate afforded 11.6 grams of 3-chloro-4-(4-chloro-1-naphthoxy)-2.5-dimethylaniline as a white solid having a melting point of 118° C.-125° C.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 200 °C

Procedure:
Into a round bottom 3-neck flask equipped with a nitrogen flow, a magnetic stirrer, and a friedrichs condenser was added (chloromethyl)trimethylsilane (0.100 mol). To the flask was added benzylamine (0.300 mol), with stirring, and the resulting solution heated at 200° C. for 2.5 hours. Sodium hydroxide aqueous solution (0.1N) was added in order to hydrolyze the white organic salt that had formed. The mixture was extracted with ether and the ether layer was dried over magnesium sulfate and concentrated under reduced pressure through a Vigreux column to give the product at b.p. 68-72° C./0.7-0.8 mm.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)C.[CH3:16][Si:17]([CH3:24])([CH3:23])[C:18]#[C:19]C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.C1(C)C=CC=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:8](/[CH:7]=[CH:6]/[CH2:5][C:19]#[C:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(C=CCOC(C)=O)c1
Reactant: C[Si](C)(C)C#CC(=O)O
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: [Cs+]
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/CC#C[Si](C)(C)C)c1
Temperature: 75 °C
Yield: 41.9 %

Procedure:
To a dried 40 mL scintillation vial fitted with a Teflon coated cap is added 3-methoxycinnamyl acetate (619 mg, 3.0 mmol), toluene (20 mL), 3-(trimethylsilyl)propiolic acid (512 mg, 3.6 mmol), cesium carbonate (1.17 g, 3.6 mmol), and tetrakis(triphenylphosphine)palladium (0) (346 mg, 0.3 mmol, 10 mol %). The vessel is evacuated and back-filled with Argon and then heated to 75° C. for 18 h. Upon cooling to room temperature, the reaction mixture is quenched with H2O (5 mL) and extracted with diethyl ether (2×10 mL). The combined organics are washed with brine, dried over MgSO4, filtered, and concentrated. The crude oil is purified by flash chromatography (12 g RediSep flash cartridge, hexanes to 1.5% ethyl acetate/hexanes) to give 307 mg (42%) of ((E)-5-(3-methoxyphenyl)pent-4-en-1-ynyl)trimethylsilane as an oil. 1H NMR (acetone-d6, 400 MHz) δ 7.23 (d, J=8.1 Hz, 1H), 6.99-6.97 (m, 2H), 6.80 (m, 1H), 6.65 (dt, J=15.7, 1.7 Hz, 1H), 6.26 (dt, J=15.7, 5.7 Hz, 1H), 3.8 (s, 3H), 3.19 (dd, J=5.7, 1.8 Hz, 2H), 0.16 (s, 9H). Reference: Tunge, J. A.; rayabarapu, D. K. J. Am. Chem. Soc. 2005, 127, 13510-13511.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.P(Br)(Br)[Br:16]>C(Cl)Cl>[Br:16][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)c(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(CBr)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of (4-methoxy-2-trifluoromethyl-phenyl)-methanol (1.04 g, 5 mmol) in DCM (20 mL) was treated at 0° C. with phosphorous tribromide (1.64 g, 6 mmol). The reaction mixture was stirred for 10 minutes at 0° C., 1 h at room temperature. The solvent was evaporated in vacuo to yield a crude oil which was purified via flash chromatography (10% DCM in hexane) to yield the title compound as an oil (1.36 g, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[C:7](Br)=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[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>[NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: COc1c(N)c(C#N)c(C)c(Br)c1F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 110 °C
Reaction time: 15 h

Procedure:
Under nitrogen atmosphere, 2-amino-5-bromo-4-fluoro-3-methoxy-6-methylbenzonitrile (I-45) (20.0 g, 77.20 mmol), phenylboronic acid (11.3 g, 92.64 mmol), potassium phosphate (34.4 g, 162.11 mmol) were dissolved in a mixed liquid of 1,4-dioxane (400 ml) and water (20 ml), tetrakis(triphenylphosphine)palladium (2.6 g, 2.32 mmol) was added, followed by stirring at 110° C. for 15 hours. After cooling, the insoluble matter was separated by filtration through Celite, the reaction solvent was evaporated away under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted wrath a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain the entitled compound (20.12 g, quant) as a yellow white solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=O.[CH3:7][CH2:8][CH2:9][CH2:10]CC>>[O:3]1[C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:1]=[CH:2]1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: c1ccc2occc2c1
Yield: 62.9 %

Procedure:
A solution of 30 (10.3 g; 39.3 mmol), EtOH (250 mL) and saturated NaHCO3 (100 mL) were heated to reflux for 1 h. The reaction mixture was cooled to room temperature and theEtOH removed in vacuo. Ice was added to the residue aqueous solution and the reaction carefully acidified to about pH 2 with 2 N HCl. The resulting mixture was extracted with EtOAc (2×300 mL) and the combined organic phase washed with brine, dried (NaSO4), filtered and evaporated to yield a brown oil (8.8 g). The crude product was run through a silica gel column with 15% EtOAc:hexane to yield 31 (5.44 g; 62.9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]3[NH:13][C:26]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][N:18]=[CH:19]5)=[CH:27][C:28](=[O:29])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Reactant: Nc1nc(-c2cccc(Cl)c2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]ncc3c2)[nH]c2nc(-c3cccc(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.52 mmol) in n-BuOH (1 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (280 mg, 1.00 mmol) and TsOH (5 mg, 0.03 mmol), and the reaction mixture was stirred overnight at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford 2-(3-chlorophenyl)-5-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (75 mg, 34%).
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[C:11]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)[S:23][C:10]=12)=[O:8])C>O1CCOCC1>[F:31][C:27]1([F:30])[CH2:28][CH2:29][N:24]([C:22]2[S:23][C:10]3[C:11]([N:21]=2)=[N:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][C:9]=3[C:7]([OH:8])=[O:6])[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2nc(N3CCC(F)(F)CC3)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccccc2)nc2nc(N3CCC(F)(F)CC3)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
An aqueous solution of 4 mol/L sodium hydroxide (1.55 mL, 6.20 mmol) and water (1 mL) were added to a solution of 2-(4,4-difluoropiperidino)-5-phenyl-7-thiazolo[4,5-b]pyridinecarboxylic acid ethyl ester (500 mg, 1.24 mmol) prepared above in 1,4-dioxane (5 mL), followed by stirring at room temperature for 3 hr. The reaction solution was concentrated, and a saturated aqueous solution of ammonium chloride was added to the residue. The precipitated crystals were collected by filtration, washed with water, and dried. The resulting crude crystals were subjected to recrystallization from acetic acid-water to obtain the title compound (442 mg, 1.18 mmol) as a yellow powder.
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:38].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[F:35][C:33]1[CH:34]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C@@H:4]([O:3][CH:1]=[O:2])[C@H:5]([CH2:6][CH2:7][N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[C:19]([OH:38])=[O:20])=[CH:28][CH:27]=2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
The compound (0.12 g) obtained from step d was taken in acetonitrile (6 mL) and water (1 mL), to this solution sodiumdihydrogen phosphate (0.05 g) was added. Reaction mixture was cooled to 0° C. and hydrogen peroxide (0.5 mL) and sodium chlorite (0.15 g) were added. After stirring the reaction mixture for additional 1 hour, solvents were evaporated on rotaevaporator, the residue was taken into water and extracted with ethyl acetate. Organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Solvent was evaporated under the reduced pressure, to get the title compound (0.12 g)
Reaction SMILES: Cl.CN(CCCN=C=NCC)C.[C:13]([C@H:16]([CH:25]=[CH:26][CH3:27])[C@H:17]([O:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])([OH:15])=O.ON1C2N=CC=CC=2N=N1.Cl.[NH2:39][C@@H:40]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:41]([NH:43][C@@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45])=[O:42].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:54][C:52]([CH3:53])([CH3:55])[C@H:40]([NH:39][C:13]([C@H:16]([CH2:25][CH:26]=[CH2:27])[C@H:17]([O:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:41]([NH:43][C@@H:44]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH3:45])=[O:42]
Reactant: CC=C[C@@H](C(=O)O)[C@H](OCC)C(=O)OC
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](OCC)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
N-(Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) was added to a stirred mixture of methyl (2S, 3R)-3-carboxy-2-ethoxy-hex-4-enoate (Preparation 7) (210 mg, 0.97 mmol) and 1-hydroxy-7-azabenzotriazole (139 mg, 1.02 mmol) in anhydrous dimethylformamide (4 mL) under nitrogen at 0° C. After 1 h, (2S)-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(276 mg, 1.02 mmol) was added, followed by diisopropylethylamine (0.18 μL, 1.02 mmol). After another 30 min, the mixture was allowed to warm to room temperature. After 17 h at room temperature, the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2×20 mL). The combined organic solutions were concentrated under reduced pressure, dissolved in ether (50 mL), washed with water (3×20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate=60:40) to give methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate (181 mg, 43%), as a colourless solid (single diastereomer by 1H NMR).
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].CS(O)(=O)=O.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: OP(O)O
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Agent: C=O
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Yield: 77.6 %

Procedure:
Cycle 1: A pressure reactor was charged with N-acetyliminodiacetic acid monohydrate (19.3 g), water (16.6 g), phosphorous acid (9.8 g) and methanesulfonic acid (15 g). The mixture was heated to 120° C. and 42% formaldehyde (6.9 mL) was added drop wise over a ¾ hour period. After another ¾ hour at 120° C. the mixture was cooled. The mixture was filtered and the solid was washed with water to give 17.6 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH:3]=1
Reactant: CC(=O)c1cc(Cl)ccn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2cc(Cl)ccn2)OCCO1
Yield: 91.9 %

Procedure:
1-(4-Chloro-2-pyridyl)ethanone (440 mg, 2.83 mmol) and ethyleneglycol (480 mg, 3 mmol) were mixed with toluene (10 ml), a catalytic amount of p-toluenesulfonic acid was added and the mixture was heated at reflux overnight. The mixture was evaporated to dryness to yield 523 mg of a solid (2.6 mmol, 93%). MS (APCI) m/z=200.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:24]#[N:25])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22]O)[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2].C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[C:1]([C:3]([C:24]#[N:25])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:32])[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCOCCO)ccc2c1
Solvent: ClCCl
Product: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCOCCF)ccc2c1
Yield: 60 %

Procedure:
0.20 g (0.6 mmol) of the fifth compound 5 is obtained to be dissolved in 10 mL of anhydrous methylene chloride. 0.16 mL (1.2 mmol) of (diethylamino)sulfur trifluoride (DAST) is added at 0° C. for reaction at a room temperature for 16 hrs. After the reaction is completed, extraction is processed with water and dichloromethane. An organic phase is collected with water removed by sodium sulfate and is concentrated under reduced pressure to be separated and purified by liquid chromatography. Thus, the final product 6,2-(1,1-dicyanopropen-2-yl)-6-{[2-(2-fluoro-ethoxy)-ethyl]methylamino}naphthalene, is obtained, which has a weight of 0.12 g and a yield of 60.0%.
Reaction SMILES: Cl[C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: COCOc1cc(C#N)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)cnc1Oc1ccc2c(c1)COB2O
Temperature: 80 °C
Yield: 37.5 %

Procedure:
To a mixture of 6-chloro-5-methoxymethoxy-nicotinonitrile (0.68 g, 3.42 mmol) and 3H-benzo[c][1,2]oxaborole-1,5-diol (0.56 g, 3.76 mmol) in DMF (10 mL) was added cesium carbonate (2.45 g, 7.52 mmol). The resulting suspension was heated at 80° C. for overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by flash chromatography on silica gel using 1-100% MeOH/EtOAc gradient elution to yield the title compound (0.40 g, 40%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.23 (s, 1H), 7.14 (d, J=7.4 Hz, 1H), 5.40 (s, 2H), 4.98 (s, 2H), 3.45 (s, 3H); MS (ES) m/z: 313 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 97 %

Procedure:
From 4-nitro-bromobenzene and 4-acetylphenyl boronic acid, yield 97%; mp 144-146° C. (lit.,7 150-151° C.); IR: 1681, 1530, 1497, 1361 and 1280; 1H NMR (400 MHz; CDCl3): 8.02 (2H, d, J 8.5), 7.64-7.56 (4H, m), 7.16 (2H, t, J 8.5) and 2.63 (3H, s); 13C NMR (CDCl3): 197.5, 164.2, 144.7, 136, 128.9, 127, 116, 115.7 and 26.6; m/z (EI) 199 (30%, M+−C2H2O), 131 (50) and 69 (100)(Found: M+−C2H2O, 199.062).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Reactant: Cc1ccc(I)cc1
Product: CCOC(=O)COc1ccc(C#Cc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from ethyl (4-ethynylphenoxy)acetate (41 mg, 0.20 mmol) and iodo-4-methylbenzene (46 mg, 0.21 mmol) according to the general procedure ID to give 47 mg (79%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.14 (EtOAc:hexanes, 1:10); 1HNMR (CDCl3) δ 7.49-7.37 (m, 4H), 7.17-7.11 (m, 2H), 6.91-6.84 (m, 2H), 4.63 (s, 2H), 4.29-4.26 (dq, 2H, J=7.2 Hz, 2.1 Hz), 2.36 (s, 3H), 1.32-1.27 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.6, 138.1, 133.0, 131.4, 129.1, 120.3, 116.8, 114.7, 88.6, 88.3, 65.4, 61.5, 21.5, 14.1; EI-MS m/z 294 (M+).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[S:14][C:15]([Cl:20])=[CH:16][C:17]=1[O:18][CH3:19].[CH:21]1([C:24]2[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1>[Cl:20][C:15]1[S:14][C:13]([C:28]([C:27]2[CH:34]=[CH:35][C:24]([CH:21]3[CH2:22][CH2:23]3)=[CH:25][CH:26]=2)=[O:29])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: COc1cc(Cl)sc1Br
Reactant: CON(C)C(=O)c1ccc(C2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)sc1C(=O)c1ccc(C2CC2)cc1
Temperature: -78 °C
Yield: 62.9 %

Procedure:
In a nitrogen stream, an n-butyllithium n-hexane solution (1.6 M, 2.43 mL, 3.88 mmol) was added dropwise to a solution of 2-bromo-5-chloro-3-methoxythiophene (882 mg, 3.88 mmol) as synthesized by the method described in a document [L. Org. Chem., 58, 4629-4633 (1993)] in anhydrous THF (15 mL) at −78° C. This mixture was stirred at −78° C. for ten minutes, and a solution of 4-cyclopropyl-N-methoxy-N-methylbenzamide (875 mg, 4.26 mmol) in THF (3 mL) was added dropwise thereto. The reaction mixture was stirred at −78° C. for 30 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:ethyl acetate (4:1)] to obtain the title compound (714 mg, 63%).
Reaction SMILES: [CH3:1][N:2]([CH:4]1[C:23](=[O:24])[C:22]([C:25]([NH2:27])=[O:26])=[C:21]([OH:28])[C:20]2([OH:29])[CH:5]1[CH2:6][CH:7]1[C:17]([C:18]2=[O:19])=[C:16]([OH:30])[C:10]2[C:11]([OH:15])=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8]1)[CH3:3].[Br:31]N1C(=O)CCC1=O.C(OCC)C.[S:44](=[O:48])(=[O:47])([OH:46])[OH:45]>>[S:44]([OH:48])([OH:47])(=[O:46])=[O:45].[Br:31][C:14]1[CH:13]=[CH:12][C:11]([OH:15])=[C:10]2[C:9]=1[CH2:8][CH:7]1[C:17]([C:16]2=[O:30])=[C:18]([OH:19])[C:20]2([OH:29])[CH:5]([CH:4]([N:2]([CH3:1])[CH3:3])[C:23]([OH:24])=[C:22]([C:25]([NH2:27])=[O:26])[C:21]2=[O:28])[CH2:6]1
Reactant: CN(C)C1C(=O)C(C(N)=O)=C(O)C2(O)C(=O)C3=C(O)c4c(O)cccc4CC3CC12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CN(C)C1C(O)=C(C(N)=O)C(=O)C2(O)C(O)=C3C(=O)c4c(O)ccc(Br)c4CC3CC12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 4.14. g of 6-demethyl-6-deoxytetracycline, prepared by the described literature procedure, and 1.99 g of N-bromosuccinimide dissolved in 50 ml of concentrated sulfuric acid is stirred at 0° C. for 45 minutes or until solution occurs. The reaction mixture is added dropwise to 2 L of cold diethyl ether. The resulting precipitate is collected and dried. The solid is dissolved in 2-methoxyethanol, triturated with methanol, collected, washed with methanol and diethyl ether and dried to give 6.22 g of crude product. The solid is recrystallized from 2-methoxyethanol and methanol to give 3.1 g of pure product. MS(FAB): m/z 493 (M+H). 1H NMR(CD3SOCD3): δ 4.3(s, lH, 4-H), 6.8(d, lH, 9-H) and 7.75(d, IH, 8-H).