Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.C(OCC)C>[ClH:23].[ClH:23].[N:11]1([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1nc(N2CCNCC2)c2cn[nH]c2n1
Reaction time: 2 h
Yield: 99 %

Procedure:
The 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.97 mmol) was dissolved in 4 mL of 1,4-dioxane and treated with 10 mL of 4M HCl in 1,4-dioxane at room temperature. The solution was allowed to stir for two hours to afford a light-yellow suspension of product. The solvent was diluted with diethyl ether, stirred for ten minutes, and filtered. The pad of product was washed with diethyl ether and allowed to dry under a stream of nitrogen to give the 4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine bis-hydrochloride salt as a light-yellow solid (539 mg, 99%). 1H NMR (D6O, 400 MHz) δ 8.59 (s, 1H), 8.42 (s, 1H), 4.29 (appt, J=5.6 Hz, 4H), 3.42 (appt, J=5.6 Hz, 4H). LCMS (APCI+) m/z 205 [M+H]+; Rt=0.34 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCC1CCOCC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC1CCOCC1
Yield: 94.1 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (265 mg, 1.0 mmol) was treated with C-(tetrahydro-pyran-4-yl)-methylamine (1.5 mmol) following general procedure B to afford 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (324 mg). 3-Ethyl-7-methoxy-1-(tetrahydro-pyran-4-ylmethyl)-1 H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 370 [M+1]+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Mg].[F:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[F:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:2]#[CH:1]
Reactant: C#CCBr
Reactant: CCCCC(=O)CF
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(CF)CCCC
Temperature: 25 °C

Procedure:
A 0.25 ml. portion of propargyl bromide is added to a stirred suspension of 0.73 g. of magnesium and 6 mg. of mercuric chloride in 7.5 ml. of ether. The reaction is initiated after a few minutes of vigorous stirring at room temperature. A mixture of 3 g. of 80% 1-fluoro-2-hexanone and 3.63 g. of propargyl bromide in 7.5 ml. of ether is added dropwise through a dropping funnel so that the reaction remains gently refluxing (25° C. to 32° C.). Cooling in a water bath is required. The reaction mixture is cooled in an ice bath, quenched with 8 ml. of cold saturated aqueous ammonium chloride, filtered through Celite and washed with ether. The mother liquor is evaporated to dryness giving a reddish oily residue, which is Kugelrohr-distilled at 45° C./-4 mm giving the product as a colorless liquid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[S:7]([C:11]1[N:12]([CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][N:15]=1)([CH3:10])(=[O:9])=[O:8].CN(C)C=O>C(Cl)Cl>[S:7]([C:11]1[N:12]([CH2:16][C:17]([Cl:2])=[O:19])[CH:13]=[CH:14][N:15]=1)([CH3:10])(=[O:9])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1nccn1CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1nccn1CC(=O)Cl
Temperature: 10 °C
Yield: 92.5 %

Procedure:
Phosphorus pentachloride (22.5 g.) dissolved in methylene chloride (150 cc.) is added dropwise and whilst cooling to 5° C., to a suspension of (2-mesyl-imidazol-1-yl)-acetic acid (12.3 g.) in methylene chloride (50 cc.). Dimethylformamide (2 cc.) is added thereafter and the mixture is then heated under reflux for 4 hours. The mixture is cooled to 10° C., the resulting solid is filtered off and washed with methylene chloride (15 ac.) to give (2-mesyl-imidazol- 1 -yl)-acetyl chloride (12.4 g.), m.p. 132°-133° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[C:4]=1[C:10]([F:13])([F:12])[F:11].Cl>O1CCOCC1>[NH2:9][C:5]1[N:6]=[CH:7][N:8]=[C:3]([OH:2])[C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ncnc(N)c1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncnc(O)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6-methoxy-5-(trifluoromethyl)pyrimidin-4-amine (N-3) (420 mg, 2.18 mmol) in 1,4-dioxane (10 mL), concentrated HCl (1.81 mL, 21.8 mmol) is added and the resulting mixture is stirred at 90° C. for 3 h. The mixture is allowed to cool to RT and then concentrated in vacuo to afford the product, 6-amino-5-(trifluoromethyl)pyrimidin-4-ol (N-4) as yellowish solid.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]>>[CH3:18][C:15]([NH:14][C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11])([CH3:19])[CH2:16][OH:17]
Reactant: CC(C)(N)CO
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Product: CC1CCC(C(C)C)C(C(=O)NC(C)(C)CO)C1

Procedure:
p-Menth-3-oyl chloride (3.0 g.) was reacted with 2-amino-2-methyl-propan-1-ol (3.0 g.) according to the procedure of Example 3. Product N-(1,1-dimethyl-2-hydroxyethyl)-p-menthane-3-carboxamide was obtained as a crystalline solid which was recrystallised from aqueous methanol. M.p. 123°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:18])[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1
Reactant: OC1(c2ccccc2F)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(2-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (5.8 g, 23 mmol) in dioxane (100 mL), cooled to 0° C. was added hydrogen chloride (1M in water, 75 ml, 75 mmol). The reaction mixture was stirred for 2 hour at room temperature, extracted with ethyl ether (2×200 mL) and washed with saturated bicarbonate solution, water and brine. Drying and solvent evaporation gave 4-(2-Fluorophenyl)-4-hydroxy-cyclohexanone in quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:12]O[C:10]=1[C:21]([O:23]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[NH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:12][N:31]2[CH2:32][CH2:33][NH:34][C:21](=[O:23])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1occ(-c2nccs2)c(=O)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1NCCn2cc(-c3nccs3)c(=O)c(OCc3ccccc3)c21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Methyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47 g) was suspended in ethanol (15 ml)-dioxane (15 ml), and tert-butyl (2-aminoethyl)carbamate (0.816 ml) was added. After stirring at 70° C. for 1.5 hr, the solvent was evaporated and 4N hydrochloric acid/dioxane solution (70 ml) and chloroform (10 ml) were added to the residue. After stirring at room temperature for 2 hr, the reaction mixture was concentration under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (20 ml) and methanol (50 ml) were added to the residue and the mixture was stirred for 2 hr. The solvent was evaporated and the obtained solid was collected by filtration and washed thoroughly with water to give 9-benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (1.07 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:31])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:31])=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
At room temperature, tert-butyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinate (1.8 g, 3.43 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (15 mL) and triethyl silane (0.2 mL) was added. The resulted mixture was heated to 50° C. and stirred for 16 h. The solvent was removed under reduced pressure. The residue was partitioned in water (50 mL) and ethyl acetate (50 mL), and separated. The organic phase was removed, and the aqueous layer was filtered. The solid was washed with water (20 mL×2) and dried in vacuum to give the title compound (1.48 g, purity 85%, yield 92%) as a grey solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24](O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Zn]>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1CCCN1CC=C(c2ccccc2)CC1
Yield: 58.1 %

Procedure:
An agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (11 g) in acetic acid (80 cc) is heated to a temperature close to 60° C. and 11.3 g of powdered zinc is added in small portions in the course of 10 minutes. The suspension obtained is then heated to a temperature close to 120° C. for 5 hours. The suspension is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 80° C. The residue is dissolved in distilled water (250 cc) and the solution is extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The precipitate formed is recrystallized from boiling acetonitrile (25 cc). 6.1 g of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are thus obtained, melting at 104° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH:4]3[O:8][C:7](=[O:9])[N:6]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:5]3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(CCCl)CN1c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C1OC(CCN2CCN(c3ccccc3)CC2)CN1c1ccccc1

Procedure:
Following the procedure of Example 2, the title compound was prepared from 5-(2-chloroethyl)-3-phenyl-2-oxazolidinone and 1-phenylpiperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[NH2:14][NH2:15].O>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:14][NH:15]2
Reactant: CC(C)C(=O)c1c(F)cccc1Br
Reactant: NN
Solvent: O
Solvent: OCCO
Product: CC(C)c1n[nH]c2cccc(Br)c12
Temperature: 160 °C

Procedure:
A mixture of 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one (1.1 g, 4.5 mmol) and anhydrous hydrazine (0.17 mL, 5.4 mmol) in ethylene glycol (10 mL) is heated for 16 hours at 160° C. Water is added and the mixture is extracted with CH2Cl2. The combined extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography to yield 4-bromo-3-isopropyl-1H-indazole. 1H NMR (CDCl3) 10.1 (br s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 3.99 (m, 1H), 1.43 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][CH:10]=O>CCO>[N:1]1[CH:9]=[CH:10][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: Nc1cnccn1
Reactant: O=CCCl
Solvent: CCO
Product: c1cn2ccnc2cn1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50% wt in H2O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90° C. in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichloromethane (DCM). The organic layer washed with saturated aqueous NaHCO3 then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product.
Reaction SMILES: [CH3:1][C:2]([SH:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1CO>C(Cl)Cl>[CH3:1][C:2]([S:8][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(S)CC(=O)O
Reactant: COc1cc(OC)c(CO)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(SC(C)(C)CC(=O)O)c(OC)c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 3-methyl-3-sulfanylbutanoic acid (Sweetman et al, J. Med Chem.,14:868 (1971), the disclosure of which is incorporated herein by reference in its entirety) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5° C. (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (Munson et al., J. Org. Chem., 57, 3013 (1992), the disclosure of which is incorporated herein by reference in its entirety) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5° C. After the addition was complete, the mixture was stirred for an additional 5 minutes at 5° C. and the volatiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material evaporated in vacuo. The residue was treated with activated charcoal and recrystalized from diethyl ether/hexane. The product was isolated as a white solid in 70% yield (7 g). mp 103-105° C.; 1H NMR(CDCl3): δ6.12 (s, 2H), 3.80-3.85 (m, 11H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3): δ173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1C(=O)C)(=[O:7])=[O:6])[CH:2]=[CH2:3].Cl[Si](C)(C)C.C([OH:28])C>S(=O)(=O)(O)O>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:28])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: CCO
Reactant: C=CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Product: C=CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 100 %

Procedure:
A solution of N-allyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide (30 mg, 009 mmol), 0.mL of chlorotrimethylsilane and 2 drops of fuming sulfuric acid in ethanol was heated to reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na,SO4) and concentrated to give the desired product (26 mg, 100%). 1H NMR (MeOD-d4): δ 8.01(d, 1H), 7.20 (d, 1H), 5.70 (m, 1H), 5.16 (m, 1H), 5.05 (m, 1H), 3.62 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](O)=[O:5].CO>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:14])([F:13])[F:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Br)cccc1OC(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: OCc1c(Br)cccc1OC(F)(F)F
Yield: 100.7 %

Procedure:
To a stirred solution of 2-bromo-6-[(trifluoromethyl)oxy]benzoic acid (1.116 g, 3.92 mmol, Parkway Scientific), in THF (45 ml), under nitrogen, was added 1.0 M borane-tetrahydrofuran complex (12 ml, 12 mmol) carefully over about 2 minutes. The solution was then heated at gentle reflux for 24 h and allowed to cool. Methanol (20 ml) was added dropwise. The solution was heated at reflux for 30 min and allowed to cool. The solvent was evaporated in vacuo and acidified with dilute aqueous HCl. The mixture was extracted with chloroform and then filtered through a hydrophobic frit. The chloroform was evaporated in vacuo to give {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol as a colourless oil (1.07 g). {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol (1.06 g, 3.91 mmol) in dichloromethane (14 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (0.37 ml, 3.91 mmol) in DCM (3.5 ml) was then added dropwise over about 12 min. The temperature was allowed to rise to ambient temperature over about 3 h then stirred for a further 2 h. Saturated aqueous sodium bicarbonate (12 ml) was then added in portions with stirring and the mixture left in a fridge over weekend. The mixture was extracted into chloroform three times. The combined chloroform extracts were filtered through a hydrophobic frit and the solvent was evaporated in vacuo to give 1-bromo-2-(bromomethyl)-3-[(trifluoromethyl)oxy]benzene as a colourless oil (0.6 g).
Reaction SMILES: N1C=CN=C1.[C:6]([C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].CN(C)C=O.[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>CCCCCC>[C:6]([C:8]1([O:14][Si:21]([CH3:24])([CH3:23])[CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC1(O)CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC1(O[Si](C)(C)C)CCCCC1
Reaction time: 0.02 h

Procedure:
A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, diluted with water and extracted with hexane. The hexane layers are washed several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17](=[CH2:28])[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])CCC>C1COCC1.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.[Cu]Cl>[CH3:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:17](=[CH2:28])[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:3]2=[N:10][N:9]=1
Reactant: Cc1nnc2c(Br)cccn12
Reactant: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)c1cccn2c(C)nnc12
Temperature: 60 °C
Yield: 72.7 %

Procedure:
To a solution of 0.13 g (0.61 mmol) of 8-bromo-3-methyl[1,2,4]triazolo[4,3-a]pyridine from Step B above in 4 mL of anhydrous THF was added a solution of 0.36 g (0.80 mmol) of benzyl 2-(tributylstannyl)acrylate (see Intermediate 62, Step B) in 1 mL of anhydrous THF, 0.11 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.067 g (0.67 mmol) of copper (I) chloride. The reaction mixture was heated to 60° C. for 6 h, cooled and filtered through a pad of Celite®. The pad was washed with 15 mL of a dichloromethane and the combined filtrates were evaporated to dryness. The crude residue was purified by silica gel chromatography eluting with a 0-6% methanol in ethyl acetate gradient to afford the title compound (0.13 g, 73%). LC-MS: m/z (ES) 294 (MH)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc(CO)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a suspension of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (40 g, 79 mmol) in Tetrahydrofuran (THF) (300 mL) was added TEA (12.08 mL, 87 mmol) and isobutyl chloroformate (11.39 mL, 87 mmol). The resulting mixture was stirred at r.t. for 1 h. LCMS showed completion of the reaction. Then the mixture was cooled down to −78° C. and a solution of DIBAL-H (158 mL, 236 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t., concentrated, diluted with sat. NH4Cl and extracted with dichloromethane twice. The organic mixture was filtered through Celite to remove any solids. The combined organic solution was then washed with brine and dried over sodium sulfate, filtered and the resulting filtrate was concentrated in vacuo to afford 1-ethyl-6-fluoro-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (33 g, 51.5 mmol, 65.3% yield) as yellow solid, which was used in the next oxidation step without further purification. LCMS: (M+H)+: 494.3.