Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[N:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([Cl:15])=[N:13][CH:12]=[C:11]([CH2:16][O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnc(Cl)c(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.9 %

Procedure:
To a solution of (5-(benzyloxy)-6-chloropyridin-3-yl)methanol (1.76 g) and tert-butyldimethylchlorosilane (1.59 g) in DMF (10 mL) was added imidazole (960 mg), and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g) as a colorless oil.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12.Cl>C(O)C.C(OCC)(=O)C>[OH:1][NH:2][C@@H:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=NO)[C@H]2SC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NO)[C@H]2SC1
Reaction time: 3 h
Yield: 78.6 %

Procedure:
In ethanol (0.6 ml) is dissolved 2,2,2-trichloroethyl 7-hydroxyimino-3-methyl-3-cephem-4-carboxylate (100 mg) and under ice-cooling, a solution of borane-pyridine complex (102 mg) in ethanol (0.7 ml) is added. Then, a 2 N-methanolic solution of hydrogen chloride (0.6 ml) is added dropwise in a nitrogen stream and the mixture is stirred at the same temperature for 3 hours. The mixture is further stirred at room temperature for an hour, after which time it is diluted with ethyl acetate, washed with water and aqueous sodium chloride in that order, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue is subjected to silica gel (4.5 g) column chromatography and elution is carried out with ethyl acetate-hexane to give 2,2,2-trichloroethyl 7 β-hydroxyamino-3-methyl-3-cephem-4-carboxylate (79 mg) as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([Br:25])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([Br:25])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCc3ccc(Br)cc3C2)CC1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 4-(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 1.5 mmol) and propionaldehyde (0.1 mL, 1.5 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (795 mg, 3.75 mmol) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 g). This was placed on top of a flash column and eluted with 20% hexanes in acetone. The fractions containing product were pooled and concentrated to afford 4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (587 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[Cl:11].[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH2:23]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:23])=[CH:5][C:4]=1[Cl:11]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:16])=O.[OH-].[NH4+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Br)cc2c(O)ccnc12
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Br)cc2c(Cl)ccnc12
Yield: 95 %

Procedure:
A mixture of 6-bromo-8-methyl-4-quinolinol (1.42 g, 5.95 mmol) and phosphorous oxychloride (10.95 g, 71.40 mmol) was heated at reflux for 1 h, cooled, poured onto ice, and neutralized by addition of 30% ammonium hydroxide. The resulting solid was filtered and dried in a vacuum oven to give the title compound (1.45 g, 95%) as a tan solid. MS(ES)+ m/e 256 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cnoc1-c1ccc(F)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-(3-bromo-4-fluorophenyl)isoxazole-4-carboxylate (10.01 g) in tetrahydrofuran (70 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 70 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3-bromo-4-fluorophenyl)-4-isoxazolylmethanol (8.26 g, yield 95%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 134–135° C.
Reaction SMILES: [BH4-].[Na+].Br.[Br:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7].Br>O.CO>[Br:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[OH:7]
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CBr)c1ccccn1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
2-Bromo-1-(2-pyridyl)ethanol can be obtained by adding, over the course of one hour, an ice-cold solution of sodium borohydride (17.2 g.) in water (310 cc.) to a solution of 2-(2-bromoacetyl)pyridine hydrobromide (82.9 g.) in methanol (830 cc.) kept at -10° C. The mixture is allowed to return to a temperature of about 20° C. and the pH is brought to 2 by adding 48% hydrobromic acid (70 cc.). The mixture is concentrated to dryness under reduced pressure (30 mm.Hg) at a temperature below 40° C. The residue is taken up in distilled water (400 cc.) and the solution is decolourised by treatment with decolourising charcoal. The solution is brought to pH 7-8 by adding sodium bicarbonate (50 g.). The mixture is extracted with diethyl ether (1,500 cc.) and the extracts are dried over anhydrous potassium carbonate. After filtration and concentration under reduced pressure (30 mm.Hg), 2-bromo-1-(2-pyridyl)-ethanol (49 g.) is obtained in the form of an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:27](Cl)(=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([O:16][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Reactant: CCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(=O)OC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 0.6 %

Procedure:
To an ice-cooled stirred solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (2.5 g, 7.78 mmol) in DMF (5 mL) was added sodium hydride (373 mg, 15.56 mmol). After stirring for 20 min, heptanoyl chloride (1.9 g, 13.23 mmol) was added into the reaction mixture, which was stirred at 0° C. for 30 min. The progress of reaction was monitored by LCMS and TLC. The reaction mixture was quenched with ice water (200 mL) and extracted with EtOAc (400 mL). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (6% MeOH-DCM), followed by reverse phase HPLC to yield heptanoic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (20 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.74 (s, 2H), 7.91 (s, 2H), 7.28 (m, 2H), 7.04 (t, 1H), 6.2 (m 1H), 4.7 (d 1H), 4.59 (m, 2H), 4.3 (m, 1H), 3.5 (t, 1H), 3.34 (m, 1H), 3.31 (m, 2H), 3.12 (s, 3H), 2.4 (s, 3H), 2.3 (m, 2H), 2.1 (m, 1H), 1.35 (m, 2H), 1.22 (m, 2H), 1.15 (m, 3H), 0.86 (t, 3H). Separation by chiral HPLC provides enantiomers 338a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH:21][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC/C(=C1\c2ccc(Cl)cc2OCc2ncccc21)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC/C(=C1\c2ccc(Cl)cc2OCc2ncccc21)c1cccc(NS(C)(=O)=O)c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. (E)-3-[1-(8-chloro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1800 g, 4.96 mol) (prepared essentially as described for Intermediate 10 using the Alternate Procedure) dichloromethane (18 L) and pyridine (588.5 g, 7.44 mol) are added to the flask. The reaction mixture is cooled to 0 to 5° C. and neat methanesulfonyl chloride (681.8 g, 5.952 mol) is added dropwise over about 20-30 min, maintaining the temperature ≦5° C. After the addition is complete, the reaction mixture is stirred at 0 to 5° C. for one hour. The cooling bath is removed and the reaction stirred at room temperature for a minimum of 12 h. The progress of the reaction is followed by TLC (straight EtOAc). Once the reaction is deemed complete, the reaction mixture is washed with a 10% aqueous citric acid solution (14 L) using a 40 L separatory funnel. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 10% aqueous citric acid solution (2 L). The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 15% aqueous sodium chloride solution (5 L) and the aqueous layer back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a half saturated aqueous sodium bicarbonate solution (5 L). The sodium bicarbonate wash should be performed for a minimum of 30 min. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are dried over sodium sulfate and filtered. A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. The dichloromethane solution containing the product is charged to the flask, followed by trithiocyanuric acid, trisodium salt (630 g, 0.35 g/g of starting material), sodium sulfate (3.6 kg, 2 g/g of starting material) and charcoal (180 g, 0.1 g/g of starting material) to the flask. The suspension is stirred for 12 h at room temperature. The suspension is filtered and the filter cake slurried with dichloromethane (3×3 L). The filtrates are combined and concentrated to an off white solid. The product is dried in a vacuum oven at 40° C. overnight.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[F:13].[P:14](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>>[F:13][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:3]=1[CH2:2][P:14](=[O:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(OCC)OCC
Reactant: O=[N+]([O-])c1cc(F)c(CBr)cc1F
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1F)OCC
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1-(Bromomethyl)-2,5-difluoro-4-nitrobenzene (8.3 g, 32.9 mmol) and triethyl phosphate (12.03 mL) were heated in an oil bath for 2.5 hours at 140° C. Additional triethyl phosphate (5 mL) was added and the reaction was stirred at 140° C. for 1 hour. The reaction mixture was evaporated under reduced pressure and chromatographed on silica eluting with dichloromethane/methanol (1:0-1%) to give the title compound (11 g, 35.6 mmol). 1H NMR (CDCl3, 400 MHz): δ 7.82 (dd, 1H), 7.37 (ddd, 1H), 4.11 (m, 4H), 3.24 (d, 2H), 1.30 (m, 6H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1)(=O)=O.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])[N:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: O=S(=O)(Oc1cccc(Cl)n1)C(F)(F)F
Product: C[Sn](C)(C)c1cccc(Cl)n1

Procedure:
6-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used in Procedure I with trimethyltin chloride to yield 2-chloro-6-(trimethylstannyl)pyridine. The crude material (˜4 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2 mmol). Purified by silica gel chromatography (545% ethyl acetate/hexane) to yield N-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.45 (25% ethyl acetate/hexanes); MS (Q1) 426 (M)+.
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:8]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2=[N:3][C:4]3[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=4)=[CH:9][C:8]2=3)[CH2:29][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)C(Cl)=Nc2ccccc2O3)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)C(N2CCOCC2)=Nc2ccccc2O3)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a stirring solution of title compound 69 (285 mg, 0.754 mmol) in toluene (5.0 mL) was added morpholine (1.00 g, 11.48 mmol) and the reaction mixture was stirred at 130° C. for 4 h. It was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography with 10%-30% ethyl acetate in hexanes to afford title compound 70 (223 mg, 69%) as a white solid. LRMS (ESI): (calc) 428.17 (found) 429.5 (MH)+. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.09 (d, J=8.6 Hz, 2H), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 7.71-7.69 (m, 3H), 7.40 (d, J=8.4 Hz, 1H), 7.17-7.01 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 3.90-3.75 (m, 4H), 3.60-3.48 (m, 4H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][C:28](=[O:30])[CH3:29])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1c(C)c(Cc2ccc(OC(C)=O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 65 °C
Yield: 68 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (1.30 g, 3.59 mmol) was dissolved in acetic anhydride (5 ml) and the resulting solution was stirred under heating at 65° C. for 3 hours. The reaction solution was cooled and after adding thereto water (20 ml) and stirring at room temperature for 1 hour, extracted with ethyl acetate. The extract was washed with saturated brine and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.99 g, 2.45 mmol, 68%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)=[O:13].O>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)=[O:13]
Reactant: C[O-]
Reactant: CCc1ccc(C(=O)c2ccc(F)cc2Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2ccc(OC)cc2Br)cc1
Reaction time: 3 h

Procedure:
Sodium methoxide (10.5 g) is added portionwise to (2-bromo-4-fluoro-phenyl)-(4-ethyl-phenyl)-methanone (43.0 g) dissolved in DMF (200 mL). The solution is stirred overnight, before another portion of sodium methoxide (5.5 g) is added. After another 3 h of stirring, water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20:1->9:1).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:32][C:26]3=[CH:27][N:28]=[C:29](O)[CH:30]=[C:25]3[C:24]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:29]1[CH:30]=[C:25]2[C:24]([C:33](=[O:34])[NH:35][CH3:36])=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[O:32][C:26]2=[CH:27][N:28]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(O)cc12
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Triflic anhydride (Tf2O, 319 μL, 1.89 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2,3-c]pyridine-3-carboxamide (270 mg, 0.943 mmol) in pyridine (13 mL) at 0° C. and the mixture was allowed to warm to room temperature. It was allowed to stir for 1 hour then concentrated and diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-c]pyridin-5-yl trifluoromethanesulfonate (188 mg, 0.449 mmol, 34.8% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (1H, s), 8.53-8.61 (1H, m), 8.01-8.11 (2H, m), 7.87 (1H, s), 7.46 (2H, t, J=8.91 Hz), 2.85 (3H, d, J=4.52 Hz). LC-MS retention time: 2.06 min; m/z (MH+): 419. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(OC([N:8]1[C:17]2=[CH:18][N:19]([C@@H:21]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:27]([O:28][C:29](=[O:32])[CH2:30][CH3:31])[C@H:22]3[O:23][C:24](=[O:26])[CH3:25])[N:20]=[C:15]3[C:16]2=[C:10]([C:11](=[O:40])[NH:12][N:13]=[CH:14]3)[C:9]1=[O:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][CH2:30][C:29]([O:28][C@@H:27]1[C@@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:34][C@@H:21]([N:19]2[CH:18]=[C:17]3[NH:8][C:9](=[O:41])[C:10]4[C:11](=[O:40])[NH:12][N:13]=[CH:14][C:15]([C:16]=43)=[N:20]2)[C@@H:22]1[O:23][C:24](=[O:26])[CH3:25])=[O:32]
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c4c(cn[nH]c(=O)c4c(=O)n3C(=O)OC(C)(C)C)n2)O[C@@H]1COC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3[nH]c(=O)c4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O

Procedure:
The product from Step 7 in DCM is cooled to 0° C., and TFA is added to the vigorously stirred mixture. The mixture is allowed to stir until product is sufficiently deboc'd as determined by TLC. The crude material is concentrated in vacuo and purified by flash chromatography to give the target compound.