Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=3)[S:10][C:3]=12
Reactant: O=Cc1cccc(Br)n1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Product: O=Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Yield: 27 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.707 g, 2.17 mmole) with 6-bromopyridine-2-carbaldehyde (0.396 g, 2.17 mmole) using tereakis(triphenylphosphine)palladium(0) (100 mg) as catalyst in a manner as previously described for example 39b to give a white solid (0.161 g, 27%). 1H NMR (300 MHz, CDCl3) δ 10.15 (1H, s), 8.61 (1H, d, J=5.1 Hz), 7.93–8.09 (4H, m) 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 275.00.
Reaction SMILES: [C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Reaction time: 2.5 h

Procedure:
(R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-but-3-enyl)-hydrazide (3.05 g, 10.5 mmol) was dissolved in 100 mL methanol. Palladium on charcoal (1%, 240 mg) was carefully added, and the mixture was shaken on a Parr hydrogenator for 2.5 hours at a starting pressure of 55 psi. Decrease in pressure was monitored as a measure of the reaction progress; after 1.5 hours, hydrogen uptake ceased. The mixture was filtered through a pad of Celite, and solvent was removed in vacuo. Analysis by TLC using several solvents was largely unsuccessful in distinguishing between the two hydrazide spots, although 3:1 hexanes:ethyl acetate (Rf=0.28) was marginally successful. The crude product was crystallized twice from 2:1 pentane:hexanes to provide >0.6 g of (R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-butyl)-hydrazide. 1H NMR (400 MHz, CDCl3) δ 7.05 (t, 1H), 6.79 (d, 1H), 6.76 (d, 1H), 3.7 (s, 3H), 2.37 (m, 1H), 2.12 (s, 3H), 1.7-1.1 (m, 4H), 0.90 (s, 9H), 0.82 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:2]1=2.[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C(O)(=O)C>C1C=CC=CC=1.C(OCC)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([N:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]3[CH3:11])[CH:8]=[CH:9][C:2]1=2
Reactant: Nc1ccc2sccc2c1
Reactant: CC(=O)CCC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(C)n1-c1ccc2sccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A stirred solution of benzo[b]thiophen-5-amine (2.48 g, 17.0 mmol), hexane-2,5-dione (1.95 mL, 17.0 mmol) and glacial acetic acid (0.2 mL) in benzene (35 mL) was heated to reflux under a Dean-Stark head. After 14 h the reaction was cooled to r.t., diluted with diethyl ether (40 mL), and successively washed with aqueous 2 N hydrochloric acid (30 mL), brine (30 mL), a saturated aqueous solution of sodium hydrogen carbonate (30 mL) and finally brine (30 mL). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to yield 1-(benzo[b]thiophen-5-yl)-2,5-dimethyl-1H-pyrrole (3.67 g, 97%) as a light orange crystalline solid. 1H NMR δ (CDCl3, 400 MHz) 2.04 (s, 6H), 5.93 (s, 2H), 7.19 (dd, J=8, 2 Hz, 1H), 7.37 (d, J=5 Hz, 1H), 7.55 (d, J=5 Hz, 1H), 7.66 (d, J=2 Hz, 1H), 7.94 (d, J=9 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[F:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:29]4[CH:28]=[N:27][CH:26]=[C:25]([F:24])[CH:30]=4)[C:3]=3[CH3:23])=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2cncc(F)c2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide with commercially available 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using the method described in Step B of Example 136 to afford a white solid (Example 200). HPLC Ret time=2.98 min. LCMS [M+H]+ 410.22.
Reaction SMILES: [C:1]([C:3](=[CH:9]OCC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:9]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Product: CCOC(=O)C(C#N)=CNc1ccc(C(=O)OCC)cc1
Temperature: 150 °C

Procedure:
The mixture of ethyl 2-cyano-3-ethoxyacrylate (28.5 g, 0.168 mol) and 4-aminobenzoic acid ethyl ester (26.5 g, 0.16 mol) was heated at 150° C. for 2 h, detected by HPLC. After cooling to room temperature, the reaction mixture was dried under reduced pressure to give 4-(2-cyano-2-ethoxycarbonyl-vinylamino)-benzoic acid ethyl ester as a grey solid. LC-MS m/e 289 (MH+).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[CH:8]=[CH:9][CH:10]=1>C(N)(C)C>[CH:14]([NH:15][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:16])[CH3:13]
Reactant: FC(F)(F)c1c[nH]c(-c2cccc(OCC3CO3)c2)n1
Solvent: CC(C)N
Product: CC(C)NCC(O)COc1cccc(-c2nc(C(F)(F)F)c[nH]2)c1

Procedure:
A solution of 2-[3-(2,3-epoxypropoxy) phenyl]-4-trifluoromethylimidazole (0.9 g.) in isopropylamine (10 ml.) is heated 6 hours at reflux. The excess isopropylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from nitromethane 0.65 g. of 2-[3-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 162.5°-163.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:17]=1.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]/[C:7](=[N:24]\[C:23]#[N:22])/[C:6]=2[CH:17]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of 8-chlorodibenzo[b,f]oxepin-10(11H)-one (732 mg, 3.84 mmol) in anhydrous DCM (30 mL) was added TiCl4 (1 M solution in DCM, 7.8 mL, 7.8 mmol) dropwise within 15 minutes at room temperature. It was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.48 g, 1.89 mL, 8.46 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g), extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(8-chlorodibenzo[b,f]oxepin-10(11H)-ylidene)cyanamide (500 mg, 68%), which was used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:7]=1
Reactant: OC(c1cccnc1)c1cc(Br)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1cccnc1)c1cc(Br)ccc1F

Procedure:
To a stirring solution of (5-bromo-2-fluorophenyl)(pyridin-3-yl)methanol (3.75 g, 13.3 mmol) in DCM (50 mL) was added Dess-Martin periodinane (6.21 g, 14.6 mmol) portion-wise over several minutes. The reaction was then quenched with saturated 1:1 Na2S2O3/NaHCO3 solution (140 mL) and stirred until gas evolution ceased. The aqueous layer was extracted with DCM, dried over MgSO4, and purified by column chromatography (gradient 0 to 30% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.83 (dd, J=4.9, 1.7 Hz, 1H), 8.14 (dd, J=7.9, 0.6 Hz, 1H), 7.73 (dd, J=6.0, 2.5 Hz, 1H), 7.68 (ddd, J=8.7, 4.5, 2.6 Hz, 1H), 7.47 (dd, J=8.0, 4.9 Hz, 1H), 7.09 (t, J=9.0 Hz, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([CH:25]([CH3:30])[C:26]([O:28]C)=[O:27])=[CH:20][C:19]=3[F:31])=[CH:14][CH:13]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4]>CC(O)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([CH:25]([CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[F:31])=[CH:16][CH:17]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4]
Reactant: COC(=O)C(C)c1cc(F)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3c(F)cc(C(C)C(=O)O)cc3F)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
Potassium hydroxide (0.396 g, 7.05 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)propanoate (Intermediate 21-1; 1 g, 2.35 mmol) in t-BuOH (15.16 mL) at room temperature. The resulting solution was stirred at 45° C. for 5 hours, a precipitate formed. The reaction mixture was quenched with 2M HCl (5 mL), evaporated to dryness and redissolved in water (10 mL), filtered through nylon, washed with water and dried under vacuum to afford product as a white solid. The product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN/MeOH as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)propanoic acid (0.530 g, 54.8%) as a white powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([Br:36])[CH:35]=1)[CH2:7][O:8][C@H:9]1[C@H:18]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1.[CH3:37]I>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([Br:36])[CH:35]=1)[CH2:7][O:8][C@H:9]1[C@H:18]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]([CH3:37])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:23][CH2:24]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN([C@@H]2c3ccccc3OC[C@H]2OCc2cc(Br)cc(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN([C@@H]2c3ccccc3OC[C@H]2OCc2cc(Br)cc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.2 g of sodium hydride (60% in oil) is added to 1 g of the compound obtained in Step B of Example 9 and 0.42 ml of methyl iodide in 10 ml of tetrahydrofuran, maintaining the temperature of the reaction mixture at 0° C. After 15 minutes at that temperature, the mixture is stirred for 48 hours at ambient temperature, diluted with water and extracted with ethyl acetate. After conventional treatment, the expected product is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]-amide (AMR01038, 100 mg, 0.274 mmol) in dry DCM (10 mL) were added pyridine (0.044 mL, 0.548 mmol) and benzoyl chloride (0.047 mL, 0.411 mmol). The reaction mixture was stirred at room temperature until TLC showed consumption of starting material (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-benzoylpiperidine-4-carboxylic acid [2-(2,4-dichloro-phenoxy)phenyl]amide (98 mg, 76%) as a white solid, mp 176-177° C. Rf: 0.17 (hexane/EtOAc 1:1) LC/MS (APCI) tr=1.10 min, m/z 471.26 (58), 469.31 (M++H, 100) HPLC tr=2.88 min (99.48%) 1H NMR (270 MHz, CDCl3) δ 1.85 (4H, m, 2CH2), 2.55 (1H, tt, CH), 3.01 (2H, m, CH2), 3.89 (1H, m, ½CH2), 4.74 (1H, m, ½CH2), 6.72 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.95 (1H, d, J=8.6 Hz, ArH), 7.01 (1H, td, ArH), 7.14 (1H, td, ArH), 7.22 (1H, dd, J=8.6, 2.5 Hz, ArH), 7.39 (5H, s, ArH), 7.49 (1H, d, J=2.5 Hz, ArH), 7.78 (1H, br s, NH) and 8.38 (1H, br d, J=8.2, ArH). Anal. Calcd. for C25H22Cl2N2O3: C, 63.97; H, 4.72; N, 5.97. Found: C, 64.10; H, 4.83; N, 5.88%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(Br)nn(-c3ccc(C)cc3)c2c1
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3c(F)cccc3F)nn(-c3ccc(C)cc3)c2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
Methyl 3-bromo-1-(4-methylphenyl)-1H-indazole-6-carboxylate 173.7 mg, 0.503 mmol), 2,6-difluorophenylboronic acid, pinacol ester (183.4 mg, 0.764 mmol), Cs2CO3 (505.1 mg, 1.550 mmol), copper(I) chloride (52.7 mg, 0.532 mmol), 1,1′-bisdiphenylphosphino ferrocene (29.3 mg, 0.053 mmol), and palladium(II) acetate (6.5 mg, 0.029 mmol) were placed in a 10-20 mL microwave vial under Ar. N,N-dimethylformamide (2.50 mL) was added and the vessel sealed. The reaction mixture was heated to 90° C. and allowed to stir for 30 min. The reaction was stopped, quenched by addition of saturated aqueous ammonium chloride (15 mL), and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with saturated aqueous ammonium chloride (1×15 mL), saturated aqueous sodium chloride (1×10 mL), dried (sodium sulfate), and concentrated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 24 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-10%). The title compound (102.1 mg, 0.270 mmol, 53.6% yield) was recovered as a white solid. LC-MS: [M+1]=379.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:13]([C:8]1[CH:7]=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:15])[CH3:14]
Reactant: COc1cccc(NC(C)=O)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(NC(C)=O)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
N-(3-Methoxy-phenyl)-acetamide (17.7 g, 107 mmol) in methylene chloride was cooled to zero degrees C., and acetyl chloride (19.0 ml, 268 mmol) was slowly added, followed by aluminum chloride (35.7 g, 268 mmol) in small portions over 15 min. The reaction mixture was stirred 15 minutes at zero degrees, then allowed to warm to room temperature with stirring. The reaction mixture was poured into ice, stirred 35 minutes, and filtered. The solid was washed with water. The filtrate was extracted with EtOAc and solvent was removed under reduced pressure. The combined solids gave N-(4-Acetyl-3-methoxy-phenyl)-acetamide (16.5 g., 74%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[O:10]1[CH2:11][CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-(Tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (42 mg, 0.21 mmol) was dissolved in dichloromethane (2.2 ml) and cooled in an ice bath. Trifluoroacetic acid (1.2 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated and dried under high vacuum to afford (S)-(Tetrahydro-pyran-3-yl)amine trifluoroacetate which was used without further purification.
Reaction SMILES: O[CH:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[BH4-].[Na+]>[Pd].C1(OC)C=CC=CC=1>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:3]1[CH:2]=[C:11]2[C:6]([CH:7]=[C:8]([O:12][CH3:13])[N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)CC1CCc2cc(OC)ncc2C1O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: COc1ccccc1
Product: COC(=O)Cc1ccc2cc(OC)ncc2c1

Procedure:
7-Aza-6-methoxy-1-tetralone is reacted with glyoxylic acid to provide 7-aza-2-carboxy-hydroxymethyl-6-methoxy-1-tetralone and this compound is dehydrated by heating in base to provide 7-aza-2-carboxy-methylidene-6-methoxy-1-tetralone. Saturation of the double bond with zinc in acetic acid followed by acid catalysed esterification with methanol and sulfuric acid provides 7-aza-6-methoxy-2-methoxycarbonylmethyl-1-tetralone. 7-Aza-6-methoxy-2-methoxycarbonylmethyl-1-tetralone to methyl 8-hydroxy-3-methoxy-5,6,7,8-tetrahydro-2-azanaphthalene-7-acetate by reaction with sodium borohydride and reaction of this product with Pd on Carbon/anisole provides methyl-3-methoxy-2-azanaphthalene-7-acetate which is alkylated with methyl iodide and base to provide methyl 3-methoxy-2-azanaphthalene-7-α-methyl-acetate and hydrolysis of this ester provides 3-methoxy-2-azanaphthalene-7-α-methylacetic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][C:8]2=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:7]=12)=[O:5])C>[OH-].[Na+]>[Cl:17][C:14]1[CH:15]=[CH:16][C:7]2[C:8](=[CH:12][CH:13]=1)[NH:9][C:10](=[O:11])[C:6]=2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c2ccc(Cl)ccc-2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c2ccc(Cl)ccc-2[nH]c1=O

Procedure:
6-Chloro-1,2-dihydro-2-oxocyclohepta[b]pyrrole-3-carboxylic acid ethyl ester (1.0 g, described in example 9) was hydrolyzed with 2 N aqueous NaOH (20 ml) under the conditions described for the hydrolysis in example 14 to give 6-chloro-1,2-dihydro-2-oxocyclohepta[b]pyrrole-3-carboxylic acid; mp 227° C. (dec); nmr (DMSO-d6) δ7.39-9.8 (m, 4H), 12.4 (s, 2H).
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[O:12][C@H:11]([CH3:13])[C@@H:9]([OH:10])[C@H:8]2[F:14])[C:5]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:4]=2[N:3]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:5]2[N:6]([C@@H:7]3[O:12][C@H:11]([CH3:13])[C@@H:9]([OH:10])[C@H:8]3[F:14])[C:2]([NH:24][CH:21]([CH3:23])[CH3:22])=[N:3][C:4]=2[CH:18]=1
Reactant: CC(C)N
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1F
Yield: 85 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.075 g, 0.2 mmoles) was heated in a solution of isopropylamine (Fluka, 2 mL) and absolute ethanol (6 mL) in a 90° C. oil bath for 18 hrs. The solvents were removed in vacuo. The residue was partitioned between water and ethyl acetate. The ethyl acetate solution was dried with MgSO4, filtered and solvent removed in vacuo to give the product (0.06 g) in 85% yield. MS (APCl+): m+1/z, 362; 1H NMR (DMSO-6) δ7.39 (s, 1H, Ar—H), 7.18 (s, 1H, Ar—H), 6.94 (d, 1H, NH, J=7 Hz), 6.09 (d, 1H, H-1′, J=19 Hz), 5.72 (d, 1H, OH-3′, J=6 Hz), 5.26 (d, 1H, H-2′, J=53 Hz), 3.9 (m, 3H,), 1.35 (d, 3H, H-5′, J=6 Hz), 1.18 (m, 6H, CH3).
Reaction SMILES: C1COCC1.C([O:13][C@H:14]1[C@H:19]([O:20]CC2C=CC=CC=2)[C@@H:18]([O:28]CC2C=CC=CC=2)[C@H:17]([O:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][CH:46]=2)[C@@H:16]([OH:53])[C@@H:15]1[CH2:54][O:55]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].CO>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C@@H:17]2[C@@H:16]([OH:53])[C@H:15]([CH2:54][OH:55])[C@@H:14]([OH:13])[C@H:19]([OH:20])[C@H:18]2[OH:28])=[C:38]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([CH2:51][CH3:52])=[CH:49][CH:50]=2)[CH:39]=1
Reactant: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2[C@@H](O)[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc(Cl)ccc2O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
14 mL of THF and methanol (1:1) was added to the flask containing the (1S,2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohexanol (28, 55 mg, 0.070 mmol). 55 mg of Pd/C (10%) was added in one portion to the reaction mixture. The mixture was degassed five times with H2 and the resulting suspension was stirred under an atmosphere of H2 for 3 h at ambient temperature. The reaction mixture was filtered and concentrated, and the residue was purified by preparative LC-MS to obtain 25 mg of (1R,2S,3R,4R,5S,6R)-4-(4-chloro-2-(4-ethylbenzyl)phenoxy)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol (29). 1H-NMR (D2O): δ 7.22˜7.2 (1H, d, J=9.2 Hz), 7.17˜7.11 (4H, q), 7.08˜7.06 (1H, dd), 6.92˜6.91 (1H, d, J=3.2 Hz), 4.11˜4.08 (1H, t J=9.2 Hz), 4.01 (2H, s), 3.92˜3.91 (2H, m), 3.69˜3.665 (1H, dd, J=10.8, 8.8 Hz), 3.46˜3.39 (2H, m), 3.35˜3.30 (1H, m), 2.66˜2.58 (2H, q), 1.52˜1.46 (1H, tt), 1.24˜1.19 (3H, t).