Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[C:9](SC)[NH:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)C(=O)O1.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24].C(OC(=O)C)(=O)C.CN(C)C.[ClH:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.[Cl-].[Na+].O>[ClH:36].[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:9]1[NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:6](=[O:8])[CH:5]=1
Reactant: NCCCN
Reactant: CSC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O
Agent: CN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: NCCCNc1cc(=O)c2sccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,2-dimethyl-5-(methylsulfanyl-thiophene-3-ylamino-methylene)-[1,3]dioxane-4,6-dione (27.83 g, 92.8 mmol) in DCM/MeOH (4:1, 120 mL) was added to a solution of 1,3-diaminopropane (54.9 g, 138 mmol) in DCM/MeOH (4:1, 140 mL) (cooled in an ice bath) over one hour. The ice bath was removed after addition was complete. The reaction was stirred for 2 h at ambient temperature, then diluted with DCM (100 mL) and the resultant organic solution was washed with water (60 mL X 4) and brine (60 mL). Then, acetic anhydride (11 mL, 116 mmol) and trimethylamine (16 mL, 111.4 mmol) was added to the above organic solution and stirred for 30 min. An aqueous work-up with 1N HCl, then NaHCO3 (saturated) and then brine was performed. The organic was dried with MgSO4, filtered and volatile solvents removed in vacuo to afford the desired product N-(3-{[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-(thiophen-3-ylamnio)-ethyl]-amino}-propyl)-acetamide (30.7 g, 84%) as a brown oil, which was used in the next step without purification. 1H NMR (CDCl3): 11.3 (1H, br s), 10.0 (1H, br s), 7.33 (1H, dd, J=3.2, 5 MHz), 7.07 (1H, d, J=3.2 MHz), 6.98 (1H, d, J=5), 3.20 (2H, quart, J 6.4 MHz), 3.90 (1H, quart. J=6.8 MHz), 1.94 (3H, s), 1.73 (6H, s), 1.68 (2H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]CC)=[O:22])[C:16]3=[O:26])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[C:16]3=[O:26])[CH2:11][CH2:10]2)=[O:8])=[CH:27][CH:28]=1
Reactant: CCOC(=O)CN1CCC(N2CCC(C(=O)c3ccc(OC)cc3)CC2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC(=O)O)C3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 130.3 %

Procedure:
To a solution of ethyl 2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetate (727 mg, 1.778 mmol) in ethanol (36 mL) was added a 2 N aqueous NaOH solution (1.8 mL). The mixture was stirred 1 hour at room temperature. The reaction was then neutralized to pH 7 with 1 N HCl. The solvents were removed in vacuo, then azeotroped 3 times with dichloromethane. The light yellow foamy solid was dried under high vacuum to afford the title racemic product (835 mg). MS (ESI) [m/e, (M+H)+]=360.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89-8.01 (m, 2H), 6.96-7.11 (m, 2H), 3.85 (s, 3H), 3.46-3.68 (m, 2H), 3.13-3.46 (m, 5H), 2.93-3.04 (m, 1H), 2.61-2.84 (m, 1H), 2.30-2.42 (m, 1H), 1.95-2.11 (m, 1H), 1.81-1.95 (m, 1H), 1.64-1.78 (m, 2H), 1.44-1.63 (m, 2H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=[O:12]>O.CO.C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH3:16])([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C)(C)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccccc1F
Temperature: 40 °C

Procedure:
A solution of sodium hydroxide (1 g) in water (50 mL) was added to a solution of methyl 2-(2-fluorophenyl)-2-methylpropanoate (example 90, step b) (2.6 g) in methanol (50 mL) and THF (50 mL). The reaction mixture was heated at 40° C. for 40 hours. The organics were removed under reduced pressure and the remaining aqueous solution washed with ethyl acetate. The aqueous layer was cooled and acidified by addition of concentrated HCl. The mixture was extracted with ethyl acetate and the organic layer washed with brine before being dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 1.5 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[K+]>C(O)(=O)C>[C:15]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(C(=O)C(C)(C)C)cc1

Procedure:
A mixture of 20.0 grams (0.0785 mole) of α-bromo-p-pivaloyl toluene, 30.0 grams (0.157 mole) of potassium acetate and 60 milliliters of glacial acetic acid is refluxed for 20 hours. The acetic acid is removed in vacuo, and the residue is treated with ice water and then extracted with methylene chloride. The methylene chloride extract is washed with 2N sodium hydroxide solution, dried with magnesium suflate, and then filtered and evaporated to give α-acetoxy-p-pivaloyl toluene.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:19]=1[O:27][CH2:28][C@@H:29]([C:38]([OH:40])=[O:39])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:34]([O:33][C:31]([NH:30][C@H:29]([C:38]([OH:40])=[O:39])[CH2:28][O:27][C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=[CH:23][C:18]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(Br)cccc1[N+](=O)[O-])C(=O)O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(-c2ccccc2)cccc1[N+](=O)[O-])C(=O)O
Temperature: 100 °C

Procedure:
331 mg of phenylboronic acid (2.72 mmol), 50.3 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (C35H30Cl4FeP2Pd, MW 816.65, 0.025 mmol) and 3.22 g of caesium carbonate (9.87 mmol) are introduced into a 100 mL round-bottomed flask, with stirring and under an argon atmosphere, containing 16 mL of water, 5 mL of dioxane and 1 g of 34 (2.47 mmol). The medium is heated at 100° C., with stirring, for 1 h. The dioxane is concentrated and the aqueous phase is acidified to pH 2-3, extracted twice with 50 ml of AcOEt. The combined organic phases are dried over MgSO4, filtered and evaporated to dryness. The crude product is chromatographed on a silica cartridge (150 g, eluent CH2Cl2/MeOH, in an MeOH gradient: 1 to 5%). 500 mg of expected product 35 (yellow oil) are recovered.
Reaction SMILES: Cl.C[O:3][C:4]1[C:15]2[CH2:14][CH:13]3[CH2:16][CH:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>>[CH:9]12[CH2:16][CH:13]([CH2:12][NH:11][CH2:10]1)[CH2:14][C:15]1[C:4]([OH:3])=[CH:5][CH:6]=[CH:7][C:8]2=1
Reactant: COc1cccc2c1CC1CNCC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2c1CC1CNCC2C1

Procedure:
6-Methoxy-11-aza-tricydo[7.3.1.02,7]trideca-2(7),3,5-triene hydrochloride (55 mg, 0.23 mmol) was brought to reflux in 48% aq. hydrobronic acid (HBr) (5 mL). After 1 hour the solution was cooled and poured into 1N aq. NaOH soln. adjusted to pH 10 and product was extracted with EtOAc (3×40 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to a white solid, which was recrystallized from EtOAc/hexanes (20 mg, 46%). 1H NMR (CDCl3) δ 6.95 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.53 (d=8.0 Hz, 1 H), 3.27 (m, 1H), 3.11 (m, 2H), 3.02 (m, 2H), 2.77 (m, 1 H), 2.57 (m, 1H), 2.33 (br s, 1H), 1.90 (m, 2H). mp 106-108° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:17]>>[C:1]([C:5]1[CH:6]=[C:7]([C:12]([NH2:11])=[O:13])[C:8](=[CH:14][CH:15]=1)[C:9]([NH2:17])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)NC2=O
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C(N)=O)c(C(N)=O)c1
Reaction time: 3 h

Procedure:
A 4 liter conical flask was then charged with 137.4 grams (0.6757 mole) of 4-t-butylphthalimide and 2 liters of 29 percent ammonium hydroxide solution and the solution was stirred vigorously with a mechanical stirrer. After 3 hours, the creamy suspension was suction filtered and washed with a small amount of water. The faint green powder was dried at 120° C. for one day to yield 134.19 grams of 4-t-butylphthalamide, which exhibited a melting point of 172° to 175° C. The identity of the 4-t-butyl-phthalamide product was confirmed by IR spectrum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH:31]2[CH2:30][CH2:29][CH:28]([C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[CH2:33][CH2:32]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNC2CCC(c3ccc(O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethylamine (EXAMPLE 2, Step D, 345 mg) and 4-(4-hydroxyphenyl)cyclohexanone (62 mg) were solvated in 8 mL dry methanol to which ca. 2 g powdered 3 Å molecular sieves were added. The pH of this mixture was adjusted to 6 by the addition of 0.65 mL of a 10% solution of trifluoroacetic acid in methanol and then 90 mg sodium cyanoborohydride was added and the mixture stirred at room temperature. After 20 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel [(methylene chloride:methanol:, 92:8) then again (chloroform:methanol, 90:10) to separate the diastereomers] to give the title compound (isomer A 40 mg, isomer B 36 mg). m/e=439 (M+H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[CH2:27](O)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9]
Reactant: CCCCCCO
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2ccccn2)=C(C)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C1=C(C)NC(C)=C(c2ccccn2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
350 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid, 102 mg (1 mmol) of hexyl alcohol, 309 mg (1.4 mmol) of N,N'-dicyclohexylcarbodiimide, 134 mg (1.1 mmol) of 4-N,N-dimethylaminopyridine were dissolved in 10 ml of toluene, with application of heat thereto. This reaction mixture was refluxed with application of heat for 1 hour, and then cooled to room temperature. To this reaction mixture, 20 ml of chloroform was added. The reaction mixture was then washed with water and dried over anhydrous sodium sulfate. The solvents contained in the reaction mixture were then distilled of and the residue was chromatographed on a silica gel column, whereby the captioned compound was obtained. The yield was 389 mg (89.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:17]1(=[O:36])=[O:35])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)[CH2:25][CH2:24]2)=[C:18]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:17]1(=[O:36])=[O:35])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccc(F)c(F)c3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 24 %

Procedure:
The title compound was prepared as described for Example 105 from 3,4-difluorobenzoyl chloride and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.033 g, 24%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.48-7.42 (m, 3H), 7.22-7.14 (m, 2H), 7.10-7.04 (m, 1H), 5.23 (d, 1H), 4.40 (bs, 1H), 3.58 (bs, 1H), 3.22-3.12 (m, 1H), 2.58-2.46 (m, 2H), 1.80-1.60 (m, 11H), 1.42-1.14 (m, 2H); 13C NMR (125 MHz CDCl3): δ 168.3, 159.7, 152.6, 152.4, 151.6, 151.4, 150.6, 150.4, 149.6, 149.4, 133.9, 132.5, 131.8, 130.3, 129.0, 125.2, 123.7, 117.9, 117.8, 116.9, 116.8, 107.8, 61.9, 50.2, 46.0, 32.5, 27.8; Mass Spectrum: M−H+ 502.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Br:16])[CH:3]=1.[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[CH:31])=[CH:24][CH:23]=1>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][C:2]2[CH:7]=[C:6]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[C:4]([Br:16])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: Brc1cc(Br)cc(C#Cc2ccccc2)c1
Reactant: C#CCOc1ccc(OCC(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of 1,3-dibromo-5-phenylethynyl-benzene (0.1 g, 0.3 mmol, intermediate 3), (4-prop-2-ynyloxy-phenoxy)-acetic acid methyl ester (66 mg, 0.3 mmol), Pd(PPh3)2Cl2 (10 mg, 0.015 mmol), CuI (16 mg, 0.008 mmol) in dry DMF (1.5 ml) and triethylamine (1.5 ml) was heated in a microwave own for 10 min at 70° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography to give {4-[3-(3-bromo-5-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester in 27 mg (20%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc2c(C3=NCCN3)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc2c(-c3ncc[nH]3)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-yl)-4,5-dihydro-1H-imidazole (1.0 g, 2.61 mmol) in DMSO (40 mL) at room temperature was added Dess-Martin periodinane (2.213 g, 5.22 mmol), and the stirring was continued at rt overnight. The reaction mixture was diluted with water. The product was extracted into EtOAc (100 mL×3), and the combined EtOAc extracts were washed with 10% NaHCO3 (100 mL×2) and brine, dried over Na2SO4 and then concentrated. The crude product was recrystallized from EtOAc and petroleum ethers to obtain 2-(2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-yl)-1H-imidazole as a yellow solid. Yield: 800 mg (80%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.46 (br. s., 1H) 8.33 (s, 1H) 7.85-8.08 (m, 2H) 7.16-7.60 (m, 5H) 4.79 (d, J=5.95 Hz, 1H) 1.15-1.47 (m, 6H). LCMS: (ES+) m/z=382.24 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 μm); M phase A: 5 mM Ammonium Acetate:MeCN (95:5); M phase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[CH:49]=[CH:54][C:53]([CH3:55])=[CH:52][C:51]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: CC(=O)NCCc1ccc(C)cc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cc(C)ccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2-(2-hydroxy-4-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.55 (EtOAc); Rt=5.73.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23].CN(C)[CH:35]=[O:36]>O1CCCC1>[F:13][C:14]1[C:19]([CH:35]=[O:36])=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CN(C)C=O
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(F)cc2F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)c(C=O)c2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
To N,N-diisopropylamine (4.50 mL, 32.1 mmol) in 130 mL of tetrahydrofuran, n-butyllithium (12.8 mL, 2.50 M in hexane, 32.1 mmol) is added at −78° C. under nitrogen. After 15 minutes, N-(2,4-difluoro-phenyl)-4-ethyl-benzenesulfonamide (60, 4.344 g, 14.61 mmol) in 20 mL of tetrahydrofuran is added at −78° C. under nitrogen. After 30 minutes, N,N-dimethylformamide (2.83 mL, 36.5 mmol) is added and the reaction continued at −78° C. under nitrogen for 1 hour, then warmed to room temperature over 60 minutes. The reaction is quenched with 6 mL of 6 N aqueous hydrochloric acid. The aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with a gradient of 5-35% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (61, 2.634 g). MS (ESI) [M−H+]−=324.2.
Reaction SMILES: [CH2:1]([CH:3]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][CH3:9])[CH3:2].[CH2:21](Br)[C:22]#[CH:23]>>[CH2:23]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][CH3:9])=[CH:13][CH:14]=1)[C:22]#[CH:21]
Reactant: CCC(C)=CCCC(CC)Oc1ccc(C(=O)O)cc1
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OC(CC)CCC=C(C)CC)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1-ethyl-5-methyl-4-heptenyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(1-ethyl-5-methyl-4-heptenyl)oxy]benzoic acid propargyl ester; nD21 = 1.5200.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:23].Cl>C1C=CC=CC=1>[CH3:10][C:11]12[C:12](=[O:23])[CH:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:20]=31)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: BrCCCCCBr
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C1(C)CCCCCC(C2)C1=O
Reaction time: 12 h
Yield: 27 %

Procedure:
Oil-free sodium hydride (5.28 g.) in benzene (50 ml.) is added to a stirred mixture of 1,5-dibromopentane (184 g.) and 1-methyl- 7-methoxy-2-tetralone (32 g.) in dry benzene (300 ml.). Stirring is continued for 12 hours at 25° and at reflux for an additional 15 hours. The mixture is cooled, sodium hydride (5.8 g.) in 50 ml. benzene added, stirring continued at 25° /10 hours, and at reflux for 12 additional hours. After cooling excess base is neutralized with concentrated hydrochloric acid and the inorganic solids which precipitate are removed by filtration. Washing and filtrate with saline, drying over sodium sulfate, concentrating and vacuum distilling gives an oil (21 g.), b.p. 160°-190° C. (0.5 mm.) containing 6.5 g. (27%) of the title product by vapor phase chromotography (3% OVI, C200-225-250).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26]O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:76]=[N+:77]=[N-:78])=O)=CC=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCCC1>[N:76]([CH2:26][C@@H:18]1[C@H:19]2[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]2[C@H:16]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]4[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:3]=4[O:2][CH3:1])[C:8]=3[CH:15]=[CH:14]2)[O:17]1)=[N+:77]=[N-:78]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of ((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.83 g, 6.20 mmol) and triphenylphosphine (2.28 g, 8.68 mmol) in dry tetrahydrofuran (32 mL) was cooled at 0° C. in an ice/water bath. Diisopropyl azodicarboxylate (1.71 mL, 8.68 mmol) was added dropwise, followed by a solution of diphenylphosphonic azide (1.87 mL, 8.68 mmol) in tetrahydrofuran (5.3 mL, 66 mmol). Upon addition of the DPPA solution, a white milky precipitate formed. After about 30 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. After 24 h, HPLC indicated that all the starting material had been consumed. The reaction mixture was concentrated to about ½ the original volume and purified by flash chromatography (175 g silica gel, 10-55% EA/hept) to yield the title compound (2.49 g, 83%) as a slightly yellow stiff foam: MS (ESI+) for C23H27N7O5 m/z 482.2 (M+H)+; (ESI−) for C23H27N7O5 m/z 480.1 (M+H)−, m/z 526.1 (M+CO2H)−; HPLC purity 97% (ret. time, 3.64 min).