Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[CH3:3][C:4](=[N:9][OH:10])[C:5](=[O:8])[CH2:6][CH3:7].[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][N:9]=[C:4]([C:5](=[O:8])[CH2:6][CH3:7])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)C(C)=NO
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCC(=O)C(C)=NOC
Reaction time: 12 h

Procedure:
49.7 g (0.35 mol) of methyl iodide are added dropwise at room temperature to a solution of 40.2 g (0.55 mol) of pentane-2,3-dione 2-oxime and 52.0 g (0.38 mol) of potassium carbonate in 400 ml of acetone, and stirring is continued for 12 hours at this temperature.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][NH:9][C:10](=[O:33])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[CH2:22][CH2:21][CH:20]([CH2:19][C:15]2[CH:14]=[C:13]([CH2:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])=[O:33])[CH:18]=[CH:17][CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)CCc1cccc(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)CCc1cccc(CC2CCNCC2)c1

Procedure:
A solution of 11-8 (225 mg, 0.48 mmoles), TFA (2.5 mL), and CH2Cl2 (2.5 mL) was stirred at ambient temperature for 1.0 h. Concentration followed by flash chromatography (silica, 10:1:1 ethanol/H2O/NH4OH) gave 11-9 as a white solid. Rf 0.44 (silica, 10:1:1 ethanol/H2O/NH4OH).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1>[I-].[K+]>[OH:3][CH2:2][CH2:1][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCCCl
Agent: [I-]
Agent: [K+]
Product: O=C(O)c1ccc(OCCO)cc1

Procedure:
That is, as the reaction formula described below, ethylene chlorohydrin and 4-hydroxybenzoic acid are refluxed under heating in an aqueous alkali solution using potassium iodide as a catalyst to obtain 4-(2-hydroxyethoxy)benzoic acid, the product is then reacted with vinyl (meth)acrylate in THF (tetrahydrofuran) having added thereto lipase PS and a small amount of p-methoxyphenol to form 4-(2-propenoyloxyethoxybenzoic acid) (meth)acrylate, and by esterifying the (meth)acrylate thus obtained in methylene chloride with an isosorbide derivative in the presence of DCC (dicyclohexylcarbodiimide) and DMAP (dimethylaminopyridine), the desired product of the formula (b1) can be obtained.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:42])[C:40]=1[F:41])/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]4[CH:31]=[C:30]([F:29])[C:40]([F:41])=[C:39]([F:42])[CH:38]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1cc(F)c(F)c(F)c1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2cc(F)c(F)c(F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3,4,5-trifluorocinnamic acid, by the method of Example 1, step K, giving a yellow solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H33F3N4O2: 539 (M+H). Found: 539
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: C=C
Reactant: O=C(O)Cc1cccc(Br)c1
Product: O=C1CCc2ccc(Br)cc2C1

Procedure:
Scheme 3 illustrates a route to 7-substituted tetralin derivative 8. 3-Bromophenylacetic acid is converted to the corresponding acid chloride and this is subjected to Friedel-Crafts reaction with ethene, affording the 7-bromo-2-tetralone 7. This intermediate may be elaborated using the procedures described in Scheme 1 to provide the acid (8).
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(Cl)Cl.S(=O)(=O)(O)O>O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:17]1[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20])[CH2:8]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1C1C2CC3CC(C2)CC1C3

Procedure:
In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10% sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72%) with m.p. 140-141° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Reactant: CNC
Solvent: CCO
Product: CCCc1nc2nc(N(C)C)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensed dimethylamine (1 ml) at 0° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reaction was cooled and the mixture was concentrated in vacuo. The residue was partitioned between CHCl3 and water, and the organic was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.065 g, 64%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1>O1CCCC1.C(O)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccnc(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccnc(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred solution of 550 g (26.7 mmol) 2-(3,6-dihydro-2H-pyran-4-yl)-4-nitro-pyridine in 230 ml tetrahydrofuran and 5 ml glacial acetic acid was added 2.84 g of 10% palladium on charcoal and the mixture was then stirred for 16 h under an atmosphere of hydrogen at room temperature and 1.7 bar pressure. The mixture was then filtered, washing with methanol, and the filtrate concentrated in vacuo. Flash chromatography (methanol/dichloromethane/triethylamine 100/5/1) afforded 4.75 g (100%) 2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a light yellow oil. ES-MS m/e (%): 179 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][N+:15]([O-:17])=[O:16])[CH2:5][CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[N:26][CH:27]=2)[C:10]1=[N:14][N+:15]([O-:17])=[O:16])[CH2:5][CH3:6])[CH3:2]
Reactant: CCOC(CC)OCN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(CC)OCN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Yield: 20.8 %

Procedure:
15.0 g of 1-(1-ethoxy-1-propoxy)methyl-2-nitroiminoimidazolidine, 11.6 g of anhydrous potassium carbonate, 11.3 g of 2-chloro-5-chloromethylpyridine and 60 ml of dimethyl sulfoxide were agitated at 75° C. for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The resultant oily residue was purified by column chromatography [silica gel, eluant: hexane/ethyl acetate (1:2)] to give 4.7 g of 1-(1-ethoxy-1-propoxy)methyl-2-nitroimino-3-(2-chloropyridin-5-ylmethyl)imidazolidine.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]2=[O:20])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].Cl[CH2:28][N:29]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=2[CH:41]([CH3:43])[CH3:42])[S:30]1(=[O:32])=[O:31]>CN(C)C=O.O>[N:2]1([CH2:8][C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]=2[O:20][CH2:28][N:29]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=3[CH:41]([CH3:43])[CH3:42])[S:30]2(=[O:31])=[O:32])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: O=C1N=C2C=CC=CN2C(=O)C1CN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1nc3ccccn3c(=O)c1CN1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
A mixture of 3-(4-morpholinylmethyl)pyrido[1,2-a]pyrimidine-2,4-dione hydrochloride (0.6 g) and potassium t-butoxide (0.49 g) in dimethylformamide (20 mL) was stirred at room temperature for five minutes. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (0.61 g) was added and stirring was continued at room temperature for one hour. The reaction mixture was diluted with water (50 mL) and extracted with dichlormethane (3×200 mL). The dichloromethane extract was dried over sodium sulfate and stripped of volatiles, finally under high vacuum. The crude product (780 mg) was combined with that (0.65 g) from another run at the same scale using sodium hydride (60% dispersion in mineral oil, 0.19 g) instead of potassium t-butoxide and purified by column chromatography on silica gel with dichloromethane-methanol (95:5) as eluant affording 2-[3-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]oxymethyl-4-isopropyl-6-methoxysaccharin (500 mg, 23% yield), part of which was recrystallized from ethanol (m.r. 177°-180 ° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:28][CH2:27][CH2:26][O:25][CH3:24])[C:16]=2[N:17]=1
Reactant: COCCO
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COCCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
Potassium t-butoxide (4 mL, 4 mmol; 1 M in THF) was added to a suspension mixture of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1 g, 4 mmol) and 2-methoxyethanol (0.32 mL, 4 mmol) in DCM (50 mL). After stirring at room temperature for 10 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford the pure title compound as a beige solid (0.91 g, yield 90%) which was characterised as follows: MS (m/z) 225.0 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.Cl.[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:18]3[CH2:17]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:13].[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH:31][S:10]([C:8]2[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=2)(=[O:12])=[O:11])[CH:18]3[CH2:17]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Reactant: NCCCN1CCc2cccc3c2C1CC3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCc2cccc3c2C1CC3)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
2,3-Dihydro-benzofuran-5-sulfonyl chloride (24.05 mg, 0.11 mmol) was added to a solution of 3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propylamine dihydro-chloride (28.92 mg, 0.1, mmol) and N,N′-diisopropylethylamine (51.7 mg, 0.4 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (33 mg, 77%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[F:12][C:13]1[C:27]([F:28])=[CH:26][C:25](F)=[C:24]([N+:30]([O-:32])=[O:31])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].O>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:14]([C:13]([F:12])=[C:27]([F:28])[CH:26]=1)[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])[CH3:2]
Reactant: CCOC(CO)OCC
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-])OCC
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
For large scale synthesis, 2,2-diethoxyethanol was added dropwise into a suspension of 60% sodium hydride in 5 L of THF at 1-2° C. over 30 minutes and then stirred at 0-5° C. for 1.5 hours. A solution of 750 g of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline in 2.25 L of THF was then added dropwise into the above suspension at 0-5° C. After the addition, the purple solution was stirred at room temperature for 2 days and 17 hours. HPLC analysis showed 4.1% remaining of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline. 150 mL of water was added very slowly (gas generated) into the pre-cooled solution at 10° C. The solution was then concentrated to dryness. The resultant oil was then suspended in 5 L of heptanes and seeded with pure 3-(2,2-diethoxyethoxy)-5,6-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline crystal and stirred for 30 minutes. After 1 hour of stirring, the precipitate was filtered and dried to yield 520 g (54.3%) of product with 96.4% purity. Further product was available in the mother liquor. 1H NMR (CDCl3, 400 MHz): δ 7.42 (dd, 1H), 7.34 (d, 1H), 6.87 (bs, 1H), 6.56-6.67 (m, 2H), 4.79 (t, 1H), 4.06 (d, 2H), 3.74-3.82 (m, 2H), 3.59-3.66 (m, 2H); 1.24 (t, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([Si:42]([C:47]#[CH:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41]>CN(C=O)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>[CH2:43]([Si:42]([C:40]#[C:41][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1)([CH2:47][CH3:48])[CH2:45][CH3:46])[CH3:44]
Reactant: C#C[Si](CC)(CC)CC
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cncnc1C#C[Si](CC)(CC)CC
Temperature: 120 °C
Yield: 94 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-chloropyrimidin-5-yl)acetate (I108) (0.823 g, 4.10 mmol) in dry DMF (15 mL) were added triethylamine (1.715 mL, 12.31 mmol) followed by triphenylphosphine (0.124 g, 0.473 mmol), trans-dichlorobis(triphenyl-phosphine)palladium(II) (0.144 g, 0.205 mmol), Cu(I)I (0.078 g, 0.410 mmol) and finally (triethylsilyl)acetylene (1.470 mL, 8.204 mmol). The reaction mixture was then heated under microwave irradiation at 120° C. for 25 minutes, concentrated in vacuo and purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I109) (1.176 g, 94% yield) as a yellow-orange oil; 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.68 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.10-1.01 (m, 9H), 0.77-0.67 (m, 6H) LCMS Method C: rt 6.64 min; m/z 305.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:37]C(OC(C)(C)C)=O)[CH2:26][O:27][C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=3[I:36])[C:31]#[N:32])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC(C)C)C(C)C.[C:56]1([S:62](Cl)(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(OCC)(=O)C>Cl.O1CCOCC1>[C:56]1([S:62]([NH:37][C@@H:25]([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[CH:23][CH:22]=2)[CH2:26][O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[I:36])[C:31]#[N:32])(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cc(C#N)ccc1I)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: CCN(CC(C)C)CC(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(I)c(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 g (2.7 mmol) of 3-[(2S)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]-2-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at room temperature overnight. The solvent was distilled off, and the residue was dissolved in dimethylformamide. 1 ml (6 mmol) of N,N-diisobutylethylamine and 0.34 ml (2.7 mmol) of benzenesulfonyl chloride were added to the solution under cooling with ice, and they were stirred for 2 hours. After the isolation process with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: NC12CC3CC(CC(N[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])(C3)C1)C2.Cl.[CH3:23][O:24][C:25]([C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][C:29]([NH2:37])([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:26].CC1N=C(C(O)=O)C=CC=1>>[CH3:23][O:24][C:25]([C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][C:29]([NH:37][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:26]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Agent: Cc1cccc(C(=O)O)n1
Agent: Cl
Product: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(C)n4)(C3)C1)C2
Yield: 75 %

Procedure:
Intermediate 1 was also made via the same synthetic procedures for Intermediate 2 (see below). Starting from 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (14.9 g, 60.8 mmol), coupling with 6-methyl-pyridine-2-carboxylic acid afforded 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester (14.9 g, 75%). The methyl ester was then hydrolyzed to give 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (12.2 g, 86%). Finally, the Curtius rearrangement of 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (10.0 g, 31.8 mmol) yielded Intermediate 1 (8.48 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[C:13](=[O:16])([O-])[OH:14].[Na+]>O1CCCC1.O.ClC(OCC1C=CC=CC=1)=O>[CH2:6]([O:14][C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12])=[O:16])[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C([O-])O
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 154.3 %

Procedure:
Methyl 4-amino-3-chlorobenzoate (5.65 g; synthesized in accordance with Synthesis, 1985, 669) was dissolved in tetrahydrofuran (112 ml) and admixed with a solution of sodium hydrogen carbonate (7.67 g) in water (84.8 ml) and benzyl chloroformate (39.1 ml) and the mixture was stirred under a nitrogen atmosphere at room temperature for 22.5 hours. The reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was washed three times with water and then twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and then the solvent was distilled off under reduced pressure, and then the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:7). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (7.51 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[F:9][C:6]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]2[C:5]=1[CH:19]=[CH:14][CH:15]=[N:4]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1cc(F)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: Fc1ccc(Cl)c2ncccc12
Temperature: 140 °C
Yield: 59.3 %

Procedure:
To a mixture of (5.0 g) 2-chloro-5-fluoroaniline (commercially available, 6.0 g), glycerol (6.0 g) and m-nitrobenzene sulfonic acid sodium salt (11.0 g), was added 20 ml of 70% sulfuric acid dropwise. The reaction temperature was raised to 140° C. for 2 hr. The mixture was then cooled, poured on ice water and filtered through celite. The filtrate was neutralized with NaOH and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2 to give 3.7 g of the desired product of a yellow solid; MP=74-76° C.; MS (ES) m/z (relative intensity): 182 (M+H)+ (100).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11]O>Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: COC(=O)CCC(=O)CN
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 500 ml glass reactor containing 200 ml methanol, was added 1 g 5-amino-levulinic acid hydrochloride and 1 drop conc. HCl. The reaction mixture was then stirred overnight at 60° C. The progress of the esterification was followed by 1H-NMR. Excess methanol was removed by distillation, and the product further dried under vacuum at 30–40° C., giving methyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.