Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:18])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:18])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: O=C(c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F)c1c[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To N-{2-fluoro-3-[hydroxy-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-methyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (27, 141 mg, 0.30 mmol) in 2 mL of tetrahydrofuran, Dess-Martin periodane (141 mg, 0.33 mmol) and sodium bicarbonate (200 mg) were added. The reaction was stirred at room temperature for one hour, then poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 50%) ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-0009, 105 mg, 75%). MS (ESI) [M−H+]−=463.4.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.[C:10]1([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)C=[N:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:25]1([CH:16]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[NH:18][CH2:17]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1=NCC(c2ccccc2)c2ccccc21
Reactant: CCOC(=O)CC(=O)[O-]
Product: CCOC(=O)CC1NCC(c2ccccc2)c2ccccc21
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
A mixture of 8.6 g (0.06 mole) of monoethyl malonate and 10.0 g (0.048 mole) of 3,4-dihydro-4-phenylisoquinoline was stirred in a preheated oil bath at 120° C. for 45 min to give 14.0 g (98.7%) of ethyl 1,2,3,4-tetrahydro-4-phenyl-1-isoquinolineacetate as a pale yellow syrup. The ester was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH:22]([OH:24])[CH3:23])[N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32]>C(Cl)Cl.O1CCOCC1>[ClH:32].[ClH:32].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH:22]([OH:24])[CH3:23])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of tert-butyl 1′-benzyl-4-(1-hydroxyethyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (0.045 g, 0.11 mmol) in DCM (2 mL) was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to yield 1-(1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)ethanol dihydrochloride (0.047 g, 100%), which was used without further purification. LCMS (APCI+) m/z 323.2 [M+H]+; Rt=2.38 min
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:36](=[O:37])[C@H:32]([CH:33]([CH3:34])[CH3:35])[NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (1.0 g, 4.2 mmol) in CH2Cl2 (21 mL) was treated with Et3N (0.76 mL, 5.44 mmol), dl-N-(tert-butoxycarbonyl)valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (20 mL), and washed with 2 N NaOH solution (2×20 mL), brine (1×20 mL) and dried (MgSO4). Concentration and chromatography (SiO2, 3% CH3OH/CH2Cl2) afforded 1-(4-chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 60%) as a pale amber oil: ESI/MS m/e 438 (M++H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C1COCC1>[NH:1]1[C:9]2=[N+:8]([O-:18])[CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: C1CCOC1
Product: [O-][n+]1cccc2cc[nH]c21
Yield: 34 %

Procedure:
7-Azaindole (commercially available from Aldrich) (Intermediate C1) (31 mmol) in THF (70 mL) was reacted with MCPBA: 3-chloroperoxybenzoic acid (˜35 mmol) at rt for 18 h. The solvent was removed under reduced pressure and partitioned between 2N NaOH and ethyl acetate. The product was extracted multiple times with ethyl acetate and the layers were combined, dried over Na2SO4, filtered, and reduced under vacuum. The residue was purified by column chromatography on SiO2 6% NH3-MeOH in CH2Cl2 to yield 1H-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate C2) (34%) (see: Minakata, S. et. aL Synthesis 1992, 661. ). 1H-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate C2) (8.95 mmol) in THF (60 mL) was treated with hexamethyldisilazane (HMDS): (90 mmol) and a dropwise addition of benzoylchloride (22.5 mmol). The mixture was allowed to stir at rt for 1 h. The mixture was diluted with sat. NaHCO3 and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered and freed of solvent. The residue was purified by column chromatography (10% EtOAc:hexane) to give the product 6-chloro-pyrrolo[2,3-b]pyridin-1-yl-phenyl-methanone (Intermediate C3) as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.O[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1>O>[Cl:3][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: OCC1COc2ccccc2O1
Solvent: O
Solvent: c1ccncc1
Product: ClCC1COc2ccccc2O1

Procedure:
In a three neck flask fitted with a stirring device, 218 g thionyl chloride are mixed with 1000 g pyridine while cooling. They are added further, portionwise 500 g 2(hydroxy methyl) (2,3-dihydro [4H] 1,4-benzodioxin) while keeping the inner temperature below 20°. When the reaction is completed, the mixture is heated at 100° for 3 hours then poured into water and extracted with chloroform. The solvent is distilled off and the raw residue is purified by fractional distillation under reduced pressure. 340 g of the chloromethylated derivative are obtained. It boils at 85°-90°/0.2 mm Hg.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:9](/[CH:10]=[CH:11]/[C@@H:12]([OH:24])[CH2:13][C@@H:14]([OH:23])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:7]=[C:6]([N:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:33])[N:5]=1)[CH3:3].[OH-].[Na+].[Na].Cl>C1COCC1.O>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([N:32]([S:34]([CH3:37])(=[O:35])=[O:36])[CH3:33])[N:7]=[C:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:9]=1/[CH:10]=[CH:11]/[C@@H:12]([OH:24])[CH2:13][C@@H:14]([OH:23])[CH2:15][C:16]([OH:18])=[O:17])[CH3:1]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Temperature: 30 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
Rosuvastatin tert-butyl ester (27.0 g, 50.2 mmol) is dissolved in 225 mL of a 4:1 mixture of THF/water. The clear solution is warmed to 30° C. and 8.0 M NaOH (6.75 mL, 54.0 mmol) is added portionwise. The reaction mixture is stirred at 30° C. for 2 hours giving a clear yellow solution. Then THF is removed completely under the reduced pressure (20 mbar) at 40° C. The remaining aqueous solution is diluted with water to 225 mL and washed with AcOEt (3×90 mL). To a vigorously stirring solution of sodium rosuvastatinate is added dropwise HCl 37% (4.2 mL, 50.2 mmol) at ambient temperature. The obtained white emulsion of a free acid is extracted with AcOEt (150 mL). After separation from the organic layer aqueous phase is additionaly extracted with AcOEt (2×50 mL). Organic layers are combined and washed with water (3×30 mL). Then AcOEt is removed under reduced pressure (20 mbar) at 40° C. The residue is dissolved in a minimal amount of acetonitrile (MeCN) and the solvent is rapidly evaporated under reduced pressure (20 mbar) at 40° C. to give 25.48 g of the solid residue of free rosuvastatin acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1Cl
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of 3,5-dichloro-4-hydroxybenzaldehyde (302 mg, 1.6 mmol) in acetone (15 mL) was added cesium carbonate (700 mg, 2.15 mmol), followed by ethyl bromoacetate (0.27 mL, 2.43 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 ml, of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 264 mg of an oil (59% yield). 1H NMR (500 MHz, CDCl3): δ 1.29 (t, J=7.2 Hz, 3H), 4.26 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.96 (s, 2H), 9.98 (s, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.0, 62.3, 70.8, 131.2, 131.4, 135.4, 156.4, 168.4, 190.5.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:18])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.9 %

Procedure:
Propanephosphonic acid cyclic anhydride (3.74 mL, 6.40 mmol) was added to a solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (500 mg, 2.134 mmol), tert-butyl 4-(methylamino)piperidine-1-carboxylate (457 mg, 2.134 mmol) and triethylamine (1.19 mL, 8.54 mmol) in dichloromethane (20 mL). The mixture was stirred at ambient temp for 3.5 hours and then concentrated under reduced pressure. The crude material was purified by silica chromatography (eluting with a solvent gradient from 2.5% methanol/97.5% dichloromethane to 5% methanol/95% dichloromethane) to afford the title compound (440 mg). MS (ESI) m/z 431.5 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26]>N1C=CC=CC=1>[CH2:30]=[CH:29][CH2:28][O:27][C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:26]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
A mixture of 4.0 gm (12.6 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 2.7 mL (25.2 mMol) allyl chloroformate in 200 mL pyridine was heated at 50° C. for 5 hours. At this point an additional 2 mL of allyl chloroformate were added and heating was continued for another 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue partitioned between 1N sodium hydroxide and chloroform. The phases were separated and the aqueous phase was extracted well with chloroform. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. This residue was dissolved in 2M ammonia in methanol for two hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with dichloromethane containing from 2-5% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 2.9 gm (60%) 5-(N-[prop-1-en-3-yloxycarbonyl]amino)-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][O:46][CH:47]1[CH2:50][NH:49][CH2:48]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:49]2[CH2:50][CH:47]([O:46][CH3:45])[CH2:48]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: COC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)C1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), 3-methoxy-azetidine (57 mg, 0.57 mmol) and DIPEA (0.27 mL, 1.5 mmol) in DMF (2 mL). MS (LC-MS): 373.0 [M]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[Cl:23]N1C(=O)CCC1=O.[OH-].[Na+]>CC(O)=O.O.CCOCC>[Cl:23][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:21][CH3:22])=[CH:4][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(C)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)C1CCN(c2cc(OC)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A sample of ethyl 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)propanoate (130 mg, 0.359 mmol) was suspended in glacial AcOH (4 mL) and water (0.5 mL). The resultant solution was treated with N-chlorosuccinimide (62.3 mg, 0.467 mmol) and then stirred at RT overnight. After this time, the mixture was diluted with water (10 mL) and Et2O (25 mL) and the pH was adjusted to pH 9 using 6 M NaOH (aq). The phases were separated and the aqueous phase was extracted with Et2O. The extracts were combined, washed with brine, dried (MgSO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using a 12 g silica gel cartridge and gradient elution from 10:1 Hex/EtOAc to 5:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give ethyl 2-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)propanoate (80 mg, 0.222 mmol, 62% yield) as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 7.32 (1 H, s), 6.58 (1 H, s), 4.15 (2 H, qd, J=7.06, 1.92 Hz), 3.87 (3 H, s), 3.34-3.41 (2 H, m), 2.60 (2 H, t, J=11.55 Hz), 2.33 (1 H, dt, J=14.30, 7.15 Hz), 1.81 (1 H, dt, J=12.92, 2.61 Hz), 1.65-1.73 (2 H, m), 1.44-1.62 (2 H, m), 1.27 (3 H, t, J=7.15 Hz), 1.16 (3 H, d, J=7.15 Hz). LC-MS: 360, [M+H]; tR=4.28 min (method b).
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:29])[CH2:9][CH2:10][C@@H:11]([CH2:27][OH:28])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH:1]1([O:7][C:8](=[O:29])[CH2:9][CH2:10][C@@H:11]([CH2:27][O:28][S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[N:14]2[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H](CO)CCC(=O)OC2CCCCC2)COC1(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC2CCCCC2)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 97.8 %

Procedure:
The (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (4.97 g, 12.0 mmol, 1.0 equiv), DMAP (1.47 mg, 12.0 mmol, 1.0 equiv) and tosyl chloride (9.2 g, 48.2 mmol, 4.0 equiv) were dissolved in pyridine (100 mL) and the solution stirred for 18 hr. The pyridine was removed in vacuo and the residue taken up in EtOAc/0.5 M HCl. The layers were separated, and the organic layer washed with 10% K2CO3, brine, dried over Na2SO4, filtered and evaporated. The tosylate was purified by flash chromatography on silica, (12 g), eluting with 0-29% EtOAc in hexanes. This afforded 6.66 g (98% yield) of (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate as a white solid. MS ESI +ve m/z 590 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15]O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:31]([CH2:15][C:11]1[CH:12]=[N:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:32]=[N-:33]
Reactant: OCc1cncc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
To a stirring solution of 250 mg (1.17 mmol) of (5-(benzyloxy)pyridin-3-yl)methanol in 8 mL of toluene was added 310 μL (1.44 mmol) of DPPA. The mixture was cooled to 0° C. and 210 μL (1.44 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene] (DBU) was added. The ice bath was removed, and stirring was continued with wanning to room temperature. After about 20 h, the solution was diluted with EtOAc, and 1N HCl was added to a pH between 7 and 8. The organic layer was washed with water (2×15 mL) and brine (15 mL) and dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (56-60% EtOAc/hexanes) to give 181 mg (65% yield) of the azide as a colorless oil.
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[N:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH3:23])=[CH:3][CH:2]=1>CO>[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:22]([C:8]1[N:7]([C:4]2[CH:3]=[CH:2][C:1]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:6][CH:5]=2)[CH:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:23]
Reactant: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN(Cc2ccccc2)Cc2ccccc2)N1c1ccc(-c2ccccc2)cc1
Solvent: CO
Product: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN)N1c1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 42 %

Procedure:
To a solution of 3-(4-biphenylyl)-2-[N-(5-dibenzylaminopentyl)-N-methylamino]-4-methoxycarbonylmethyl-3,4-dihydroquinazoline (19) (362 mg, 0.556 mmol) in methanol (20 ml) was added 10% Pd(C) (883 mg), and the reaction mixture was stirred under hydrogen atmosphere for 24 hours. After the reaction was completed, the resulting reaction mixture was filtered with celite, extracted with dichloromethane three times and washed with a saline solution. The combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: dichloromethane:methanol:ammonia water=100:9:1) to give the target compound as a yellow liquid (110 mg, 42%).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:39](=[O:41])[CH3:40])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=3[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:39]([C:9]1[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=2[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:42])=[O:2])[CH:15]=[CH:14]2)(=[O:41])[CH3:40]
Reactant: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)O)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 88.8 %

Procedure:
A solution of 1.8 g of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester and 31 ml of 1N sodium hydroxide in 60 ml of methanol was stirred at reflux for 1 hour. The methanol was removed in vacuo and the aqeuous solution was acidified to pH 3. The gummy precipitate was extracted with methylene chloride, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil which was triturated with ether to yield 1.56 g, m.p. 110°-111° C. (89%) of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([O-])=O.[Na+].S(O)(O)(=O)=O.[NH2:21]O.[Cl-].[Na+]>O.C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:21]
Reactant: COc1ccc(C=O)cc1O
Reactant: NO
Agent: O=C[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: O=CO
Product: COc1ccc(C#N)cc1O
Temperature: 85 °C
Yield: 138.4 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (36.7 kg) and sodium formate (30.6 kg) were added to formic acid (96%, 204 kg) and the resultant mixture was heated to approximately 85° C. Hydroxylamine sulphate (21.6 kg) was added in eight equal portions at 30 minute intervals and the mixture was heated to 85° C. for 5 hours. The resultant mixture was cooled to approximately 25° C. and added to a solution of sodium chloride (140 kg) in water (700 liters). The resultant solid was collected by filtration, washed with water and dried to give 3-hydroxy-4-methoxybenzonitrile (34 kg, 94%; Chemical Abstracts Registry Number 5280546-6).