Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[I:21]
Reactant: [I-]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
An alternative synthetic procedure is as follows. 75 g (435 mmol) of 2-chloro-5-nitroaniline was added to a solution of water (600 mL) and conc. sulfuric acid (60 mL) in a 3 L 3-neck flask equipped for mechanical stirring. The solution was cooled to 0° C. and a solution of sodium nitrite (34.2 g, 496 mmol) in water (130 mL) was added slowly. The mixture was stirred for ½ hr. and then a solution of potassium iodide (130 g, 783 mmol) in water (520 mL) was added dropwise over ½ hr keeping the temperature below 15° C. The solution was stirred for 2 hr, then extracted with EtOAc (3×500 mL). The combined organic extracts were washed with sat. Na2S2O3 (2×500 mL), dried (Na2SO4), and concentrated. The crude iodide was dissolved in hot iPrOH (500 mL) and hexanes (200 mL) were added. The reaction was allowed to cool with stirring and the product was collected by suction filtration after stirring at 0° C. for 2 hr yielding 90 g (318 mmol, 73%) 2-chloro-5-nitro-iodobenzene as a light tan crystalline solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[NH:11][C:10]1=[O:22])([CH3:8])[CH3:7])(=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br.[OH-].[Na+]>CN(C)C=O.CO.O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:11]1[C:12]2[C:13](=[N:14][CH:15]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:17]=2)[N:9]([C:6]([CH3:8])([CH3:7])[CH2:5][OH:4])[C:10]1=[O:22]
Reactant: CC(=O)OCC(C)(C)n1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Reactant: COc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n(C(C)(C)CO)c3ncc(C(F)(F)F)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a solution of 3-(2-acetoxy-1,1-dimethylethyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (150 mg) in anhydrous N,N-dimethylformamide (1.5 mL) was added portionwise sodium hydride (20.8 mg, 60% dispersion in mineral oil) at 5° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. After adding 3-chloro-4-methoxybenzylbromide (117 mg), the mixture was stirred at room temperature for 4 hours. After adding tetrahydrofuran (2 mL), methanol (1 mL) and 1N-sodium hydroxide solution (1 mL), the mixture was refluxed for an hour. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with water, 1N-hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was washed with diethyl ether to give 1-(3-chloro-4-methoxybenzyl)-3-(1,1-dimethyl-2-hydroxyethyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (161.6 mg) as an orange solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>C(O)(=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[F:16]
Reactant: Nc1ccccc1F
Reactant: O=[N+]([O-])c1cnc2ccc(F)cc2c1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(F)cc2c1Nc1ccccc1F

Procedure:
0.4 g (1.8 mmol) of 4-chloro-6-fluoro-3-nitro-quinoline (Example 19c) and 0.17 ml (1.98 mmol) 2-fluoroaniline in 5 ml acetic acid are stirred overnight at rt. Crystals are formed. The mixture is poured into water, the solid material is filtered off and washed with water. The residue is dissolved in CH2Cl2 and washed twice with water. The organic phase is dried over MgSO4 and most of the solvent is evaporated. The title compound is obtained from this solution as yellow crystals by adding hexane. The compound is filtered off, washed with hexane and dried (70° C., high-vacuum). mp: 161-162° C.; MS: 302 (M++1); HPLC: tret=10.24 min (Grad 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[CH:5][N:4]=1.O.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(OC)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(C(=O)O)cn1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A solution of methyl 2-methoxypyrimidine-5-carboxylate (944 mg) (Z. Budesinsky and J. Vavrina, Collect. Czech. Chem. Commun. 37 (1972)1721-1733) in dioxan (33 ml)/water (33 ml) was treated with 2N NaOH (3.37 ml), left overnight and evaporated to low volume. The residue was taken up in water (30 ml), the pH adjusted to 2 by addition of 2N HCl and the mixture extracted with EtOAc (4×30 ml). The EtOAc was dried and evaporated to give the title compound as a white solid (605 mg) 1HNMR δ(DMSO) 4.00(3H,s), 9.03(2H,s).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.Cl[CH2:19][O:20][CH2:21][CH3:22]>CC#N>[CH2:21]([O:20][CH2:19][N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]1=[O:8])[CH3:22]
Reactant: Oc1ncc(F)c(NCc2ccccc2F)n1
Reactant: CCOCCl
Solvent: CC#N
Product: CCOCn1cc(F)c(NCc2ccccc2F)nc1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A 25 mL screw-top vial was charged with 5-fluoro-4-(2-fluorobenzylamino)pyrimidin-2-ol (49.7 mg, 0.210 mmol), CH3CN (1 mL), and BSA (0.054 mL, 0.0221 mmol), and the mixture was agitated on an rotary shaker at 65° C. for 30 min. After cooling to room temperature, (chloromethoxy)ethane (0.022 mL, 0.237 mmol) was added, and the resulting mixture was agitated on a rotary shaker at room temperature for 16 h. The crude reaction mixture was concentrated in vacuo and was purified by normal phase chromatography (gradient, 0 to 25% MeOH/CH2Cl2) to afford 1-(ethoxymethyl)-5-fluoro-4-(2-fluorobenzylamino)-pyrimidin-2(1H)-one (55.0 mg, 89%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J=5.8 Hz, 1H), 8.05-7.95 (m, 1H), 7.40-7.26 (m, 2H), 7.26-7.10 (m, 2H), 5.01 (s, 2H), 4.59 (d, J=5.9 Hz, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.09 (dd, J=9.0, 5.0 Hz, 3H); ESIMS m/z 296 ([M+H]+), m/z 294 ([M−H]−).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCc1ccncc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
to a solution of 4-(aminomethyl)pyridine (12.9 ml, 127 mmol) and pyridine (51.4 ml, 636 mmol) in 150 mL dichloromethane cooled by an ice bath was added 4-nitrobenzoyl chloride (24.8 g, 133 mmol) all at once, generating a dark red reaction solution. LC-MS at 5 minutes indicated reaction complete and the desired product predominated. The reaction was stirred at room temperature overnight then the solid collected by filtration. LC-MS indicated that the filtrate was desired product. The solid was washed with 5% aqueous sodium hydroxide solution until aqueous layer was alkaline then the solid collected by filtration. The solid was dried overnight in a vacuum dessicator over P2O5 (28.4 g, 87%). ESI+ m/z=258.1 [MH]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24].[Cl:26]C1SC(S(/N=C2\C=C(Cl)C(=O)C3C\2=CC=CC=3)(=O)=O)=CC=1>>[Cl:26][C:18]1[S:17][C:16]([S:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([OH:1])=[C:3]([S:21][CH2:22][C:23]([OH:25])=[O:24])[CH:4]=2)(=[O:15])=[O:14])=[CH:20][CH:19]=1
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Product: O=C(O)CSc1cc(NS(=O)(=O)c2ccc(Cl)s2)c2ccccc2c1O

Procedure:
5.2.57 2-(4-(5-chlorothiophene-2-sulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid (14o) was prepared according to the procedure of procedure B for 10a except using (E)-5-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (12d), which afforded the title compound 32.4 mg (54%) as a white solid, m.p.: 143-145° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[C:14]([O:24][CH3:25])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:27][NH:28][CH3:29]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:28]([CH3:29])[CH3:27])=[C:14]([O:24][CH3:25])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCl
Reactant: CNC
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCN(C)C

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(4-chlorobutoxy)-3-methoxycinnamamide (Example 133), 100 ml of methylisobutylketone, and 150 ml of 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 2.01 g of N-(trans-4-methylcyclohexyl)-4-(4-dimethylaminobutoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as light-greenish white crystal, which had the following physiochemical properties:
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[N:15]=2)=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[N:15]=2)=[CH:11][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(Nc2ccnc(Nc3cc(OC)c(OC)c(OC)c3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Nc2nccc(Nc3ccc(CC(=O)O)cc3)n2)cc(OC)c1OC
Yield: 38 %

Procedure:
The compound of Example 103 (250 mg, 0.57 mmol) in a solution of ethanol (10 ml) containing 6N aqueous NaOH (2.0 ml) was heated a reflux for 2 h. On cooling the ethanol was removed under reduced pressure and the basic solution brought to pH 5 with 2M hydrochloric acid. The resulting solution was concentrated under reduced pressure, and the residue taken up in hot ethanol (20 ml). This solution was filtered and the filtrate evaporated under reduced pressure to give a residue which was crystalised from ethanol to give the title compound (89 mg) as a white solid m.p. 144-150°. MS m/z 411 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.O>[CH3:10][C:9](=[CH2:11])[C:8](=[N:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:12][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)C(=O)Nc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)C(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 1.0 g (6.20 mmol) of N-phenylmethacrylamide in 4 ml of toluene was added 1.30 g (6.24 mmol) of phosphorus pentachloride and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of DMF and then cooled to 0° C. To a solution of 1.17 g (12.4 mmol) of phenol in 5 ml of DMF was added 546 mg (13.6 mmol) of sodium hydride (60% in oil) under ice cooling and stirred for 5 minutes. The mixture was added portionwise to the above-described DMF solution of the residue under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was poured into water wad extracted with tert-butyl methyl ether (twice). The combined organic layer was washed sequentially with water and saturated NaCl, dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 1.28 g of phenyl 2-methyl-N-phenyl-2-propenimidate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]([CH3:15])[CH3:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[N:24][C:25]([O:27][Si](C)(C)C)=[CH2:26])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([CH:13]([CH3:14])[CH3:15])[CH2:27][C:25](=[O:26])[NH:24][CH:23]3[C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)/C=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 56.4 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-chloro-3-isobutylidene-1,3-dihydro-indol-2-one (0.25 g, 1.1 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (1.2 g, 4.7 mmol) prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[N:14]1[CH:19]=[CH:18][C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(-c2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a vial containing methyl 1H-indole-3-carboxylate (402 mg, 2.297 mmol), pyridin-4-ylboronic acid (847 mg, 6.89 mmol), copper (II) acetate (542 mg, 2.99 mmol), 4 {acute over (Å)} molecular sieves (4 g) and 1,10-phenanthroline (828 mg, 4.59 mmol) were added DCM (9 ml) and triethylamine (0.320 ml, 2.297 mmol). The mixture was stirred at RT for 4 days then filtered through a pad of Celite (washed with MeOH). Evaporation and purification by HPLC (after dilution with DMF and filtration) afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Cl)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26][O-:27].[Na+]>C1COCC1.CO>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13](=[O:14])[CH2:15][O:27][CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
2.5 ml of a solution of 0.879 mg (2.66 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in 2.5 ml of THF was added dropwise to a suspension of 160 mg of sodium hydride (60% oily) in 5 ml of THF at 0° C. and they were stirred for 30 minutes. 820 μl of 28% solution of sodium methoxide in methanol was added to the obtained mixture. After stirring overnight, methanol was added to the reaction mixture, and the obtained mixture was concentrated and fractionated with ethyl acetate and water. After the drying over sodium sulfate followed by the purification by the silica gel chromatography (hexane/ethyl acetate=3/1), the title compound was obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH3:23]O>>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:23])=[O:16])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCc1nccc2ccc(C(=O)O)cc12
Agent: O=S(=O)(O)O
Product: CCCCc1nccc2ccc(C(=O)OC)cc12

Procedure:
A solution of 1-butylisoquinoline-7-carboxylic acid (325 mg, 1.41 mmol) in methanol (25 mL) containing concentrated sulfuric acid (800 μL) was refluxed overnight. The reaction mixture was then concentrated under reduced pressure, diluted with methylene chloride, washed with water, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated to yield methyl 1-butylisoquinoline-7-carboxylate (350 mg): ESI MS m/z 244 [M+H]+;
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH2:39][CH2:40][C:41](O)=[O:42])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH2:39][CH2:40][C:41]([N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:42])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)CCc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Yield: 77.7 %

Procedure:
Condensation between 4-(4-fluorobenzoyl) piperidine.hydrochloride (682 mg) and 3-(2,4-dibenzyloxyphenyl)propionic acid (1.04 g) is carried out in the same manner as in Example 1, (i) to yield 1-[3-(2,4-dibenzyloxyphenyl)propionyl]-4-(4-fluorobenzoyl)piperidine (1.20 g) in the colorless columnar crystal form.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][N:25]([O:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[S:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)(=[O:13])=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
A mixture of 1,4-benzodioxan-6-sulfonyl chloride (Eur. Pat. Appl. 583960, 23 Feb. 1994; 60 mg; 0.253 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,4-benzodioxan-6-sulfonyl chloride (12 mg, 0.051 mmol) was added and the reaction was heated for an additional 30 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate (125 mg, 86%) as a white solid. H1-NMR (chloroform-D3): 1.20 (m, 6H), 1.60 (m, 5H), 2.07 (m, 2H), 2.90 (m, 4H), 3.09 (b, 1H), 3.67 (m, 2H), 3.90 (m, 4H), 4.23 (m, 1H), 4.31 (m, 4H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.95 (d, 1H) 7.25 (m, 7H). MS(ESI): 655(M+Na).
Reaction SMILES: Cl[C:2]1[C:3](=[O:12])[N:4]([CH2:9][O:10][CH3:11])[N:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O-:14].[Na+]>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[N:5][N:4]([CH2:9][O:10][CH3:11])[C:3](=[O:12])[C:2]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: COCn1ncc(Cl)c(Cl)c1=O
Agent: [Na+]
Solvent: C1COCCO1
Product: COCn1ncc(Cl)c(OC)c1=O
Reaction time: 19 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4,5-dichloro-2-methoxymethyl-2H-pyridazin-3one (1.00 g, 4.78 mmol) in 1,4-dioxane (25 mL) at room temperature was added sodium methoxide (271 mg, 5.02 mmol). After 19 h, the reaction was added additional 271 mg of sodium methoxide and was continued to stir for 6 h. The reaction was filtered and the filtrate was concentrated to give 915 mg (93% crude) 5-chloro-4-methoxy-2-methoxymethyl-2H-pyridazin-3-one.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[C:1]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
Acetyl chloride (3.95 ml) was added dropwise to a stirred solution of 4-amino1-benzylpiperidine (10.0 g) and triethylamine (7.7 ml) in dry dichloromethane (100 ml) at 4° C. The mixture was allowed to reach ambient temperature and stirred for 16 hours. Water was then added, the organic phase separated and dried (MgSO4), and removal of the solvent by evaporation gave 4-acetylamino-1-benzylpiperidine, 10.23 g, as a light brown solid which was used without further purification: NMR (CDCl3) δ 7.29(5H,m), 5.29(1H,b), 3.79(1H,m), 3.49(2H,s), 2.80(2H,dm), 2.12(2H,dt), 1.95(3H,s), 191(2H,dm), 1.46(2H,dq); m/e 233 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([F:25])[C:13]=1[CH3:26].CO>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[C:14]([F:25])[C:13]=2[CH3:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Yield: 103.8 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-3-fluoro-5-(3-fluorophenyl)-2-methyl-benzamide (0.9 g, 2.4 mmol, 1.0 eq) in THF (20 mL) under N2 was added a solution of BH3 (1 M in THF, 11.9 mL, 11.9 mmol, 5.0 eq). The reaction mixture was heated at reflux overnight. Methanol was added to quench the reaction and the solution was then concentrated in vacuo to give the title compound (900 mg, 100%) which was used without further purification.