Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C1(C)C=CC=CC=1.[Br:13][C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[C:18]([CH3:20])[CH:19]=1.[CH2:23]([N:30]1[CH2:35][CH:34]=[C:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH2:23]([N:30]1[CH2:31][CH2:32][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH:34]([C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([Br:13])[CH:15]=2)[CH2:35]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: Cc1cc(Br)cc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1cc(C)cc(Br)c1
Temperature: -15 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A 2.5 M THF/toluene solution of (3-bromo-5-methylphenyl)magnesium bromide (40 mL, 99 mmol) was cooled to −15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (9.85 g, 42.6 mmol) in benzene (17.5 mL) was slowly added for 3 h at −15° C. The reaction mixture was stirred additional 2 h at −15° C. and warmed to 20° C. The reaction was quenched by addition of saturated NH4Cl aqueous solution followed by extraction with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give methyl 1-benzyl-3-(3-bromo5-methyl-phenyl)piperidine-4-carboxylate (12.2 g, 30.3 mmol).
Reaction SMILES: [CH2:1]([N:3]([CH2:17]C)[C:4]([NH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5])C.CN(C)C(Cl)=O>>[CH3:1][N:3]([CH3:17])[C:4]([NH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CCN(CC)C(=O)NC1CCCc2ccccc21
Agent: CN(C)C(=O)Cl
Product: CN(C)C(=O)NC1CCCc2ccccc21

Procedure:
1,1-Diethyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea, melting point 86°C. to 87°C., is prepared by the above procedure by substituting diethylcarbamyl chloride for dimethylcarbamyl chloride.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S(O)(=O)=O)=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[N:10]1([CH:1]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[C:2]([CH3:7])([CH3:3])[CH2:29][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1
Reactant: NC(=O)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccc2[nH]nnc2c1
Solvent: Cc1ccccc1C
Product: CC(C)(Cc1ccccc1)C(NC(=O)c1cccnc1)n1nnc2ccccc21

Procedure:
The product from Example 18A, nicotinamide, benzotriazole, and p-toluenesulfonic acid in xylene were processed as described in Example 18B to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[CH:5][C:6]=1[CH2:7][OH:8].CCN(CC)CC.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl>[C:55]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:10]2)[S:3][C:2]=1[Cl:1])(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.5 %

Procedure:
To a solution of alcohol 35 (5.2 g, 7.75 mmol) in CH2Cl2 (50 mL) were added Et3N (3.5 mL, 23.3 mmol) and benzoyl chloride (1.2 mL, 10.1 mmol) at 0° C. The mixture was allowed to slowly warm to room temperature and stirred at room temperature for 15 hours. The mixture was washed with aq. saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the mixture of anomers of the title compound (6.1 g). The anomeric mixture of 36 was recrystallized with EtOH (50 mL). The precipitate was collected by filtration and washed with cold EtOH (30 mL) and dried under high vacuum to obtain β-anomer of the title compound 36 (4.64 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:19][C:20]1[CH:27]=[C:25]([I:26])[C:24]([O:28][C:29]2[CH:36]=[C:34]([I:35])[C:33]([OH:37])=[C:31]([I:32])[CH:30]=2)=[C:22]([I:23])[CH:21]=1)[NH:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][O:41][CH2:40]1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:19][C:20]1[CH:21]=[C:22]([I:23])[C:24]([O:28][C:29]2[CH:30]=[C:31]([I:32])[C:33]([OH:37])=[C:34]([I:35])[CH:36]=2)=[C:25]([I:26])[CH:27]=1)[NH:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:43](=[O:44])[CH2:42][O:41][CH2:40][C:39]([OH:46])=[O:45])[CH2:16][CH2:17]1)=[O:11]
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCNCC1
Reactant: O=C1COCC(=O)O1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCN(C(=O)COCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(Piperazinocarbonylmethoxyacetyl)thyroxine methyl ester from step 1 (3.1 g, 0.0034 mole) and diglycolic anhydride (0.6 g, 0.0046 mole) in chloroform (200 mL) were heated to 50°-60° C. (hot water) and allowed to stir at ambient temperature for 16 hours. Chloroform (200 mL) was added. The mixture was washed with 5% HCl solution (2×100 mL), water (100 mL), saturated NaCl solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed on a rotary evaporator in vacuo. This material was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([N:10]([CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)[C:11](=[O:23])[CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[CH2:4][C:3]1([CH3:36])[CH3:35].[H-].[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:32][N:27]1[C:26]([CH3:34])([CH3:33])[CH2:25][CH:24]([N:10]([CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:36])([CH3:35])[CH2:4]2)[C:11](=[O:23])[C:12]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([OH:15])=[O:14])[CH2:29][C:28]1([CH3:31])[CH3:30]
Reactant: BrCc1ccccc1
Reactant: CN1C(C)(C)CC(N(C(=O)C(Cc2ccccc2)C(=O)O)C2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CC(N(C(=O)C(Cc2ccccc2)(Cc2ccccc2)C(=O)O)C2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
With stirring, a solution of 20 g of benzylmalonic bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)-amide in 50 ml of toluene and 100 ml of dimethylformamide is added dropwise in the course of about 1/2 hour to a suspension of oil-free sodium hydride (0.97 g) in toluene (20 ml). After the addition of the amide, the reaction mixture is stirred for a further 20 hours at 60° C. until all the sodium hydride is reacted. A solution of 7.7 g of benzyl bromide in 10 ml of toluene is then added dropwise to the reaction mixture at room temperature in the course of 40 minutes, the temperature is raised to 70° C. and stirring is continued for 12 hours at this temperature. For working up, the reaction solution is filtered warm to remove precipitated sodium bromide, the residue is washed well with chloroform and the combined filtrates are freed as completely as possible from all solvents by rotary evaporation. The residue is dissolved in 400 ml of chloroform, the solution is extracted repeatedly with water, dried over sodium sulphate and the solvent removed in vacuo. The crystalline residue is recrystallised once in toluene and once in benzene, affording dibenzylmalonic bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)-amide with a melting point of 275°-277° C. (Stabiliser 4).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:25][C:17]=2[F:16])=[C:4]([F:9])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Reactant: Nc1ccc(Br)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (1.2 ml, 13.8 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84 mmol). After continuing stifling at rt for 15 mins, reaction mixture diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O>[Pd].O1CCOCC1>[CH3:24][C:20]1([CH3:25])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:27])[C:16]2[CH:15]=[C:14]([C:12](=[O:13])[CH2:11][O:10][C:8]3[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[CH:9]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C=O)c(O)c3)ccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
1 g (2.7 mmol) of 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethyloxy)benzaldehyde, 100 mg of palladium on charcoal (5%) and 50 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 3 bars, the catalyst is filtered off and the filtrate is evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of hexane and ethyl ether (70:30). After evaporation of the solvents, 600 mg of the expected product, melting point 144°-5° C., are collected.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (5.0 g, 43.0 mmol) in CH2Cl2 (40 mL) and pyridine (30 mL) was added 4-(dimethylamino)pyridine (0.26 g, 2.2 mmol) followed by p-toluenesulfonyl chloride (8.2 g, 43.0 mmol). The mixture was allowed to stir at ambient temperature for 16 hours then was quenched with 5% aqueous HCl (15 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (9.1 g, 33.7 mmol, 78% yield). MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.C(N(CC)CC)C.Cl>[Cl-].[Cl-].[Zn+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:6]1
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(C=O)c1OC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C2OC(=O)CC2C(=O)O)c1OC
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Into a flame-dried 3-neck flask, fitted with a condenser and addition funnel were placed 25.0 g (0.184 mol) of anhydrous, powdered ZnCl2. Then 100 mL of CH2Cl2 were added, followed by 15.3 g (0.092 mol) of 2,3-dimethoxybenzaldehyde and 13.8 g (0.138 mol) succinic anhydride. Triethylamine (25.6 mL, 0.184 mol) was added dropwise to the flask with rapid stirring and the reaction was heated at reflux for 4 days. The reaction was cooled to room temperature and poured over a mixture of ice and conc HCl. The mixture was extracted with EtOAc (3×250 mL), then washed with 2 N HCl (1×250 mL), and brine (1×250 mL). The product was extracted with saturated NaHCO3 (4×200 mL) until TLC indicated no product remaining in the organic layer. The aqueous layer was washed with CH2Cl2 (1×200 mL) and acidified with conc HCl. The white, milky solution was extracted with CH2Cl2 (3×250 mL), the organic extracts were dried over Na2SO4, and evaporated under vacuum to produce 18.0 g (0.068 mol, 73.6%) of pale yellow solid that was recrystallized from EtOAc/hexanes; mp 129-130° C. (lit.34 mp 132° C.). 1H NMR: (300 MHz, CDCl3): δ 7.01 (t, 1H, J=7.5 Hz, ArH); 6.89 (dd, 1H, J=8.1 Hz, J=2.5 Hz, ArH); 6.82 (dd, 1H, J=8.1 Hz, J=2.5 Hz, ArH); 5.73 (d, 1H, J=6.6 Hz, ArCH); 3.81 (s, 3H, ArOCH3); 3.80 (s, 3H, ArOCH3); 3.44 (dt, 1H, J=8.5 Hz, J=6.6 Hz, CHCOOH); 2.90 (d, 2H, J=8.5 Hz, COCH2). EIMS (M+)=266. Additional details are described in Stevens et al., “A New Synthetic Route to Furofuranoid Lignans Via the Intramolecular Mukaiyama Reaction,” J. Chem. Soc., Perkin Trans. 1, 185-190 (1992), the disclosure of which is incorporated herein by reference.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:31][OH:32])[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(Br)cc32)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(CO)cc32)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
A 2.5 M solution (16 ml) of n-butyllithium in hexane was added dropwise at ±78° C. into a solution of 1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-bromoindoline (10 g) in tetrahydrofuran (250 ml) over 5 mm. After 10 mm, dimethylformamide (3.0 ml) was added and the resultant mixture was allowed to warm to room temperature. Next, a saturated aqueous solution of ammonium chloride and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added ethanol (50 ml) and sodium borohydride (1.0 g) and the resultant mixture was stirred at room temperature for 30 mm. Then ice water and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (7.9 g) (yield: 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[CH:12]([NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1)[CH2:11][CH2:10]2)=O.C([OH:34])C.OO.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]1[NH:17][C:16](=[O:34])[C:15]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:30][CH:31]=4)[C:13]=3[CH:14]=2)[N:6]=1
Reactant: CCO
Reactant: COCC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of tert-butyl 4-[N-(5-methoxyacetamido-6-cyanoindan-1-yl)-amino]benzoate (0.295 g, 0.70 mmol), ethanol (3.2 ml), and water (0.64 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (0.60 ml) was added followed by granulated sodium hydroxide pellets (0.047 g, 1.19 mmol). The reaction mixture was stirred at ˜0° C. for 10 min then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 30 min. The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜15 ml). The pH of this mixture was adjusted to ˜12 with 1N NaOH (got a clear solution), then to ˜4 with 1N hydrochloric acid. The off white precipitate was collected by filtration, washed with water, dried in vacuo over P2O5: 0.262 g (89%), m.p. >122° C. (softens); 1H-NMR (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(CH3)3), 1.87, 2.56 (2×m, each 1H, 7-H), 3.00 (m, 2H, 8-H), 3.34 (s, 3H, OCH3), 4.30 (s, 2H, 2-CH2), 5.16 (m, 1H, 6-H), 6.78 (d, J=8.55 Hz, 2H, 3′, 5′-H), 6.89 (d, J=8.10, N10-H), 7.52, 7.90 (2×s, each 1H, 5-H, 9-H), 7.67 (d, J=8.45 Hz, 2′, 6′-H), 12.12 (s, 1H, N3-H); MS (ESI, m/z) 444 {(M+Na)+, 40%}; Found: C, 67.19; H, 6.31; N, 9.69; C24H27N3O4 0.5H2O requires C, 66.96; H, 6.50; N, 9.76%.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]([N:27]([CH3:36])[C:28](N1C=C[N+](C)=C1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28](=[O:29])[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:36])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(Cc1ccccc1)C(=O)n1cc[n+](C)c1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, (1:5) (69%, colourless oil) HPLC-MS m/z=403.2 (M+1), Rt: 5.11 min
Reaction SMILES: O[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].S(Cl)([Cl:20])=O>>[Cl:20][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3]
Reactant: CC(O)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Reactant: O=S(Cl)Cl
Product: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C

Procedure:
10 g of 8-α-hydroxyethylcaffeine (Arch. der Pharmazie, 289, 453, 1956) are added and under shaking with 100 ml of thionyl chloride. After 6 hours of reflux, the excess of reagent is evaporated to dryness under reduced pressure and the solid residue washed with petroleum ether. Nearly pure 8-α-chloroethylcaffeine is obtained with a quantitative yield, melting at 190° C from anhydrous benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[NH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=2)[C:4]([NH:6][CH2:7][C:8]23[CH2:9][CH:10]4[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]4)[CH2:15]2)[CH2:17]3)=[O:5])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCCN(CCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.5 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-piperidinyl-carbamic acid, 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then by HPLC eluting with a gradient of 0-2% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.032 g).
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (34 g, 110 mmol) and a stir bar were added to a 2000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous diethyl ether (400 mL) was added via canulla. A solution of γ-linolenyl mesylate (20 g, 58 mmol) in anhydrous ether (300 mL) was then added, and the suspension stirred overnight. The suspension was poured into 500 mL of chilled water and transferred to a 2000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×250 mL) and all ether phases combined. The ether phase was washed with water (2×250 mL), brine (250 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated and purified by flash chromatography. Final yield 18.9 g, 99%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14](O)=[O:15].C(N=C=NC(C)C)(C)C.O>N1C=CC=CC=1>[CH2:19]([O:18][C:12](=[O:17])[CH2:13][C:14]([NH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1)=[O:15])[CH3:20]
Reactant: CCOC(=O)CC(=O)O
Reactant: CCOC(=O)c1cc(N)[nH]n1
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cc(C(=O)OCC)n[nH]1

Procedure:
To a solution of ethyl 5-aminopyrazole-3-carboxylate (5.00 g, 26.1 mmol) and ethyl hydrogen malonate (3.62 g, 27.4 mmol) in pyridine (130 mL) was added N,N′-diisopropylcarbodiimide (4.28 g, 33.9 mmol) at 0° C. After being stirred at same temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=19:1) and triturated with diisopropyl ether to give ethyl 5-[(3-ethoxy-3-oxopropanoyl)amino]-1H-pyrazole-3-carboxylate. MS (APCI): m/z 270 (M+H).