Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)CCCCC1.C1(C)C=CC(S(O)(=O)=[O:15])=CC=1.C[N:20](C)[C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[N:27]([CH3:40])[C:28](=O)[C:29]1C=C[C:32](S(C)(=O)=O)=[CH:31][CH:30]=1.[Cl:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[Cl:52])[C:46](Cl)=[O:47]>>[Cl:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[Cl:52])[C:46]([NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[N:27]([CH2:28][C:29]1[O:15][CH:32]=[CH:31][CH:30]=1)[CH3:40])=[O:47]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)[C@@H]1CCCC[C@H]1N(C)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: NC1CCCCC1
Product: CN(Cc1ccco1)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Yield: 50 %

Procedure:
This titled benzamide was prepared according to the general acid chloride method described above on a 0.01 mol scale by reacting the trans-2-[N-(2-furylmethyl)methyl)methylamino]cyclohexylamine, prepared as described in part (a) above with 3,4-dichlorobenzoyl chloride. The reaction product mixture was extracted with methylene dichloride to extract the benzamide product therefrom. The crude product was chromatographed on 380 g. of silica gel using a 1 percent methanol-in-chloroform eluant. Fraction 1 (1000 m.) and fractions 2 to 17 (25 ml. each) gave no material. Fractions 18 to 54 (25 ml. each) gave a solid which was crystallized from ether giving colorless needles, 1.91 g., (50% yield) of the named benzamide product, melting point 149°-150° C. The Ultraviolet, Infrared, and Nuclear Magnetic Resonance spectral analyses were consistent for the named benzamide.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[I-].[K+].[OH-].[K+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(O)C.O>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: OCCCCCCCl
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 35 °C

Procedure:
To a mixture of 24.62 g (0.15 mole) 4-hydroxycinnamic acid and 0.29 g (1.65 mmole) of potassium iodide in 60 ml of ethanol were added under a nitrogen atmosphere in 10 min a solution of 20.72 g (0.314 mole) of potassium hydroxide in 60 ml of water using a dropping funnel. The resulting solution was heated to 30-40° C. and 6-chlorohexanol (22.54 g, 0.165 mole) was then added in about 10 min. The solution was then refluxed overnight. After cooling, 70 ml of water were added to the solid reaction mixture, and the ethanol was removed using a rotary evaporator. The residue was cooled in an ice/water bath and 70 ml of conc. hydrochloric acid were added under stirring. The solid was collected and washed with water. Then the solid was stirred at 50° C. with 250 ml of acetone. After drying at 100° C. in vacuo 24.5 g (62%) of product 13 were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:3]=1[CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7]>O1CCCC1.C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:3]([CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[C:2]([CH3:1])[CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1CNS(C)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N)ccc1CNS(C)(=O)=O
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a stirred solution of N-(2-methyl-4-nitrobenzyl)methanesulfonamide (100 mg, 0.409 mmol) in tetrahydrofuran and ethanol as co-solvent were added 10% Pd/C (40 mg). The mixture was charged with H2 (gas) balloon. The resulting mixture was stirred for 24 h, then filtered using celite. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(4-Amino-2-methylbenzyl)methanesulfonamide (61 mg) was obtained as 70% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]=[C:9]([NH:15][CH2:16][CH3:17])[C:8]([CH2:18]O)=[CH:7]2)[CH3:2].O=S(Cl)[Cl:22]>C(Cl)Cl>[ClH:22].[Cl:22][CH2:18][C:8]1[C:9]([NH:15][CH2:16][CH3:17])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[C:13]([F:14])[CH:12]=2
Reactant: O=S(Cl)Cl
Reactant: CCNc1nc2cc(F)c(OCC)cc2cc1CO
Solvent: ClCCl
Product: CCNc1nc2cc(F)c(OCC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methanol SMA 44104 (61 mg, 0.23 mmol) in dry CH2Cl2 (10 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (0.33 mL, 4.56 mmol) and the mixture was stirred for 3 h at RT. The mixture was then concentrated to dryness at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness (done 3 times) to give 3-(chloromethyl)-6-ethoxy-N-ethyl-7-fluoroquinolin-2-amine hydrochloride SMA 44106 as a brown solid (88 mg, >100% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[N:18]=[C:17](OC2N(C)N=C(C(F)(F)F)C=2)[CH:16]=1)#[N:14]>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[C:17]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:4]=2[F:3])[N:18]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)#[N:14]
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(Oc2cc(C(F)(F)F)nn2C)n1
Reactant: OCc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(OCc2ccc(F)cc2F)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
Sodium hydride (0.1 g, 60%, 2.5 mmol) is added to a solution of 2,4-difluorobenzyl alcohol (0.28 ml, 2.5 mmol) in sulfolane (5 ml) at 50° C. After 1 hour at 50° C., 4-cyano-2,6-bis(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (1 g, 2.3 mmol) (from Example 2) is added to the reaction mixture. The mixture is heated to 90° C. overnight. After cooling, the reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed 6 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v) and washing of the product with diisopropyl ether yields the title compound (0.2 g, 21% yield) of melting point 109° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:33]([C:29]3[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=3)=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1csc2ccccc12
Reactant: Cn1ccnc1C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde. 448.5 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:30][CH3:31].CN(C1N=CC=CN=1)C.Cl.CN(C)CCCC(N=C=N)C.Cl>ClCCl>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:35][S:32]([CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])=[O:23])=[CH:17][N:16]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cn1
Reactant: CCCS(N)(=O)=O
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ncccn1
Agent: Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)NC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 2-(N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylic acid (0.89 g) in dichloromethane (50 ml) was added propanesulphonamide (0.3 g), dimethylaminopyrimidine (0.493 g) and 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (0.58 g). The mixture was stirred at ambient temperature for 18 hours, and poured into 2N HCl. The organic layer was separated and washed with water and brine, then dried (MgSO4), filtered and evaporated. The resulting oil was purified by chromatography on silica gel (eluting with 5% ethylacetate/dichloromethane to give N-(2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carbonyl)propanesulphonamide (271 mg) as a white foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([O:43]C)=[O:42])[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([OH:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)OC)c1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 26.2 %

Procedure:
Methyl (1RS,2SR,3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M, 1 ml, 1 mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5%AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[N:12][N:13]([CH3:15])[CH:14]=[C:9]3[C:8]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[N:7][C:6]=2[CH:23]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[OH2:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[N:12][N:13]([CH3:15])[CH:14]=[C:9]3[C:8]([N:16]3[CH2:17][CH2:18][N+:19]([O-:32])([CH3:22])[CH2:20][CH2:21]3)=[N:7][C:6]=2[CH:23]=1
Reactant: CN1CCN(C2=Nc3cc(F)ccc3Nc3nn(C)cc32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc2c(n1)Nc1ccc(F)cc1N=C2N1CC[N+](C)([O-])CC1
Product: O
Reaction time: 0.5 h

Procedure:
7-Fluoro-2,10-dihydro-2-methyl-4-(4-methyl-1-piperazinyl)-pyrazolo[3,4-b][1,5]benzodiazepine (2.0 g) was stirred in dichloromethane (50 ml) at 0°-5° C. whilst m-chloroperbenzoic acid (1.5 g) was added in portions. The solution was stirred for 30 minutes then filtered through a column of basic alumina, eluting with 9:1 chloroform:methanol to give, after removal of the solvent and crystallisation from acetonitrile-diethyl ether, the title compound m.p. 228°.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19]O>C(O)(=O)C>[CH:1]1([CH2:7][S:8]([C:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[CH2:11][C:10]=2[OH:18])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: CC1(C)CC(=O)C(SCC2CCCCC2)=C(O)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)CC2CCCCC2)=C(O)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(cyclohexylmethylthio)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (8.0 g., 0.029 mole), 50 ml. of glacial acetic acid and 30 percent hydrogen peroxide (3.26 g., 0.029 mole) was allowed to stand at room temperature for 24 hours. The solution was then poured into ice-water, and the precipitated pink crystals were filtered and dried (7.7 g., m.p. 77°-79.5°C.).
Reaction SMILES: O.NN.[CH3:4][CH:5]([NH:11][C:12](=[O:25])[CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C>[NH2:14][CH2:13][C:12]([NH:11][CH:5]([CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:25]
Reactant: CCCCCC(C)NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCC(C)NC(=O)CN
Temperature: 25 °C

Procedure:
A solution of hydrazine hydrate (1.14 g; 22.8 mmol) and N-(1-methylhexyl)-2-phthalimidoacetamide (6.9 g; 22.8 mmol) in ethanol (50ml) was heated under reflux for 1 hour. It was then cooled to room temperature and evaporated in vacuo (Buchi, r.t.; then oil-pump, 0.5 mm/r.t./10 min.). The resultant semi-solid mixture was treated with dilutesulphuric acid (0.5 N; 85 ml) pre-cooled to 5°. The mixture was cooled to 0°, filtered and the precipitate mixed with more of the acid (2 N; 3×20 ml). The filtrate was kept in the refrigerator overnight and then filtered once more. After basification with sodium hydroxide solution (5 N; 40 ml), the mixture was extracted with dichloromethane (3×50 ml), the extracts dried (sodium sulphate) and evaporated in vacuo. The resultant oil was dried at 0.5 mm./r.t./0.5 h. T.l.c. (silica; chloroform:methanol: 3:2): 1 major spot, Rf. ca 0.5. I.v. and n.m.r. spectra were consistent with the structure. The product was purified as its hydrogen succinate.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][C:42]([C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)[N:49]=1)([CH3:44])[CH3:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][C:42]([C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:53]=[N:52]2)[N:49]=1)([CH3:44])[CH3:43]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COC(C)(C)c1nc(Cn2ncc(N)n2)co1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(C)(C)c1nc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)co1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (18 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (3.0 mg, 0.02 mmol), HOBt (15.7 mg, 0.12 mmol), EDC (46.5 mg, 0.24 mmol) and DIPEA (0.07 mL, 0.39 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((2-(2-methoxypropan-2-yl)oxazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine (23.0 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10.0 mL), the layers were separated and the org. phase was washed with water (5.0 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.27. LC-MS-conditions 07: tR=0.86 min, [M+H]+=408.89.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:19]([O:29]COC)=[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:19]([OH:29])=[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH:17]=2)=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCOc1c(-c2cccc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cccc(C)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2O)c1
Yield: 76.5 %

Procedure:
To a solution of N-7-phenylheptyl-3,5-bis-(3-methylphenyl)-4-methoxymethoxybenzamide (1.04 g, 1.94 mmol) in 3.5 mL THF was added 2N HCl (1.1 mL, 2.2 mmol) at room temperature and the reaction mixture was refluxed for 2 hours before a catalytic amount of camphorsulfonic acid was added. The reaction was refluxed overnight and the resulting goo was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. This yielded an oil that was passed through a pad of silica gel using 20% EtOAc:80% Hexanes. There yielded 730 mg, 81% of a light yellow viscous oil. 1H NMR (CDCl3) 8 1.33-1.39 (m, 61) 1.59-1.63 (m, 6H); 2.42 (s) 6H); 2.58 (t, J=7.69 Hz, 2H); 3.44 (quartet, J=7.03 Hz, 2H); 6.06 (t, J=7.50 Hz, 1H); 7.14-7.18 (m, 3H); 7.22-7.28 (m, 4H); 7.34-7.40 (m, 6H); 7.68 (s, 2H); IR 3525, 3025, 2925, 2850, 1630, 1600, 1530, 1460, 1325, 1230, and 700 cm−1; mass spectrum [(+)ESI], m/z 492 [M+H]+; Anal Calcd. For C34H37NO2: C, 83.06; H, 7.59; N, 2.85; Found: C, 83.80; H, 7.62; N, 2.93.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[O:18]=[C:19]1[NH:23][C@H:22]([C:24]([OH:26])=O)[CH2:21][S:20]1.[N+]([O-])(O)=O.[N+:31]([O:34][CH2:35][CH2:36][NH2:37])([O-:33])=[O:32]>O1CCCC1>[N+:31]([O:34][CH2:35][CH2:36][NH:37][C:24]([C@@H:22]1[CH2:21][S:20][C:19](=[O:18])[NH:23]1)=[O:26])([O-:33])=[O:32]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
11.4 ml of triethylamine and 5.3 ml of diethyl cyanophosphonate were added, whilst ice-cooling, to a suspension of 4.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 4.6 g of N-(2-nitrooxyethyl)amine nitrate in 80 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residual brown oil thus obtained was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The brown crystals thus obtained were recrystallized from ethyl acetate, to give 1.68 g of the title compound as colorless needles, melting at 130°-131° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:3]=1[C:4]([OH:6])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.F[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:3]=1[C:4]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]1[CH2:24][NH:25][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1)=[O:6]
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1F
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.45-6.45 (m, 8H), 4.90-2.70 (m, 5H), 2.35-0.65 (m, 11H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.CS(O)(=O)=O.[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[OH:1][C:2]1[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: C=CCCCCCC
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: CS(=O)(=O)O
Product: CCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
In a flask fitted with an nitrogen blanket, stirrer, reflux condenser and addition funnel, 225 grams of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole, 65 ml of methanesulfonic acid and 156 ml of 1-octene are heated at 120° C. for a six-hour period. Throughout said period another 467 ml of 1-octene is added to the reaction mixture. The mixture is then cooled and extracted with two 200 ml portions of methanolic potassium hydroxide solution (40 grams potassium hydroxide in 100 ml of methanol). The extracts are washed with 1×400 ml and then with 4×200 ml of heptane. Water (200 ml) is added to the heptane extracts and the upper heptane layer is separated, washed with 5×200 ml of aqueous methanol (methanol 2:water 1). The washed heptane layer is dried over anhydrous magnesium sulfate and treated with 1×10 grams and then 3×5 grams of an acidic absorbent clay (FILTROL 13). After removal of the clay absorbent, the heptane solution is vacuum stripped at 110° C./2 mm to give 23 grams of the above-named product as a yellow liquid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH2:2][CH3:3].N[C:26]1C=C(C2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1.C1(C(Cl)=O)CC1>>[CH:2]1([C:1]([NH:5][C:6]2[CH:7]=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:26][CH2:3]1
Reactant: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: O=C(Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Yield: 100 %

Procedure:
According to the procedure used for the synthesis of tert-butyl 4-[3-(propionylamino)phenyl]-1-piperidinecarboxylate, tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate (16.47 g 0.0596 mol) and cyclopropanecarbonyl chloride (6.27 g, 0.0597 mol) provided the tert-butyl 4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperidinecarboxylate (18.1 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.55-7.46 (m, 2H), 7.29-7.21 (m, 2H), 6.96-6.89 (m, 1H), 2.79 (t, 2H, J 12.1 Hz), 2.68-2.58 (m, 1H), 1.84 (d, 2H, J=12.6 Hz), 1.83-1.76 (m, 4H), 1.48 (s, 9H), 1.19-1.12 (m, 1H), 1.09-1.05 (m, 2H), 0.89-0.75 (m, 2H); ESMS m/e: 345.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](#[N:11])[CH3:10].C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([CH2:10][C:9]#[N:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCc1ncccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0 equiv) and acetonitrile (1.3 mL, 25 mmol, 1.1 equiv) in toluene (50 mL) was added sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 mL, 25 mmol, 1.1 equiv). The resulting mixture was stirred for 2 hours at 0° C. and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the crude desired product as an oil which was used without further purification.