Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br.[CH2:11]([NH:13][CH2:14][CH2:15][CH2:16]Br)[CH3:12]>>[Cl:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][CH2:16][CH2:15][CH2:14][NH:13][CH2:11][CH3:12])=[C:2]([CH3:1])[CH:8]=1
Reactant: CCNCCCBr
Reactant: Cc1cc(Cl)ccc1N
Agent: Br
Product: CCNCCCNc1ccc(Cl)cc1C

Procedure:
Prepared in the manner of Example 1, Step A using 2-methyl-4-chloroaniline and the N-ethyl-1-amino-3-bromopropane hydrobromide salt of Step C (12.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:7]2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[CH3:13])[CH2:7]2.[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[CH3:13])[CH2:7]2
Reactant: CC(c1ccc(Cl)cc1)N1Cc2cccc(Cl)c2C1=O
Solvent: CC(C)O
Product: C[C@@H](c1ccc(Cl)cc1)N1Cc2cccc(Cl)c2C1=O
Product: C[C@H](c1ccc(Cl)cc1)N1Cc2cccc(Cl)c2C1=O

Procedure:
Chromatography (HPLC) of racemic mixture of 7-chloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (1.2 g) through ChrialCel OD (250×20 mm i.d., 10 μm)] using 5% isopropyl alcohol in hexanes as an eluent afforded (S)-7-Chloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.044 g) and (R)-7-Chloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.058 g)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[NH:17][CH:16]2[C:36]([OH:38])=O)[CH:12]=[CH:13][CH:14]=1.[CH3:39][C:40]1([CH3:48])[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:39][C:40]1([CH3:48])[O:44][C@@H:43]([CH2:45][CH2:46][NH:47][C:36]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[NH:17]2)=[O:38])[CH2:42][O:41]1
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: N#CC1(c2ccc(Cl)cc2)C(c2cccc(Cl)c2)NC(C(=O)O)C1c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC[C@H](CCNC(=O)C2NC(c3cccc(Cl)c3)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)O1

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 42b (0.3 g, 0.5 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4 mmol) in CH2Cl2 (30 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a off white solid (0.25 g, 83%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=1[S:36](=[O:39])(=[O:38])[NH2:37]>O.O1CCOCC1>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[C:28]([S:36](=[O:38])(=[O:39])[NH2:37])[CH:29]=2)[NH2:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NN(C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 56.4 %

Procedure:
By using the process of Example 1(B), 28 g of 4-benzoyl-2-nitrophenylhydrazine, 272 ml of dioxane, 5.8 g of anhydrous sodium carbonate dissolved in 110 ml of water and 27.6 g of 4-chloro-3-sulfamoylbenzoyl chloride dissolved in 217 ml of dioxane were used as starting materials to yield 29.1 g (61%) of 4-benzoyl-2-nitro-N-(4'-chloro-3'-sulfamoylbenzoyl)phenylhydrazine, m.p.: 148° C. after recrystallization from methanol.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.O>CS(C)=O>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)[C:12]=3[N:34]3[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2N2CC[C@H](N(C)C)C2)cs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-4-carbonitrile (I-80) (3.96 g, 12.65 mmol) was dissolved in dimethyl sulfoxide (40 ml), then triethylamine (4.27 ml, 30.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (1.93 ml, 15.18 mmol) were added, followed by stirring at 90° C. for 4 hours under nitrogen atmosphere. After cooling to room temperature, water was added, the precipitated solid was collected by filtration, recrystallized and purified with a mixed solvent of diethyl ether/ethyl acetate/methanol to obtain the entitled compound (3.16 g, 61%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[CH:16](O)=O>>[F:9][C:8]([F:10])([F:11])[C:4]1[C:3]2[N:12]([CH2:13][CH2:14][OH:15])[CH:16]=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=CO
Reactant: Nc1cccc(C(F)(F)F)c1NCCO
Product: OCCn1cnc2cccc(C(F)(F)F)c21
Yield: 55 %

Procedure:
A solution of 2-{[2-amino-6-(trifluoromethyl)phenyl]amino}ethanol (0.57 g) in formic acid (20 mL) was heated at reflux for 20 min. The excess of formic acid was removed in vacuo; the residue was dissolved in a 2 M hydrochloric acid, and heated at reflux for 10 min. The solution was concentrated in vacuum and the residue was co-evaporated with acetonitrile and ethanol. The residue was treated with a saturated solution of sodium bicarbonate and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica using ethyl acetate as an eluent affording 2-[7-(trifluoromethyl)-1H-benzimidazol-1-yl]ethanol, 0.36 g (55% yield) as a white solid. MS (ESI) m/z 231 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.74-3.70 (m, 2H), 4.37 (t, J=5.3 Hz, 2H), 5.06 (t, J=4.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.33 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=O)=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[N:17][N:16]=2)[CH:15]=1
Reactant: CC(C)NC(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Nc1nnc2ccc(F)cn12
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Hexachloroethane (1.77 g, 7.75 mmol) was added portionwise to a solution of Intermediate 8a 822 mg, 3.87 mmol), triphenylphosphine (2.03 g, 7.75 mmol) and triethylamine (2.2 mL, 15.49 mmol) in dry THF (15 mL) at RT and stirred for 16 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give the title compound as a buff-coloured foam (618 mg, 82%). LCMS (Method 1): Rt 1.55 min, m/z 195 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]Br)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:19].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(=O)c2cc(CBr)ccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromomethyl)-4(1H)-quinazolinone (Example 3) in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silical gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH3:19])[C:8]([N+:20]([O-])=O)=[CH:7][C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH3:19])[C:8]([NH2:20])=[CH:7][C:6]=1[OH:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (3.0 g, 9.5 mmol) in methanol (30 ml) was added Raney Ni (300 mg). The mixture was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-ethyl acetate, 6:1) to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (C-15) (2.35 g, 92%). 1HNMR (DMSO-d6) δ 8.89 (s, 1H), 7.19 (t, 1H, J=4.2 Hz), 7.10 (d, 1H, J=1.8 Hz), 7.08 (d, 1H, J=1.8 Hz), 6.94 (t, 1H, J=3.6 Hz), 6.67 (s, 1H), 6.16 (s, 1H), 4.25 (s, 1H), 4.00 (q, 2H, J=6.9 Hz), 1.26 (s, 9H), 1.21 (t, 3H, J=6.9 Hz); ESI-MS 286.0 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl.[CH3:20][N:21]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>CN(C)C=O>[ClH:1].[CH3:20][N:21]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[N:22]=[C:2]1[C:15]2[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CN(N)c1nccs1
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Cl)c12
Agent: Cl
Solvent: CN(C)C=O
Product: CN(N=c1c2ccccc2[nH]c2cccc([N+](=O)[O-])c12)c1nccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.3 g of 9-chloro-1-nitroacridine, 1.65 g of N-methyl-N-(2-thiazolyl)hydrazine hydrochloride and 100 ml of dimethylformamide is stirred at room temperature for about 18 hours. The dark red solution is evaporated, whereupon the residue is made alkaline with sodium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. The residue is taken up in ethanol, acidified with ethanolic hydrochloric acid and the product is precipitated by the addition of ether. After filtration and washing with ether and petroleum ether, the hygroscopic salt is dried over phosphorus pentoxide. There is obtained 1-nitro-9-acridanone methyl (2-thiazolyl)hydrazone hydrochloride of melting point 185° (decomposition).
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH:11]=O)[CH2:9][CH2:8][C:7]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][CH3:21]>C1(C)C=CC=CC=1.C(OCC)C.C1COCC1>[CH3:19][N:20](/[CH:11]=[C:10]1\[C:2](=[O:1])[C:3]2[CH:4]=[N:5][N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH2:8][CH2:9]\1)[CH3:21]
Reactant: O=CC1CCc2c(cnn2-c2ccccc2)C1=O
Reactant: CNC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)/C=C1/CCc2c(cnn2-c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 62.3 %

Procedure:
To a stirred solution of 4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carbaldehyde (1.1 g, 4.58 mol) in toluene (50 mL) and diethylether (25 mL) was added dimethylamine (3 mL, 6 mmol) as a solution in THF (10 mL). The reaction was stirred for at room temperature for 40 hours. The reaction was then concentrated under reduced pressure to give a brown residue, which was triturated with hexane to give the desired product (1 g, 80%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δδ 7.91 (s, 1H), 7.59-7.53 (m, 4H), 7.45-7.42 (m, 1H), 7.36 (s, 1H), 3.07 (s, 6H), 2.95 (s, 4H); LCMS [M+H]: 267.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=O.[CH:16]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)C.[BH4-].[Na+]>O>[CH:16]1([NH:23][CH2:1][C:3]2[CH:15]=[CH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][C:5]=3[CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: NC1CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)Cc1cc(CNC3CCCCCC3)ccc1-2
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
2-Formylfluorene (2.27 g, 11.7 mmol) and cycloheptylamine (1.39 g, 12.3 mmol) were heated together at 120° C. for 14 hrs. After cooling, the reaction mixture was distilled under reduced pressure. Then, ethanol (30 ml) and sodium borohydride (0.44 g, 11.7 mmol) were added to the residue and the mixture was stirred for 0.5 hr. The mixture was then diluted with water (100 ml) and extracted with chloroform (80 ml×2 times). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 3.15 g of a pale yellow solid residue.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5]CC)[CH3:4].Cl.[NH2:9][C@@H:10]([CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[C:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)[CH2:19][CH2:18]1)=[O:16])[CH2:11][OH:12].C(Cl)(=O)C>O.C(OCC)(=O)C>[CH:33]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:23](=[C:20]3[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C@H:10]([NH:9][C:3](=[O:5])[CH3:4])[CH2:11][OH:12])[CH2:22][CH2:21]3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCOCC
Reactant: N[C@H](CO)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)N[C@H](CO)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of 1 N aqueous sodium hydroxide solution, 3 ml of diethyl ether and 2 ml of ethyl acetate were added to 151 mg (0.36 mmol) of (S)-2-amino-5-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-5-oxo-1-pentanol hydrochloride. 0.04 ml (0.56 mmol) of acetyl chloride was added dropwise to the obtained solution under vigorous stirring, and they were stirred at room temperature for 2 hours. Water was added to the reaction mixture. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform:methanol-200:1 to 50:1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCNC(=O)OC(C)(C)C)ccc2c1
Yield: 82.4 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 7.60 g, 33.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (5.30 g, 32.9 mmol), N,N-dimethylaminopyridine (DMAP, 0.35 g, 2.86 mmol) and 1,3-dicyclohexylcarbodiimide (6.80 g, 33.0 mmol) in CH2Cl2 (200 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The filtrate was concentrated, dissolved in EtOAc (50 mL) and then cooled in a dry-ice bath to precipitate the remaining dicyclohexyl urea and then filtered. The filtrate was concentrated, dissolved in CH2Cl2 (15 mL) and hexane (200 mL) and then stirred until the product precipitated. The solid was dried under vacuum to give the title compound (10.12 g, 82% yield). Mp 82-84° C. 1H NMR (300 MHz, CDCl3) δ 7.72-7.65 (m, 3H), 7.42-7.38 (m, 1H), 7.16-7.11 (m, 2H), 5.05 (br, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.87 (q, J=7.1 Hz, 1H), 3.30 (br. q, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 155.6, 135.4, 133.6, 129.2, 128.8, 127.1, 126.0, 125.8, 119.0, 105.5, 79.3, 63.7, 55.2, 45.2, 39.5, 28.2, 18.3. Mass spectrum (API-TIS) m/z 374 (MH)+. Anal. calcd. for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.43; H, 7.16; N, 3.66.
Reaction SMILES: Cl.Cl.[N:3]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:8][CH2:7][CH:6]([N:9]2[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]3[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].[OH-].[Na+]>ClCCl>[O:18]=[C:10]1[N:9]([CH:6]2[CH2:5][CH2:4][N:3]([CH:19]3[CH2:24][CH2:23][N:22]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:20]3)[CH2:8][CH2:7]2)[C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[NH:11]1
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
(3aS,7aS)-1-(1,4′-bipiperidin-4-yl)hexahydro-1H-benzo[d]imidazol-2(3H)-one dihydrochloride (0.68 g, 1.79 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.75 mL, 5.38 mmol) was added. Isopropyl chloroformate (1.792 mL, 1.79 mmol) (solution 1M in toluene) was added drop wise at 0° C. The mixture was stirred for 2 hours then diluted in dichloromethane (60 mL) and the mixture made basic with 1N NaOH. The phases were separated and aq. phase was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with brine (5 mL) and concentrated under reduced pressure. The crude was then purified by high pH prep LCMS to provide the title compound as a white solid (560 mg, 80%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.22 (d, J=6.25 Hz, 6H), 1.26-1.49 (m, 6H), 1.58-1.70 (m, 2H), 1.72-1.84 (m, 7H), 1.94 (d, J=11.33 Hz, 1H), 2.14-2.32 (m, 3H), 2.33-2.47 (m, 1H), 2.69 (t, J=13.09 Hz, 2H), 2.84-2.96 (m, 2H), 2.96-3.06 (m, 1H), 3.65-3.81 (m, 1H), 4.07-4.28 (m, 2H), 4.43 (s, 1H), 4.80-4.94 (m, 1H). MS (M+1): 393.2
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[C:17](N3CCOCC3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.O=C1C2C(=CC=CC=2)C(=O)[N:26]1[CH2:35][CH2:36][CH2:37][CH:38]=O.[BH-](OC(C)=O)(OC(C)=O)[O:41][C:42](C)=[O:43].[Na+].NN.O>>[NH2:26][CH2:35][CH2:36][CH2:37][CH2:38][N:10]([CH2:11][C:12]1[N:13]=[CH:14][CH:15]=[CH:16][C:17]=1[C:42]([OH:43])=[O:41])[CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cnc(CNCc2ncccc2N2CCOCC2)c(C)c1
Agent: NN
Agent: [Na+]
Solvent: O
Product: Cc1cnc(CN(CCCCN)Cc2ncccc2C(=O)O)c(C)c1

Procedure:
Using General Procedure B: Reaction of C-(3-morpholin-4-yl-pyridin-2-yl)-methylamine, 3.5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3-morpholin-4-yl-pyridin-2-ylmethyl)-amine as a colorless oil. 1H NMR (CDCl3) δ 2.27 (s, 3H), 2.30 (s, 3H), 2.92-2.95 (m, 4H), 3.79-3.82 (m, 4H), 3.95 (s, 2H), 4.03 (s, 2H), 7.14 (dd, 1H, J=4.5, 8.1 Hz), 7.23 (s, 1H), 7.33 (dd, 1H, J=1.2, 8.1 Hz), 8.22 (s, 1H), 8.31 (dd, 1H, J=1.2, 4.5 Hz). Further reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-(3-morpholin-4-yl-pyridin-2-ylmethyl)-amine, 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde and NaBH(OAc)3 following General Procedure B gave a colorless oil. Deprotection with NH2NH2.H2O, following General Procedure E, gave a colorless oil. Subsequent conversion to the HBr salt gave COMPOUND 201 as a pale yellow solid. 1H NMR (D2O) δ 1.58-1.70 (m, 4H), 2.42 (s, 3H), 2.44 (s, 3H), 2.78-2.84 (m, 2H), 2.94-3.02 (m, 2H), 3.04 (s, br., 4H), 3.96 (s, br., 4H), 4.24 (s, 2H), 4.28 (s, 2H), 7.80-7.88 (m, 1H), 8.07-8.15 (m, 2H), 8.8.36-8.42 (m, 2H); 13C NMR (D2O) δ 17.21, 17.49, 23.06, 25.05, 39.66, 51.91, 52.65, 54.34, 55.96, 66.81, 126.80, 135.15, 136.40, 137.34, 137.78, 137.91, 147.61, 148.92, 149.75. ES-MS m/z 384 (M+H). Anal. Calcd. for C22H33N5O.3.3HBr.1.5H2O.0.3C4H10O: C, 39.82; H, 6.09; N, 10.01; Br, 37.68. Found: C, 39.83; H, 6.20; N, 10.08; Br, 37.59.
Reaction SMILES: [CH3:1][C@H:2](CC1CCCCC1)[C:3](Cl)=[O:4].[CH3:13][CH:14]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)[CH3:15].C(Cl)(=O)CC.C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[CH3:13][CH:14]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:3](=[O:4])[CH2:2][CH3:1])[CH3:15]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C[C@H](CC1CCCCC1)C(=O)Cl
Agent: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
α(R)-Methylcyclohexanepropionic acid chloride: Under argon, a 1.6M hexane solution of burylithium (100 mL, 160 mmol) was added to a cooled solution (-30° to -40°) of 4(S)-(1-methylethyl)-2-oxazolidinone (20.7 g, 160 mmol), see L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989), in dry THF (200 mL). After 15 min, the mixture was cooled to -78° and propionyl chloride (14.2 mL, 163 mmol) was added. After 5 min at -78°, the reaction mixture was allowed to warm to 0°. The mixture then was treated with a saturated aqueous solution of NaHCO3 (500 mL). The resultant mixture was extracted with EtOAc (2 X). The combined organic extracts were dried (MgSO4) and concentrated to afford a yellow liquid. This material was purified by flash chromatography [SiO2, eluent: EtOAc-hexane (1:10 to 1:4)] to provide (4S)-(1-methylethyl)-3-(1-oxopropyl)-2-oxazolidinone as a clear liquid (10.9 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 4.46-4.41 (m, 1H), 4.29-4.19 (m, 2H), 3.03-2.86 (m, 2H), 2.43-2.33 (m, 1H), 1.17 (t, J=7.3 Hz, 3H), 0.92 (d, J=7 Hz, 3H), 0.88 (d, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: BrCCCCCCCCCCCCOc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Product: COC(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1O
Yield: 75 %

Procedure:
The reaction of 2,5-dihydroxybenzoic acid methyl ester with 12-phenoxydodecyl bromide under condition described in Example 101 gave 2-hydroxy-5-[(12-phenoxydodecyl)oxy]benzoic acid methyl ester (75% yield, mp 61°-64° ).