Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH2:11]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CS(C)=O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:25][CH2:24]1
Reactant: COC(CCCCBr)OC
Reactant: c1ccc(CNCC2CCNCC2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: COC(CCCCN1CCC(CNCc2ccccc2)CC1)OC
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 5-bromopentanal dimethyl acetal and 4-[(benzylamino)methyl]piperidine using a similar method to that described for Example 8 (step 2). δ (250 MHz, d6 -DMSO) 1.26-2.14 (13H, m), 2.49 (2H, t, J=7.0 Hz), 2.63 (2H, d, J=6.6 Hz), 3.04-3.14 (2H, m), 3.49 (6H, s), 3.95 (2H, s), 4.61 (1H, t, J=5.7 Hz), 7.44-7.62 (5H, m), m/e (ES) 335 (M+1+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].Cl.N1C=CC=CC=1>O>[OH:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[O:15][C:13](=[O:14])[CH:12]=[CH:11]2
Reactant: COc1ccc(OC)c(/C=C/C(=O)O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccc2cc(O)ccc2o1
Yield: 49 %

Procedure:
The carboxylic acid (1.97 g; prepared in reference example 24) and pyridine hydrochloride (12 g) were heated to 180°-190° C. The mixture was reacted for 3.5 hr. The reaction mixture was cooled and then dissolved in water. The solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate=3:1→1:1). The obtained crystals were washed with a mixture of n-hexane and ethyl acetate (3:1→1:1) to give the title compound (751 mg) having the following physical data.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N+:4]=1[O-:32].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N+:4]=1[O-:32])[CH2:36][CH3:37])[CH3:34]
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CCl
Reactant: CCNCC
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CN(CC)CC

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate 1-oxide was reacted with diethylamine to give ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate 1-oxide. This compound was recrystallized from ethanol. Colorless prisms, mp. 143°-144° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:17]([O-:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([O:18][P:17]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCOP([O-])OCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-bromo-4-nitrobenzene (400 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.20 mmol) and cesium carbonate (734 mg, 2.2 mmol) in a 30 mL microwave vial was purged and backfilled with nitrogen. Tetrahydrofuran (20 mL) was added followed by diethyl phosphite (0.360 mL, 2.8 mmol). The mixture was vortexed, then microwaved for 45 minutes at 120° C. Reaction was repeated three times to achieve total scale then the combined reaction mixtures were purified via chromatography (120 g silica gel 5%->75% ethyl acetate in hexane). (4-Nitro-phenyl)-phosphonic acid diethyl ester isolated as a light yellow oil (969 mg, 47%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.35 (d, J=8.0 Hz, 2H), 7.16 (s, 1H), 5.93 (s, 2H), 3.40 (s, 4H), 2.36 (s, 4H), 2.20 (s, 3H), 8.05-7.95 (m, 2H), 4.09 (m, 4H), 1.25 (t, J=13.8, 7.4 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(#N)C>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(COCC(N)Cn2ccnc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CNC(COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Yield: 3.6 %

Procedure:
A solution of 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (1.70 g, 0.0065M) in dry acetonitrile (10 ml) containing triethylamine (0.5 ml) was treated with 4-methoxybenzyl chloride (1.12 g, 0.0072M) and heated under reflux for 18 hours under a stream of dry nitrogen. The solvent was evaporated off under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give the crude product as an oil which was further purified by chromatography (silica gel), 10% ethanol in chloroform) to give N-[(4-methoxyphenyl)methyl]-α-[[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole-1-ethanamine (0.09 g ) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.CS(O[CH2:19][C:20]1[C:21]2[CH:29]=[C:28]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[S:27][C:22]=2[N:23]=[C:24]([CH3:26])[N:25]=1)(=O)=O>O>[CH:30]1([C:28]2[S:27][C:22]3[N:23]=[C:24]([CH3:26])[N:25]=[C:20]([CH2:19][N:1]4[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]4)[C:21]=3[CH:29]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Reactant: O=S1(=O)CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCS(=O)(=O)CC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
To a mixture of thiomorpholine-1,1-dioxide (65 mg) and DMF (4 mL) were added (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (110 mg) and TEA (150 μL), followed by stirring at room temperature for 24 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (94 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)#[N:2]>C(O)C.O.N.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: N#CCCC1CN(Cc2ccccc2)CCO1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: NCCCC1CN(Cc2ccccc2)CCO1
Yield: 86 %

Procedure:
A solution of 2-(2-cyanoethyl)-4-benzylmorpholine (8 g) in a mixture of ethanol (60 ml) and 28% ammonia water (4 ml) is hydrogenated over Raney nickel at 25° C. After the calculated amount of hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound (7 g) as an oil.
Reaction SMILES: ClC1C(C(OO)=[O:9])=CC=CC=1.[CH2:12]([O:14][C:15](=[O:37])[C:16]([Cl:36])([Cl:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH3:13]>ClCCl>[CH2:12]([O:14][C:15](=[O:37])[C:16]([Cl:36])([Cl:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)=[O:9])[CH3:13]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCSc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCS(=O)c1ccc(Cl)cc1
Yield: 79.8 %

Procedure:
0.59 g (3.41 mmol) chloroperbenzoic acid dissolved in 15 ml dichloromethane was added dropwise to a solution of 1.5 g (3.41 mmol) 104 in 30 ml dichloromethane analogously to example 25 (preparation of 77). 1.24 g (80%) 105 was obtained after flash chromatography on silica gel. 1.24 g (2.72 mmol) 105 was admixed with 5.5 ml ethanol and 5.5 ml 1 N KOH and cooled for 5 hours at room temperature. It was cooled to 0° C. and acidified with 2 N HCl. The precipitated precipitate was suction filtered, washed with water and isohexane and dried in a vacuum, yield: 0.65 g (56%) 55. The sodium salt prepared from 55 and pulverized NaOH in ethanol melted at 91-94° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([OH:13])=O)[O:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.O[NH:25][C:26](=[NH:28])[CH3:27]>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]2[O:13][N:28]=[C:26]([CH3:27])[N:25]=2)[O:1][CH2:2][CH2:3]1
Reactant: CC(=N)NO
Reactant: O=C(O)C1CCCCC12OCCO2
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1noc(C2CCCCC23OCCO3)n1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 60.2 %

Procedure:
A mixture of 1,4-dioxa-spiro[4.5]decane-6-carboxylic acid (3.72 g, 20 mmol), N,N-dicyclohexyl-carbodiimid (2.06 g, 22 mmol) and 1-hydroxy-benzotriazole (3.03 g, 22 mmol) in tetrahydrofuran (40 mL) was stirred at 0° C. for 3.5 h. N-Hydroxy-acetamidine (1.48 g, 20 mmol) was added to the mixture and stirring was continued at 20° C. for 18 h. The reaction mixture was cooled to 0° C. and insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure. Toluene (250 mL) was added to the remaining oil and the mixture was heated at reflux for 5 h, water being removed using a Dean-Stark trap. The solution was cooled, solvents were evaporated under reduced pressure, and the residual material was purified by column chromatography on silica gel (100 g) using heptane/20-80% ethyl acetate as eluent to give the title compound (2.70 g, 60%). Obtained as light-yellow oil. MS ISP (m/e): 225.1 [(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](=[O:47])[NH:19][CH:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:21]([N:23]2[CH2:27][CH:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH:24]2[CH2:36][CH:37]=[CH2:38])=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:36]([CH:24]1[CH2:25][CH:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:23]1[C:21](=[O:22])[CH:20]([NH:19][C:18]([CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH:37]=[CH2:38]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1
Reaction time: 5 h

Procedure:
3-[2-(2-Allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 55, (200 mg) is dissolved into CH2Cl2 (3 mL) and trifluoroacetic acid (1 mL) is added. The reaction mixture is stirred for 5 hours and concentrated. The residue is purified by reverse phase HPLC to afford 50 mg of the desired product. 1H NMR (CDCl3, 300 MHz) δ 6.80˜7.50 (m, 13H), 5.75 (m, 1H), 5.06 (m, 2H), 4.30˜4.70 (m, 6H), 4.06 (m, 2H), 3.75 (m, 1H), 2.90˜3.30 (m, 6H), 2.69 (m, 1H), 2.23 (m, 1H), 1.80˜2.00 (m, 2H); MS (ES-MS) m/z 542 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(=S)=S>[C:17]1([CH2:23][C:24]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][CH:3]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 61.2 %

Procedure:
To a solution of 1.00 g of methyl 3-phenylpropionate in 6 ml of carbon disulfide, 1.62 g of anhydrous aluminium chloride was added under ice-cooling, and then 0.94 g of phenylacetyl chloride was added dropwise and stirring was continued at room temperature for 6 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed successively with water, aqueous potassium carbonate solution and water, dried, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1) to afford 1.05 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 77°~78° C.
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[CH:6]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Fc1cc2c(cc1F)C(Cl)Cc1ccccc1S2
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2Cc3ccccc3Sc3cc(F)c(F)cc32)CC1

Procedure:
A mixture of 7,8-difluoro-10-chloro-10,11-dihydrodibenzo(b,f)thiepine (5.08 g), 1-methylpiperazine (4 ml) and chloroform (5 ml) was refluxed for 7 hours. Chloroform was evaporated and the residue shaken with water and benzene. The organic layer was washed with water and shaken with dilute (1:2) hydrochlorid acid (50 ml). The formed suspension was filtered and the thus-obtained solid hydrochloride added to the aqueous layer of the filtrate. Addition of 15% sodium hydroxide solution liberated the desired base which was extracted with benzene, m.p. 106°-108° C. (acetone). Neutralization of this base with methanesulfonic or maleic acid in ethanol, followed by the addition of ether, yields the corresponding salts, i.e., the methanesulfonate (m.p. 244°-247° C.) or maleate (hemihydrate, m.p. 161°-163° C.), which were purified by crystallization from a mixture of ethanol and ether.
Reaction SMILES: C([C:5]1([O:11][CH2:12][CH2:13][CH2:14]Br)[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(C)(C)C.[OH:16][CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1>CN(C=O)C>[S:20]1[CH:21]=[CH:22][C:18]([CH2:17][O:16][CH2:14][CH2:13][CH2:12][O:11][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:19]1
Reactant: CC(C)(C)C1(OCCCBr)CCCCO1
Reactant: OCc1ccsc1
Solvent: CN(C)C=O
Product: c1cc(COCCCOC2CCCCO2)cs1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (RS)-2-(3-bromo-propoxy)-tetrahydro-pyran with 3-hydroxymethyl-thiophene in DMF there was obtained (RS)-2-[3-(thiophen-3-ylmethoxy)-propoxy]-tetrahydro-pyran, which after cleavage of the THP group analogously to Example 53(c) yielded 3-(thiophen-3-ylmethoxy)-propan-1-ol. Subsequent conversion into the mesylate according to a procedure known from the literature and alkylation therewith effected analogously to Example 44(e) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] gave tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate. By alkylation with 2-chloromethyl-1,4-dimethoxy-naphthalene analogously to Example 1(g) there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow solid; MS: 648 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2oc(-c3ccc(F)cc3)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2oc(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-5-methoxybenzoxazole (2.89 g, 11.89 mmol) in methylene chloride (70 mL) was added BBr3 (1 M in CH2Cl2, 13.08 mL) dropwise in an ice-bath. The resulting mixture was stirred at room temperature for 36 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed sequentially with saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated under reduced pressure. Column chromatography (ethyl acetate:Hexanes=1:4) gave 2-(4-fluorophenyl)benzoxazol-5-ol as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CC(CC)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:22]2[O:24][CH2:23]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Reactant: BrCC1CO1
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Yield: 57.8 %

Procedure:
Methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g, 0.0028 mole) anhydrous potassium carbonate (0.39 g, 0.0028 mole), epibromohydrin (0.78 g, 0.00565 mole) and dry ethyl methyl ketone (20 ml) were stirred and heated under reflux for 16 hours. The cooled mixture was filtered and evaporated under reduced pressure to an oil which was purified by elution from a silica column with chloroform-methanol to give methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)-benzoyl]propionate (0.52 g, 57%, m.p. 84°-87°). (Found: M+, 321, C16H19NO6 requires M, 321).
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][S:12](Cl)(=[O:14])=[O:13])([O:8][CH3:9])=[O:7].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH2:16]([CH:10]([CH2:11][S:12]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)(=[O:14])=[O:13])[C:6]([O:8][CH3:9])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 1L round bottom flask was added the resultant compound from Example 3E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0° C. in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed, the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1 ; 1H NMR (CDCl3 ) delta 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H, J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDCl3) delta 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]CC1C=CC=CC=1)=[O:5])[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)COCCCCCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COCCCCCO

Procedure:
58 g (0.21 mol) of benzyl 5-ethoxycarbonylmethoxypentyl ether are dissolved in 580 ml of tetrahydrofuran and the solution is hydrogenated under normal pressure at room temperature by addition of 5.8 g of 10% Pd/C as catalyst. Upon cessation of hydrogenation, the catalyst is removed by filtration and the filtrate is concentrated by evaporation. Distillation of the residue gives 5-ethoxycarbonylmethoxypentanol as a colourless liquid of b.p. 107°-111° C./2.10-2 torr.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1.O>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:20][C:21](=[O:23])[CH3:22])[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CC(=O)/C=C/c1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of benzaldehyde (1.650 ml, 16.32 mmol) in DMF (5 ml) was added dropwise over the course of ½ hour to a mixture of sodium cyanide (0.401 g, 8.17 mmol) in DMF (20 ml) at 35° C. Stirring was then continued for 1.5 hours at 35° C. A solution of (E)-4-(4-fluorophenyl)but-3-en-2-one (2.0 g, 12.18 mmol) and DMF (10 ml) was then slowly added dropwise over the course of 3.5 hours at 35° C. Stirring was then continued for 3.5 hours at the same temperature. The reaction mixture was treated with twice its volume of water and extracted with DCM. The combined extracts were washed with water and brine, dried with Na2SO4, filtered and concentrated to give a liquid, which was further purified by chromatography on silica gel using an automated Biotage system and EtOAc/Hex (0-50%) to give 2-(4-fluorophenyl)-1-phenylpentane-1,4-dione (1.5 g, 5.55 mmol, 45.6% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95-7.93 (m, 2H), 7.50-7.46 (m, 1H), 7.40-7.32 (m, 3H), 7.26-7.21 (m, 3H), 5.11 (dd, 1H), 3.59 (dd, 1H), 2.76 (dd, 1H), 2.19 (s, 3H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:45]([O:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][NH:58][CH2:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[CH:64]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>O1CCCC1>[C:45]([O:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][N:58]([CH2:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[CH:64]=1)[C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:51])([CH3:48])([CH3:46])[CH3:47]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(Cc2cc3ccccc3o2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC

Procedure:
Experimental condition analogous to Example 1, from 3,4,5-trimethoxy benzoic acid 72 mg (0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 75 mg (0.39 mmol), 1-hydroxybenzotriazole 45 mg (0.33 mmol), triethylamine 0.05 mL (0.39 mmol), and 2-(S)-{[(benzofuran-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 100 mg (0.3 mmol) in 3 mL tetrahydrofuran. The compound was purified through silica gel chromatography elution with ethyl acetate: methanol 9:1, gave 93 mg of white oily compound.