Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19]C3C=CC=C(Cl)C=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:27](N)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl[C:37]1C=C(C=CC=1)N>>[C:2]1([CH3:37])[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(Nc3cccc(Cl)c3)c12
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Chlorophenyl)-1,4-dihydro-4-oxo-5-(3-chlorophenylamino)-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that phenethylamine was replaced with 3-chloroaniline. MS 382 (M+1)+.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([Si:6]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:7]1(O)[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[C:13]([Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])(O)[C:12]2[C:11]3[C:31]([C:35]#[CH:36])=[CH:32][CH:33]=[CH:34][C:10]=3[S:9][C:8]1=2)[CH3:5]>C(O)(=O)C.CC(C)=O>[CH2:40]([Si:6]([CH2:4][CH3:5])([CH2:38][CH3:39])[C:7]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[C:13]([Si:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:29][CH3:30])=[C:12]2[C:8]=1[S:9][C:10]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[CH:36])[C:11]=12)[CH3:41]
Reactant: C#Cc1cccc2sc3c(c12)C(O)([Si](CC)(CC)CC)c1sc2ccccc2c1C3(O)[Si](CC)(CC)CC
Agent: Cl[Sn]Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: C#Cc1cccc2sc3c([Si](CC)(CC)CC)c4c(sc5ccccc54)c([Si](CC)(CC)CC)c3c12
Temperature: 2.5 °C

Procedure:
A solution of tin(II)chloride dehydrate (2.08 g, 9.2 mmol) in 50% acetic acid (35 ml) is added within ten minutes to a solution of 6,12-bis-triethylsilanylethynyl-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 4) (2.40 g, 6 mmol) in acetone (30 ml). There is a slight temperature increase (2-3° C.), and formation of a yellow suspension takes place. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with 50% acetic acid (30 ml), water (twice with 40 ml), and acetone (2*40 ml). The residue is then dried to give crude product which is filtered over a pad of silica (60 g) with chloroform to give product which is recrystallised from ethyl acetate (40 ml). The product is filtered off, washed with ethyl acetate (2*10 ml), and hexane (10 ml). After drying, the title product is obtained as yellow crystals. Mp. (DSC) 82° C. and 204° C. 1H-NMR (CDCl3, 300 MHz) δ 0.92 (q, 6H, SiCH2); 1.26 (tr, 9H, CH3); 7.48 (m, 1H, H-2), 7.51 (m, 1H, H-3), 7.91 (d, 1H, H-4); 9.29 (d, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 4.95 (CH2); 8.10 (CH3); 102.69, 107.26 (C≡C); 112.46 (C-6); 122.74 (C-4); 124.39 (C-2); 125.05 (C-1); 127.47 (C-3); 132.72 (C-6a); 135.49 (C-6b); 140.53 (C-4-a); 143.08 (C-5a).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27](O)=[O:28])[C:10]=2[C:30](O)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)[CH3:34].O>C(O)(=O)C>[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[C:27](=[O:28])[C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]4=[C:9]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:10]=3[C:30]2=[O:31])=[CH:42][CH:43]=1)[CH3:34]
Reactant: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.0 g, 4.67 mmol) and ethyl(4-aminophenyl)acetate (1.67 g, 9.35 mmol) were heated to 120° C. in acetic acid (30 ml) for 2 hours. The mixture solidified on standing at room temperature overnight. Water was added and the solid collected by filtration and washed with water. This was dried under vacuum to give the title compound (2.65 g, 4.64 mmol). LC/MS: Rt=4.24, [MH]+ 572.
Reaction SMILES: [C:1]([CH:4]1[CH:9]2[CH:5]1[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.O>[C:1]([CH:4]1[CH:5]2[CH:9]1[CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2C(C#N)C2C1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 2 (1.83 g, 8.09 mmol) in DMF (30 mL) was added cyanuric chloride (1.50 g, 8.09 mmol) and stirred for 2 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (2×80 mL). The combined organic extracts were washed with water (2×100 mL), brine (120 mL), dried over MgSO4 and concentrated under vacuum to afford 3 (1.67 g, 99%) as a clear yellow oil; 1H-nmr (400 MHz, CDCl3) δ 3.80-3.58 (m, 2H), 3.40 (d, J=12.0 Hz, 2H), 2.16 (s, 2H), 1.43 (s, 9H), 1.25 (t, J=3.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][CH2:12][CH2:13][C:14]2([OH:27])[CH2:26][CH2:25][C:17]3([O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]3)[CH2:16][CH2:15]2)[CH3:10])=[CH:5][CH:4]=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([N:11]2[CH2:12][CH2:13][C:14]3([CH2:15][CH2:16][C:17](=[O:22])[CH2:25][CH2:26]3)[O:27][C:29]2=[O:31])[CH3:10])=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:12][CH2:13][C:14]3([CH2:15][CH2:16][C:17]4([O:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][O:22]4)[CH2:25][CH2:26]3)[O:27][C:29]2=[O:31])[CH3:10])=[CH:5][CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)cc1
Product: COc1ccc([C@H](C)N2CCC3(CCC(=O)CC3)OC2=O)cc1
Product: COc1ccc([C@H](C)N2CCC3(CCC4(CC3)OCC(C)(C)CO4)OC2=O)cc1
Yield: 27 %

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-methoxy-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; besides the title compound the intermediate 3-[(S)-1-(4-methoxy-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one (27% of theory) is also isolated. Yield: 38% of theory; LC (method 4): tR=1.41 min; Mass spectrum (ESI+): m/z=318 [m+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC=CC=1>[O:15]([C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 84 h
Yield: 97.9 %

Procedure:
Dry benzene (450 mL) was added to 1.50 g acridone (1 equiv.) under N2-atmosphere. SOCl2 (3.37 mL, 6 equiv.) was added and the reaction mixture was refluxed over night followed by removal of solvent by evaporation. Dry DMF (75 mL), phenol (2.17 g, 3 equiv.) and K2CO3 (4.26 g, 3 equiv.) were added under N2. The reaction was stirred at 60° C. for 3.5 days. After filtration and evaporation the crude product was purified using flash chromatography (CH2Cl2 to CH2Cl2:Et2O, 6:1) giving 2.04 g of 2, 98% yield. 1H NMR (CDCl3): 8.28 (5+4, br ddd, J=8.9, 1.1, 0.8 Hz, 2H), 8.11 (8+1, ddd, J=8.7, 1.3, 0.8 Hz, 2H), 7.79 (6+3, ddd, J=8.9, 6.6, 1.3 Hz, 2H), 7.47 (7+2, ddd, J=8.7, 6.6, 1.1 Hz, 2H), 7.28 (2′+4′, m, 2H), 7.06 (3′, m, 1H), 6.86 (1′+5′, m, 2H). 3.40 (6, m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33][CH:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:33][CH:32]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC3=C(Oc4cccc(OC)c4C3)C2=O)nc1
Yield: 18.3 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.54 mmol) (Example 7, Step 2c), commercially available 6-amino-nicotinic acid methyl ester (98 mg, 0.64 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (113 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (80 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl ester (50 mg, 18.4%), as a white solid. 1H NMR (DMSO-d6) δ: 11.32 (br. s., 1H), 8.87 (br. s., 1H), 8.28 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.10 (br. s., 1H), 4.38 (d, J=18.6 Hz, 1H), 4.04 (d, J=19.1 Hz, 1H), 3.84 (d, J=15.7 Hz, 6H), 3.55 (br. s., 2H), 1.48-1.89 (m, 7H), 0.85-1.29 (m, 6H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(OC(C)C)(OC(C)C)OC(C)C.C([O:25][C:26]([C:28]1[CH:53]=[CH:52][C:31]([O:32][C:33]2[C:38]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:30][CH:29]=1)=O)C.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1.C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33]2[C:38]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:52][CH:53]=1)=[O:25]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1ccc(Oc2ncccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)OC(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzimidazole (0.351 g, 2.97 mmol) and triisopropyl orthoformate (3.9 mL, 17.61 mmol) in toluene (25 mL) was heated in a 100 mL round bottom flask equipped with a Dean-Stark trap and reflux condenser under an atmosphere of nitrogen. After 1 h the solvent was removed in vacuo. The residue was dissolved in THF (8 mL) and to the solution was added a solution of tert-butyl 4-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.07 g, 2.509 mmol) in THF (8 mL). The mixture was cooled (−78° C.) and lithium diisopropylamide (2.0M solution in heptane/THF/ethylbenzene, 1.80 mL, 3.60 mmol) was added dropwise resulting in a reddish solution. After 2 h the reaction was quenched with saturated NH4Cl and allowed to warm to rt. The mixture was partitioned between EtOAc/saturated NaHCO3. The organic layer was washed with brine and dried over Na2SO4. The solution was filtered and the filtrate was evaporated onto silica gel and purified by flash chromatography (Isco, (120 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 499.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: OC1C2C(=CC=CC=2)C=CC=1.C(OC1C=CC(C2C=CC(C([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44][CH:45]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:46]([F:49])([F:48])[F:47])=[O:43])=[C:38]([F:56])[CH:37]=3)=O)=CC=2)=CC=1)CCCCCCC.C(N(CC)CC)C>C(Cl)Cl>[F:56][C:38]1[CH:37]=[C:36]([OH:35])[CH:41]=[CH:40][C:39]=1[C:42]([O:44][CH:45]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:46]([F:48])([F:49])[F:47])=[O:43]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Agent: Oc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F

Procedure:
To a solution of the hydroxynaphthalene (0.64 g) obtained in (2) above and triethylamine (0.3 g) in methylene chloride (40 ml) was added drop by drop the 6-(1,1,1-trifluoro-2-octyloxycarbonyl)naphthalene-2-carboxychloride (0.8 g) obtained in (1) above. To the solution was added dimethylaminopyridine (0.02 g) and the mixture was stirred at room temperature overnight. The solution was neutralized with dilute aqueous hydrochloric acid solution and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer: hexane/ethyl actate=20/1) to obtain the titled compound (0.4 g) having specific rotation, [α]D20 =+45.5°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].CS(C)=O.Br.[Br:15][C:16]1[CH:17]=[N:18][C:19]([OH:22])=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[N:20]([CH2:7][CH3:8])[CH:21]=1
Reactant: CCI
Reactant: Oc1ncc(Br)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCn1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
With cooling with ice, potassium carbonate (13.2 g, 95.7 mmol) and ethyl iodide (2.84 mL, 35.6 mmol) were added to a dimethyl sulfoxide (130 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (7.0 g, 27.3 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=1/1) to obtain the entitled compound (3.34 g, 60%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:5][CH2:4][O:3]1.[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: [H][H]
Reactant: CC(C(=O)OCc1ccccc1)N1CCOC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)O)N1CCOC1=O
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A 25 mL round bottom flask under an atmosphere of nitrogen was charged with 0.030 g (0.028 mmol) of 10 weight percent palladium on activated carbon and wet with 2 mL of ethanol. Next, a solution of 0.37 g (1.5 mmol) of benzyl 2-(2-oxo-1,3-oxazolidin-3-yl)propanoate from step B above in 10 mL of ethanol was added and the mixture placed under 1 atmosphere of hydrogen. The reaction was stirred for 3 h then filtered through a pad of Celite®. The pad was washed with 20 mL of ethanol and the filtrate was evaporated in vacuo to afford the title compound as a colorless solid (0.24 g, quantitative yield). 1H-NMR (500 MHz, CD3OD) δ: 4.60-4.30 (m, 3H), 3.80-3.60 (m, 2H), 1.45 (d, J=3.5, 3H). LC-MS: m/z (ES) 160 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([O:14]C(OCC(Cl)(Cl)Cl)=O)[CH2:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH2:10][CH:9]2[CH2:31][CH2:32][CH3:33])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]([CH2:31][CH2:32][CH3:33])[CH2:10][NH:11][CH2:12][CH:13]2[OH:14])=[CH:4][CH:3]=1
Reactant: CCCC1CN(C(=O)OCC(Cl)(Cl)Cl)CC(OC(=O)OCC(Cl)(Cl)Cl)C1c1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCC1CNCC(O)C1c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 54.7 %

Procedure:
A mixture of 13.05 g (21.6 mmol) of 2,2,2-trichloro-ethyl (3RS,4SR,5SR)-4-(4-chloro-phenyl)-3-propyl-5-(2,2,2-trichloro-ethoxycarbonyloxy)-piperidine-1-carboxylate and 14.5 g of zinc in 200 ml of glacial acetic acid was treated in an ultrasound bath for 15 hours. In order to complete the reaction, a further 5 g of zinc were subsequently added and the mixture was left in the ultrasound bath for a further 5 hours. For the working-up, the zinc was filtered off under suction, the residue was rinsed with glacial acetic acid and the solution was evaporated to dryness under reduced pressure. The residue was partitioned between 1N NaOH and ethyl acetate, the separated aqueous phase was then again extracted with ethyl acetate and finally the combined organic phases were evaporated under reduced pressure. The crude product obtained was crystallized from diethyl ether and gave 3.0 g (55% of theory) of (3RS,4RS,5SR)-4-(4-chloro-phenyl)-5-propyl-piperidin-3-ol as colourless crystals; MS: 253 (M)+. For purification, the mother liquor was chromatographed on silica gel using a 90:10:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained a further 1.1 g (20% of theory) of (3RS,4RS,5SR)-4-(4-chloro-phenyl)-5-propyl-piperidin-3-ol.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by hydrolysis of 9a using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: C([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)(=O)C.[Br-:18].[Br-].[Br-].[C:21]1([N+](C)(C)C)[CH:26]=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:18][CH2:26][CH2:21][C:11]1[C:12]2[CH2:13][CH2:14][C:15]3[C:6](=[CH:5][CH:4]=[CH:17][CH:16]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc2c(c1)CCc1ccccc1-2
Reactant: [Br-]
Reactant: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: BrCCc1cccc2c1CCc1ccccc1-2
Reaction time: 0.33 h

Procedure:
To a stirred solution of 5.56 (25 mmol) of (8) in 100 mL of THF, 9.78 g (26 mmol) of phenyltrimethylammonium tribromide was added. After stirring for 20 min, the solution became pale yellow and a precipitate of phenyltrimethylammonium bromide separated. Water (300 mL) was added and the mixture was extracted with ethyl acetate. The extract was washed with water and evaporated to dryness to yield (28) which was further purified by trituration with ether and recrystallized from methanol to furnish pure (28), 5.66 g; m.p. 82°-83° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:9][C:10]1[CH:15]=[C:14](Br)[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]([O:21]C)=[O:20]>CN(C=O)C.[Cu]I>[CH3:17][C:12]1[CH:13]=[C:14]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:15]=[C:10]([CH3:9])[C:11]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1c(C)cc(Br)cc1C
Reactant: OCC(F)(F)F
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(F)(F)F)cc(C)c1CC(=O)O

Procedure:
18.05 g (451 mmol) of sodium hydride are initially charged in 500 ml of DMF, 41.05 g (410 mmol) of trifluoroethanol are added dropwise, after the evolution of gas has ended 15.63 g (82 mmol) of copper(I) iodide are added, a solution of 21.10 g (82 mmol) of methyl 2,6-dimethyl-4-bromophenylacetate in 100 ml of DMF is slowly added dropwise and the mixture is boiled at reflux for 2.5 h.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1.Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39])=[O:27].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=1)[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=1[C:38]([F:39])([F:40])[F:41])=[O:27]
Reactant: CC(C)c1ccc(NC(=O)CBr)c(C(F)(F)F)c1
Reactant: COCCNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
0.533 g (1.65 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (Example III-33) is initially charged in 6 ml of dimethylformamide. At room temperature, 0.588 g (1.81 mmol) of 2-bromo-N-[4-isopropyl-2-(trifluoromethyl)phenyl]acetamide (Example III-17) and 0.152 g (1.81 mmol) of sodium bicarbonate are added. The mixture is set at 90° C. for 2 hours. The reaction mixture is then allowed to cool, and water is added. The mixture is extracted once with ethyl acetate and the organic phase is washed three times with water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (cyclohexane/ethyl acetate 4:1) and the product is then dried under reduced pressure. This gives 0.885 g (95% of theory) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([Br:20])=[C:15]([CH3:21])[CH:14]=1)(=O)=O.[O:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1>CN(C=O)C>[Br:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:27]2[CH2:28][CH2:29][O:24][CH2:25][CH:26]=2)=[CH:14][C:15]=1[CH3:21]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCOCC2)cc(C)c1Br
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (1.99 g) and Pd(dppf)Cl2-DCM complex (196 mg) were added to a solution of 4-bromo-3,5-dimethylphenyl trifluoromethanesulfonate (1.6 g) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS No. 287944-16-5) (1.11 g) in DMF (16 mL). The reaction mixture was stirred at 85° C. for four hours. The reaction mixture was returned to room temperature, and the reaction mixture was then concentrated under reduced pressure. MTBE, water and brine were added to the residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 2%) to give the title compound (747 mg).