Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[C@H:12]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH2:13].C(OC(N[C@H](C(O)=O)CC1CCCCC1)=O)(C)(C)C.[C:42]([O:46][C:47]([NH:49][C@@H:50]([C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][CH3:54])=[O:48])([CH3:45])([CH3:44])[CH3:43]>>[C:42]([O:46][C:47]([NH:49][C@@H:50]([C:55]([NH:57][CH2:58][C:59]([NH:13][C@H:12]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:22])=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][CH3:54])=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)CCCCCNC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CC1CCCCC1)C(=O)NCCCCCC(=O)OC

Procedure:
After preparing N-(6-methoxy-6-oxohexyl)-3-cyclohexyl-L-alaninamide monohydrochloride from the title product of Example 36 by the methods of Examples 1 and 3, the title compound was prepared by coupling this material with the title product of Example 99 using the general mixed anhydride procedure of Example 1. Structure assignment of the product isolated by chromotography was supported by elemental analysis.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH3:31][O:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[CH3:31][O:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: COCCc1ccc(N)cc1
Product: COCCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Light yellow solid. MS (ESI): 513.3 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(2-methoxy-ethyl)-phenylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)(O)[O-].[Na+].CI>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:23])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoic acid (45.0 g, 145 mmol) was dissolved in DMF (425 mL) and treated with sodium bicarbonate (24.4 g, 290 mmol) followed by methyl iodide (36.1 mL, 580 mmol). The solution stirred at rt for 16 h. The solution was diluted with ethyl acetate (500 mL), washed with water (500 mL), saturated aqueous sodium bicarbonate solution (300 mL), aqueous hydrochloric acid solution (1.0 N, 500 mL), and the organic phase dried over sodium sulfate. The solvent was removed in vacuo to afford product as a slightly yellow solid (46.2 g, 98%). 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 4.45–4.41 (m, 1H), 3.71 (s, 3H), 3.30–3.26 (m, 1H), 3.05–2.99 (m, 1H), 1.36 (s, 9H); LCMS found for C15H20N2O6Na (M+Na)+: m/z=347.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:12][C:13]1C(Cl)=N[CH:16]=[N:17][C:18]=1Cl)=O.N[C:22]([NH2:24])=[S:23].CC[OH:27]>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[S:23][C:22]2[N:24]=[CH:16][N:17]=[C:18]([OH:27])[C:13]=2[N:12]=1
Reactant: O=C(Cc1c(Cl)cccc1Cl)Nc1c(Cl)ncnc1Cl
Reactant: CCO
Reactant: NC(N)=S
Solvent: O=CO
Product: Oc1ncnc2sc(Cc3c(Cl)cccc3Cl)nc12
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-(2,6-dichloro-phenyl)-N-(4,6-dichloro-pyrimidin-5-yl)-acetamide (77.0 g, 221 mmol), thiourea (16.8 g, 221 mmol), and EtOH (500 mL) was added formic acid (3 mL) at rt. The resulting mixture was heated to 90° C. After 12 h, the reaction mixture was cooled and concentrated. The resulting residue was collected by filtration and washed with H2O (100 mL) followed by hexanes (100 mL). The title compound as a dark brown solid was further dried by high vaccum for 12 h and used crude (68 g, 70% apparent purity by analytical HPLC). An analytically pure sample could be obtained by purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid. MS (ESI): mass calcd. for C12H7Cl2N3OS, 310.9; m/z found, 312.0 [M+H]+. 1H NMR (CD3OD): 8.04 (s, 1H), 7.44-7.37 (m, 2H), 7.31-7.26 (m, 1H), 4.70 (s, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:6][C:5]1=[O:16])([CH3:3])[CH3:2].OS(O)(=O)=O.[N+:22]([O-])([OH:24])=[O:23]>>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:22]([O-:24])=[O:23])=[CH:11][CH:12]=2)[C:7]([CH3:14])([CH3:15])[CH2:6][C:5]1=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)CC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)N1C(=O)CC(C)(C)c2cc([N+](=O)[O-])ccc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
N-Isopropyl 4,4,-dimethyl-2-oxo-quinoline (Compound 39, 472 mg, 2.18 mmol) was added dropwise to H2SO4 (con. 0.3 mL) cooled to -5° C. with a salt-ice bath. To this brown oil was added a mixture of HNO3 (0.16 mL) and H2SO4 (0.65 mL) at a rate so slow that the internal temperature did not exceed 0° C. The resulting dark oil was stirred vigorously for 10 minutes, followed by addition of ice-water. The yellow reaction mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with NaHCO3 (10%), dried over MgSO4 and concentrated to give yellow solids. 1H NMR d 1.34 (s, 6H), 1.53(d, J=6.8 Hz, 6H), 2.48 (s, 2H), 4.70-4.79 (m, 1H), 7.25 (d, J=6.3 Hz, 1H), 8.10-8.15 (m, 2H).
Reaction SMILES: [CH3:1]I.[OH:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[C:9]=2[CH:8]=[CH:7]1>>[CH3:1][O:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[C:9]=2[CH:8]=[CH:7]1
Reactant: CI
Reactant: O=Cc1cccc2c1ccn2CC(O)c1ccccc1
Product: COC(Cn1ccc2c(C=O)cccc21)c1ccccc1
Yield: 93 %

Procedure:
The same procedures used in Example 324 were repeated except for using 113 mg of methyl iodide and 189 mg of 1-(2-hydroxy-2-phenylethyl)indole-4-carbaldehyde prepared in Example 321 as a starting material to give 185 mg of 1-(2-methoxy-2-phenylethyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 93%.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:21](Cl)([Cl:23])=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([N:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2[CH:8]=1)[C:21]([Cl:23])=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)Cl
Reactant: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: Cc1ccccc1
Product: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (51) (200 mg, 0.73 mmole) in 2 mL toluene was treated with 0.4 mL of a 20% phosgene solution in toluene, stirred at room temperature for 12 hours and concentrated in vacuo to provide 0.24 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (53) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine and nicotinic acid as starting materials, MS (LC/MS): 408.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:20][O:19][B:18]([OH:21])[C:17]=2[CH:22]=1)(=[O:11])=[O:10].[N:23]([CH2:26][CH3:27])=[C:24]=[O:25]>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:20][O:19][B:18]([OH:21])[C:17]=3[CH:22]=2)(=[O:10])=[O:11])=[C:2]([NH:1][C:24]([NH:23][CH2:26][CH3:27])=[O:25])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(N)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
To a solution of 2,4-diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.0 g, 3.13 mmol) in DMF (15 ml) was added isocyanatoethane (0.5 g, 7.0 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with H2O, brine. The organic fraction was then dried (MgSO4) and concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound as a white powder (0.3 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (s, 1H), 9.17 (s, 1H), 7.99 (s, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.12 (dd, J=2.0, 8.4 Hz, 1H), 7.02 (t, J=5.2 Hz, 1H), 6.08 (dd, J=2.0, 8.4 Hz, 1H), 5.88 (s, 2H), 4.87 (s, 2H), 3.04˜3.11 (m, 2H), 1.07 (t, J=7.2 Hz, 3H); MS (ESI) m/z=389 (M−1, negative); HPLC purity: 93.6% (MaxPlot 200-400 nm), 90.3% (220 nm).
Reaction SMILES: [C:1](OC)(=O)[CH:2]=[CH2:3].[CH3:7][CH2:8][C@@H:9]1[C@@H:14]2[CH2:15][C@@H:16]([C@H:17](O)[C:18]3C=CN=C4C=3C=C(OC)C=C4)N(C[CH2:13]2)C1.[C:31]([O:34][C:35](=[O:37])[CH3:36])(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:3])[CH2:7][CH2:8][CH2:9][C:14]2([CH3:13])[C:15]1=[CH:16][CH:17]=[CH:18][CH:36]2[C:35]([O:34][CH3:31])=[O:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1C=CC=C2C(C)(C)CCCC21C
Yield: 84 %

Procedure:
A solution of 3.86 g (20 mM) of the amine obtained according to letter b above, 3.44 g (40 mM) of methyl acrylate in 20 ml of toluene containing 20 mg of hydroquinine was heated in an autoclave of stainless steel under nitrogen at 150° during 3 h. Then, 4.1 g (40 mM) of acetic anhydride were added and the mixture was heated at 150° during 1 h. The evaporation of the solvent and distillation of the residue gave 3.95 g (yield: 84%) of the desired ester; bp 160°-180°/2.66 Pa.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]1([C:7](=[O:8])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To deoxybenzoin (0.500 g, 2.55 mmol) in THF (12 mL) at −78° C. were added a THF solution of potassium tert-butoxide 1M (2.5 mL, 2.55 mmol) and MeI (0.396 mL). After a period of 0.5 h, at room temperature, NH4OAc aqueous was added to the reaction mixture. The organic phase was separated, dried over NaSO4, filtered and evaporated. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[F:25][CH:26]([F:29])[CH2:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:28][CH2:27][CH:26]([F:29])[F:25])=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: NCC(F)F
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)NCC(F)F

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and 2,2-di-fluoro-ethylamine (28.5 mg, 0.35 mmol). The title compound was obtained as a solid (84.0 mg, 62% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.24 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 8.36 (1H, m), 5.98 (1H, m), 3.85 (2H, m), 3.50 (2H, m). MS m/z: 469.05, 471.06 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.O1CCC[CH2:35]1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:35])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Dissolve 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (860 mg, 2.08 mmoles) in diethyl ether (100 mL) under N2. Cool the solution to 0° C. in an ice bath, and add sodium hydride (1.1 equiv; 2.29 mmoles; 91.52 mg), followed by injecting methyl iodide (2.00 equiv; 4.16 mmoles; 259.12 μL). Stir the mixture for 1 hour at 0° C., and then warm to room temperature. Inject tetrahydrofuran (40 mL) into the above mixture, and then stir at room temperature overnight. Concentrate the mixture under reduced pressure, and then dissolve the residue in EtOAc. Wash with saturated aqueous sodium chloride. Purify the residue via silica gel chromatography, eluting with EtOAc:hexane (7:3) to offer 270 mg (30% yield) of a title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:15]1[O:19][C:18]2[CH:20]=[C:21](O)[CH:22]=[CH:23][C:17]=2[O:16]1>>[O:16]1[C:17]2[CH:23]=[CH:22][C:21]([O:1][CH2:2][CH:3]3[CH:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:7][CH2:6][NH:5][CH2:4]3)=[CH:20][C:18]=2[O:19][CH2:15]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: OCC1CNCCC1c1ccccc1
Product: c1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1

Procedure:
reaction of 3-hydroxymethyl-4-phenyl-piperidine of formula (V) coming from step b) with sesamol (VI) to obtain the formula (I) 3-[(1,3-benzodioxol-5-yloxi)methyl-]4-phenyl-piperidine:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:38]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:38])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCN(C(=O)Cc2ccccc2O)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
Triethylamine (1.06 ml) and octadecyl isocyanate (2.35 ml) were added to a solution containing 2-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-ethanone (1.60 g) in methylene chloride (16 ml) and stirred for 15.5 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1 to 30:1), thereby yielding the entitled compound (3.23 g) as white solid.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].CCCCCCC.CC(OC)(C)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[F:54])=[CH:43][CH:42]=1)[CH2:36][C:37]([OH:39])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[F:54])=[CH:43][CH:42]=1)[CH2:36][C:37]([O:39][CH:3]([O:2][C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:13])[CH3:4])=[O:38])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC(OC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)OC(C)(C)C)OC(=O)OC1CCCCC1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
1-chloroethyl cyclohexyl carbonate was resolved by HPLC on a preparative Chiralpak ID column using Heptane/TBME 98:2 and a polarimetric detector. From this resolution, Peak 2 was determined to have 98% ee on a Chiralpak ID column and was used in the subsequent step. To a solution of 1-chloroethyl cyclohexyl carbonate (second-eluting isomer from a Chiralpak ID column Heptane/TBME 98:2) (1.75 g, 8.47 mmol) and (R)-3-((tert-butoxycarbonyl)amino)-4-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)butanoic acid (1.5 g, 3.68 mmol) in 35 mL anhydrous DMF at 0° C. was added cesium carbonate (1.2 g, 3.68 mmol). After the reaction mixture was stirred for 5 min, the ice-bath was removed and the reaction mixture was stirred at 23° C. for 4.5 hours. LCMS showed that the reaction was approximately 40% complete. The reaction mixture was stirred approximately 18 hours, at which point LCMS showed the reaction was approximately 95% complete. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride (pH of aqueous layer approximately 6-7). After separation, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with water, once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography on an Isco RediSep 120 g silica cartridge (0-20% ethyl acetate-heptane) to afford (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)butanoate (2.07 g, 97% yield, 95.8% ee as determined on analytical supercritical fluid HPLC using a Chiralpak AD-H 5-55% MeOH with 20 mM NH4OH in CO2. LCMS (ES+) C30H37ClFNO7: Calc.: 577.2; Found: 578.3[M+H]+.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.[N:29]12[CH2:36]C[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][NH:21][C:5](=[O:11])[O:4][CH:2]1[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:36]1
Reactant: OC1CN2CCC1CC2
Reactant: NCc1cccc(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(Br)c1)OC1CN2CCC1CC2
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a stirred and cooled (0° C.) solution of triphosgene (0.80 g, 2.7 mmol) in THF (20 mL) was added, dropwise, a mixture of (3-bromophenyl)methanamine (1.0 g, 5.4 mmol) and triethylamine (1.08 g, 10.7 mmol) in THF (30 mL) over 2 h. After the addition was complete, the mixture was refluxed for 1 h and then cooled to room temperature. Quinuclidin-3-ol (1.40 g, 10.7 mmol) was added, and the mixture was refluxed for 18 h. The solvent was removed in vacuo, and the residue was dissolved in EtOAc, washed with water, dried over Na2SO4, and concentrated. The crude residue was purified by silica gel column chromatography (eluting with EtOAc/methanol=10/1) to give quinuclidin-3-yl 3-bromobenzylcarbamate as a colourless liquid (0.68 g, 37%).
Reaction SMILES: O[CH:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.Cl.C[OH:62]>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[C:51]([O:58][CH:2]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:11][CH:12]=1)(=[O:62])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CO
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC(O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(OC(CCCOc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50 %

Procedure:
A solution of 30 mg (0.052 mmol) of tert-butyl (3RS,4RS)-4-[4-(4-hydroxy-4-phenyl-butoxy)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate (configuration unknown in the butoxy part), 25.5 gl (0.186 mmol, 3.6 eq.) of triethylamine and 1.7 ml of methylene chloride was treated in succession with 21.6 gl (0.186 mmol, 3.6 eq.) of benzoyl chloride and 2 mg (0.01 6 mmol) of 4-dimethylaminopyridine. This reaction solution was stirred at room temperature for 10 hours, then poured into 5 ml of water and extracted three times with 10 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The light yellow resin (62 mg) was dissolved in 1 ml of methanol, again concentrated, dried in a high vacuum. Without further purification and characterization the product obtained was reacted with hydrogen chloride in methanol analogously to the procedure described in Example 22(l). The brown-yellow resin (56 mg) was separated on silica gel using a 95:5 mixture of methylene chloride and methanol (extracted against 5 vol. % conc. ammonia) as the eluent. There were obtained 15 mg (50% of theory) of 4-[4-[(3RS,4RS)-3-naphthalen-2-ylmethoxy-piperidin-4-yl]-phenoxy]-1-phenyl-butyl benzoate (configuration unknown in the butoxy part) as a colourless resin; MS: 586 (M+H)+.