Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(C2CCC2)N=C(C)C=1)=O.[OH-].[Li+].C1(N2C(N3C[C@H](S(C4C=CC=CC=4C(F)(F)F)(=O)=O)C[C@@H]3C(O)=O)=CC(C)=N2)CCC1>>[CH:29]1([N:24]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]2)[CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)n(C2CCC2)n1
Agent: [Li+]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as white solid which was used in the next step without further purification. MS (ESI): m/z=456.1 [M−H]−.
Reaction SMILES: C(O[SiH](O[CH2:9][CH3:10])OCC)C.[C:11]1([C:13](=[CH:15][C:16](=[C:18]([CH:20]=1)C)C)C)[CH3:12]>>[C:11]1([CH:12]([C:10]2[CH:9]=[CH:18][CH:20]=[CH:11][CH:12]=2)[CH2:13][CH2:15][CH3:16])[CH:20]=[CH:18][CH:16]=[CH:15][CH:13]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: Cc1cc(C)c(C)cc1C
Product: CCCC(c1ccccc1)c1ccccc1

Procedure:
Triethoxisilane (compound 2, 0.6 mmol) instead of pentamethyldisiloxane was used for the same reaction to Example 14A. 1H-NMR analysis with durene as an internal standard material without isolation of products showed that (4,4-diphenylbuthyl) triethoxysilane (compound 3) was produced with the yield of 85%, and 1,1-diphenylbutane (compound 4) was produced with the yield of 6%.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1.CCOC(C)=O.O>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:24]([C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)(=[O:26])=[O:25])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
2-Amino-5-chlorobenzophenone (5.33 g, 23 mmol) was dissolved in 100 mL pyridine and stirred at room temperature. 4-Bromobenzenesulfonyl chloride (6.17 g, 24.1 mmol) was added and the mixture was stirred overnight. The mixture was poured in a steady stream into 350 mL vigorously stirring chilled 6M HCl which resulted in the precipitation of a reddish oil. The solution was diluted with 100 mL EtOAc and 200 mL H2O, shaken in a separating funnel and the aqueous layer discarded. The organics were dried and reduced in vacuo to yield title compound (10.2 g, 98%). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 7.43-7.48 (m, 5H), 7.62 (t, 1H), 7.74 (d, 1H), 9.62 (s, 1H). MS: m/z=449.9 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17]C)[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(F)cc1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(c2ccc(F)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 180 °C

Procedure:
A stirred mixture of 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone (1.2 g., 0.00354 mole) and pyridine hydrochloride (12 g.) is heated at 180° C. for one hour, then poured into water (500 ml.). The 2-(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone melts at 193°-200° C. and is used without further purification.
Reaction SMILES: [F:1][C:2]1(F)[C:7]([N:8]2[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[F:16][C:11]1([CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: CC(=O)NC[C@H]1CN(C2=CC=C(N3CCC(F)(CO)CC3)C(F)(F)C2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(COS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[3-fluoro-4-(4-fluoro-4-hydroxymethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.76 mmol) with methanesulfonyl chloride (0.91 mmol) in dichloromethane (10 ml) at 10° C. in presence of triethylamine (1.3 mmol) followed by purification by using silica gel column chromatography in 75% yield. M.P. 182-183° C. and MS (M+1)=462 (MH+, 100%) M.F.=C19H25F2N3O6S.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][CH:5]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[CH2:19][CH2:18]2)[N:3]=1.CCN(CC)CC.[C:38](Cl)(Cl)=[O:39].CO>C1COCC1.C1(C)C=CC=CC=1>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:4]2[CH:5]=[CH:6][C:7]3[C:8]([CH3:10])([CH3:9])[O:11][C:38](=[O:39])[NH:1][C:2]=3[N:3]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(O)c1ccc(CCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)nc1N
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)Nc2nc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 2-(2-amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-3-yl)-propan-2-ol (442 mg, 0.98 mmol) in THF (4 mL) and toluene (1 mL) was added Et3N (0.30 mL, 2.15 mmol, 2.2 equiv). The mixture was cooled to 0° C. and phosgene (20% in toluene, 0.65 mL, 1.3 mmol) was added. A precipitate formed. The reaction was stirred at 0° C. for 15 min and at room temperature for 2 h. MeOH was added to quench the excess phosgene. Saturated NaHCO3 and H2O were added and the mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (3.5% MeOH/CH2Cl2) gave the title compound as a white foam (411 mg, 0.861 mmol, 88%). The foam was dissolved in Et2O/CH2Cl2 and 1 M HCl in Et2O (0.86 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a fluffy white solid (400 mg). MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Reaction SMILES: ClC(OCC)=O.[F:7][C:8]1[CH:45]=[CH:44][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:23]3[C:41]([OH:43])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.CN1CCOCC1.C[Si](C)(C)[O:55][NH2:56]>CN(C=O)C>[OH:55][NH:56][C:41]([CH:23]1[C:24]2[C:29](=[C:28]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:44]=[CH:45][C:8]([F:7])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1)(=[O:20])=[O:21])=[O:43]
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NO)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
8.16 μl (85.6 μmol) of ethyl chloroformate are added to a solution of 38 mg (68.5 μmol) of 2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-(2-piperidin-1-ylethoxy)-1,2,3,4-tetra-hydroisoquinoline-1-carboxylic acid and 16.6 μl (151 μmol) of N-methylmorpholine in 2 ml of DMF at −20° C., and the mixture is stirred at −20° C. for 30 minutes. Then 37.2 μl (274 μmol) of O-trimethylsilylhydroxylamine are added, and the solution is warmed slowly to room temperature. After standing overnight, it is concentrated in vacuo and the residue is purified by chromatography on silica gel, allowing the title compound to be isolated as a colorless solid. Yield 46%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]4)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:31])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(O)(=O)C.C(O)(=O)C(O)=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]4)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:31])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(C)c4)n3)cn2)C1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)nc3)no2)ccc1CC(C)C
Yield: 94.1 %

Procedure:
The title compound (0.13 g) was synthesized in a yield of 83% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 21 (21d) using methyl 1-({5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methyl)azetidine-3-carboxylate (0.14 g, 0.34 mmol) that was obtained in Example 28 (28b), a 1 N aqueous solution of sodium hydroxide (11.0 mL, 1.0 mmol), acetic acid (58 μL, 1.0 mmol), and oxalic acid (15 mg, 0.17 mmol).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][O:14][C:15]1([C:32]([F:35])([F:34])[F:33])[CH2:18][CH:17]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([CH:30]=3)[NH2:29])[N:20]=2)[CH2:16]1.CCCP(=O)=O>C(OC(=O)C)C.C(=O)(O)[O-].[Na+]>[CH3:13][O:14][C:15]1([C:32]([F:34])([F:35])[F:33])[CH2:16][CH:17]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH:29][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:12])[CH:30]=3)[N:20]=2)[CH2:18]1
Reactant: COC1(C(F)(F)F)CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: O=C(O)c1cnc2ccccn12
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC1(C(F)(F)F)CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 70 °C

Procedure:
A stirring mixture of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (10 mg, 0.064 mmol) and 5-(5-(3-methoxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (125) (21 mg, 0.064 mmol) in ethylacetate (1 mL) was added propylphosphonic anhydride solution 50 wt. % in ethyl acetate (76 uL, 0.128 mmol). The reaction was heated at 70° C. for 3 hours. The reaction was cooled to room temperature and diluted with a solution of saturated sodium bicarbonate. The organic was separated and washed with 2× water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography using DCM:EtOAc:MeOH (1:1:0.1). N-(5-(5-(3-methoxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F97). 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 9.47-9.44 (m 1H), 8.59 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 7.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.55-7.50 (m, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 1H), 3.76-3.68 (m, 1H), 3.38 (s, 3H), 2.88-2.85 (m, 4H), 2.36 (s, 3H) MS m/z 471.15 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:44]4[CH2:45][CH2:46][CH:41]([C:34]5[C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[NH:32][CH:33]=5)[CH2:42][CH2:43]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(1H-indol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z=630.92 (M+H+); retention time=0.99 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[CH:18]([OH:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:24])([CH3:25])[C:18](=[O:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc2c(cc1/C=C/c1ccc(C(=O)O)c(C)c1)C(C)(C)CC(O)C2(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cc1/C=C/c1ccc(C(=O)O)c(C)c1)C(C)(C)CC(=O)C2(C)C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 1.6 g (4.2 mmol) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-methyl-6-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid in 50 ml of methylene chloride at room temperature was added 1.97 g (4.65 mmol) of Dess-Martin periodinane. After 1 h, the reaction mixture was poured into brine and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, adsorbed onto silica gel and purified by flash chromatography (gradient elution: hexane-8% ethyl acetate/hexane) to afford 1.45 g (92%) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-methyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid (M+=376).
Reaction SMILES: ClC1C=CC(Cl)=CC=1OC1N=CC=CC=1C(O)=O.[Cl:19][C:20]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:21]=1[O:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=O.F[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH2:43][CH2:42][CH2:41]2.N1C2C(=CC=CC=2)CCC1>>[Cl:19][C:20]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:21]=1[O:22][C:23]1[C:24]([C:25]([N:44]2[C:45]3[C:40](=[CH:39][CH:38]=[CH:47][CH:46]=3)[CH2:41][CH2:42][CH2:43]2)=[O:27])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(Cl)cc1Cl
Reactant: Fc1ccc2c(c1)CCCN2
Agent: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cccnc1Oc1ccc(Cl)cc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 37 replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,4-dichloro-phenoxy)-nicotinic acid and 6-fluoro-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 399.0 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=[O:12].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH:10]([CH3:9])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CBr
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of lithium diisopropylamide (Aldrich, 100 mL, 2M solution in THF) in THF (950 mL) at −78° C. was added a suspension of 4-benzyloxypropiophenone (Lancaster, 50 g) in THF (75 mL) over one minute. After 45 minutes, ethyl bromoacetate (Aldrich, 23 mL) was added during one minute. After one hour, the mixture was allowed to warm to 0° C. over 3 hours. The reaction was quenched with saturated NH4Cl (500 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by chromatography over silica gel using 10% ethyl acetate in hexane as eluant to provide the above compound as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42]>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:42]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: COc1cccc(C(=O)OCCCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3OCc3ccc4ccccc4c3)cc2)c1

Procedure:
(bb) In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24(t)] with 3-methoxy-benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-{4-[3-(3-Methoxy-benzoyloxy)-propyl]-phenyl}-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 610 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]2[N:6](C(OC(C)C)=O)[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Cl-].[Na+]>O.CS(C)=O>[CH3:1][C:2]1[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1C(F)(F)F)NCCCC2=O
Yield: 79.9 %

Procedure:
Heat a degassed mixture of isopropyl 7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (6.68 g, 20.28 mmol) and sodium chloride (37.5 g) in water (7 mL) and dimethyl sulfoxide (180 mL) at reflux under nitrogen for 5 h. Dilute the cooled mixture with water (500 mL) and extract with ethyl acetate (2×300 mL). Wash the combined organic extracts with brine (200 mL), dry over anhydrous sodium sulfate and filter. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:4), to afford the title compound as a yellow solid (3.94 g, 80%). ESI MS m/z 242 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:15][CH2:16][CH2:17][CH:18]=[O:19])[CH2:12][CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:11]([N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH:13]=[CH2:14]
Reactant: COc1nnc(N=C=O)s1
Reactant: C=CCCNCCC=O
Solvent: c1ccccc1
Product: C=CCCN(CCC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 3-but-3-enylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield the desired product the diethyl acetal of 3-[1-but-3-enyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]-propionaldehyde.
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][C:12]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:15]1)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:30]([O:29][C:27](=[O:28])[NH:26][C@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][N:14]1[CH2:15][CH:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:17]1)([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CC(Oc2ccc(Cl)cc2)C1)C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]4-oxo-butyric acid benzyl ester (1.0 g, 2.04 mmol) in dry THF (10 ml) is treated with a 1M solution of lithium aluminium hydride (5.1 ml) keeping the temperature between 20-30° C. using an ice-water bath. The reaction mixture is stirred at ambient temperature under argon for 2 hours, then quenched by addition of saturated aqueous Na2SO4 and filtered through a celite™ filter. The filtrate is partitioned between ethylacetate and saturated brine. The ethylacetate phase dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 5:95 methanol/dichloromethane) to afford {(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-carbamic acid tert-butyl ester. [MH]+ 371.0.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[O:22][CH3:23].[CH3:24][C:25](O)([CH3:27])[CH3:26]>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:18])=[CH:15][C:14]=1[O:22][CH3:23]
Reactant: CC(C)(C)O
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Br
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
To MgSO4 (4.8 g, 1.8 mL, 40 mmol) in DCM (40 mL) was added H2SO4 (1.0 g, 533 μL, 10 mmol) at 0° C. and the reaction mixture was allowed to stir for 30 minutes. 4-Bromo-3-methoxy-benzoic acid (2.3 g, 10 mmol) was added followed by 2-methylpropan-2-ol (3.7 g, 4.8 mL, 50 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. MgSO4 was removed by filtration and 1N NaOH solution was added until pH 9 was achieved. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield tert-butyl 4-bromo-3-methoxy-benzoate (0.4 g, 14%).