Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].O.[C:10]1([S:16]([OH:19])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:19][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)c1ccccc1
Reactant: CCCC(=O)C=[N+]=[N-]
Solvent: CCOCC
Solvent: O
Product: CCCC(=O)COS(=O)(=O)c1ccccc1
Yield: 77.2 %

Procedure:
A 1.2 g quantity of 1-diazo-2-pentanone is dissolved in 50 ml of ether, and 2.3 g of benzenesulfonic acid monohydrate is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter followed to give 2.0 g of 2-oxopentylbenzene sulfonate in the form of a colorless transparent oil (Compound 6). Yield 77.2%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2,2,2]octane-1-carboxylic acid (1.00 g) was suspended in dichloromethane (10 mL). To this suspension, 3,4-dihydro-2H-pyran (1.20 mL) and then p-toluenesulfonic acid monohydrate (6.3 mg) were added and the mixture was stirred at room temperature for 30 minutes. Subsequently, the reaction mixture was sequentially washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1) to give 2-tetrahydropyranyl 4-benzyloxycarbonylaminobicyclo[2,2,2]octane-1-carboxylate (1.18 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C(OCC)(=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Br)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 85.2 %

Procedure:
To a solution of methyl 4-bromo-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoate (0.207 g, 0.5 mmol) in 1,2-dimethoxyethane (3 mL) was added 4-chlorophenyl-boronic acid (0.094 g, 0.6 mmol), tetrakis(triphenylphospine)palladium(0) (0.010 g), and 1 M aq potassium phosphate (0.8 mL). The reaction mixture was heated at 80° C. overnight under a nitrogen atmosphere. The reaction was then cooled to room temperature and water (10 mL) and ethyl acetate (50 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by RPHPLC (ethyl acetate/hexane 1:4) to give 0.190 g (85%) of product.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl.O>[CH2:32]([O:31][C:29]([NH:28][C@@H:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([NH:20][C@H:8]([CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[CH2:7][C:6]([OH:40])=[O:5])=[O:39])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN1CCc2cc(F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)O)CN1CCc2cc(F)ccc21
Reaction time: 8 h

Procedure:
The title compound of example 158 (46 mg, 83 μmol) was dissolved in a mixture of TFA, dichloromethane and water in a ratio of 45:45:10 (1 mL) and stirred overnight. The solvent was removed and the reaction was lyophilized to afford 58.1 mg (114% of theory) of material that likely had some water or multiple TFA salts included; 1H NMR (MeOD, 400 MHz) δ 0.91 (s, 9H), 1.49 (dd, 1H, J1=9.3, J2=14.4), 1.67 (dd, 1H, J1=3.1, J2=14.5), 2.63 (d, 1H, J=6.5), 2.98 (dd, 1H, J1=J2=8.1), 3.17 (dd, 1H, J1=5.5, J2=13.6), 3.26-3.34 (m, 1H), 3.47 (dd, 1H, J1=8.6, J2=17.3), 3.58 (dd, 1H, J1=8.4, J2=16.6), 4.13 (dd, 1H, J1=3.0, J2=9.3), 4.46-4.55 (m, 1H), 4.98-5.11 (m, 2H), 6.68 (dd, 1H, J1=4.1, J2=8.6), 6.77-6.84 (m, 1H), 6.86-6.91 (m, 1H), 7.24-7:33 (m, 5H); HPLC-MS calcd. for C27H34FN3O5 (M+H+) 500.2, found 500.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CN([CH:31]=[O:32])C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([CH:31]=[O:32])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=Cc1cnccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution (50 ml) of 4-chloropyridine (25.0 g, 0.22 mol) in tetrahydrofuran was added dropwise to a tetrahydrofuran solution (300 ml) of lithium diisopropylamide prepared from a solution (179 ml, 0.29 mol) of 1.6 M n-butyllithium in hexane and diisopropylamine (33.4 g, 0.33 mol) under an argon atmosphere at −78° C. After stirring for 30 min., DMF (19.3 g, 0.26 mol) was added and the mixture was gradually heated to room temperature. The reaction mixture was extracted with ethyl acetate (200 ml)-5% NH4Cl aq. (300 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a crude title compound (27 g, 86%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH:18][CH:36]([CH3:38])[CH3:35])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CC1(CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)NCC1(c2ccccc2)CC1(NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
To the obtained 2-aminomethyl-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic acid t-butyl ester (60 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL) were added acetone (13 μL, 0.17 mmol) and sodium triacetoxyborohydride (37 mg, 0.17 mmol) at 0° C. under argon atmosphere, and the mixture was stirred at room temperature for 20 hours. To the obtained solution was added acetic acid (50 μL), and the mixture was further stirred for 21 hours. Then saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added and the aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layer was washed with water (2.0 mL) and saturated aqueous sodium chloride solution (2.0 mL), and dried over magnesium sulfate. After filtration and evaporation, the obtained residue was purified by silica gel chromatography (chloroform:methanol=25:2) to give the title compound (45 mg, yield 69%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:20]=3[NH2:21])[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:20]=3[NH:21][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][CH:44]=[C:36]([C:34]([N:33]([CH3:32])[CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:35])[CH:37]=3)[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(-c2cn(Cc3ccccc3)nn2)ccn1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(-c3cn(Cc4ccccc4)nn3)ccn2)c1
Yield: 37.6 %

Procedure:
A solution of 22 mg of 2-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-(piperidin-1-yl)aniline 24d, 15.2 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 22.6 mg of HATU, and 27.9 mg of diisopropylethylamine in 0.3 mL of DMF was stirred for 1 h. The solution was filtered and the product was isolated from the filtrate by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 13.4 mg of product. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.97 (s, 1H), 8.78 (d, J=5.0 Hz, 1H), 8.35 (s, 1H), 8.32-8.26 (m, 1H), 8.03-7.94 (m, 2H), 7.91 (d, J=5.2 Hz, 1H), 7.70-7.50 (m, 3H), 7.35 (mj, 4H), 7.28-7.19 (m, 1H), 5.69 (s, 2H), 4.09-3.90 (m, 3H), 3.85-3.76 (m, 2H), 3.71-3.53 (m, 4H), 2.91 (s, 3H), 1.69 (s, 4H), 1.55 (s, 2H). MS (ESI, m/z) 685.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([CH2:9][NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:15][CH2:14]2)=[O:8])=[C:5]([O:37][CH3:38])[CH:4]=1.CS(C)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:2]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([CH2:9][NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:15][CH2:14]2)=[O:8])=[C:5]([O:37][CH3:38])[CH:4]=1)=[O:1]
Reactant: COc1cc(CO)ccc1C(=O)CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(C=O)ccc1C(=O)CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-hydroxymethyl-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-yl ester (78 mg, 1.5 mmol; prepared as described in Preparation 20) in DCM (2.5 mL) at −15° C. was added DMSO (130 μL, 22.5 mmol), and DIPEA (130 μL, 7.5 mmol). To the solution was added sulfur trioxide-pyridine complex (240 mg, 15 mmol). After 30 minutes, the reaction mixture was quenched with water (˜3 mL). Two layers were separated, the organic layer was dried over MgSO4; filtered and the title intermediate was used directly in the next reaction.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=[O:12].Cl.O1CCCC1>O>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=[O:12]
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1oc(-c2ccccc2)nc1CO
Yield: 70.3 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde (4.50 g), 1N hydrochloric acid (50 mL) and tetrahydrofuran (100 mL) was heated under reflux for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:1, v/v) to give 4-hydroxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde as pale-yellow crystals (2.6 g, yield 70%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 134-135° C.
Reaction SMILES: [O:1]=[C:2](N1CCOC1=O)[CH2:3][CH2:4][CH:5]=O.[CH3:13][C:14]1([NH2:24])[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:13][C:14]1([N:24]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:1])[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1
Reactant: CC1(N)CCC2(CC1)OCCO2
Reactant: O=CCCC(=O)N1CCOC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(N2CCCC2=O)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 8.9 %

Procedure:
Dissolve 4-oxo-4-(2-oxo-oxazolidin-3-yl)-butyraldehyde (7.35 g, 42.96 mmol) in DCE (400 mL). Add 8-methyl-1,4-dioxa-spiro[4.5]dec-8-ylamine (7.36 g, 42.96 mmol), and acetic acid (2.58 g, 42.96 mmol) at room temperature under nitrogen. Stir the solution for one hour and then add sodium triacetoxyborohydride (18.21 g, 85.92 mmol). Stir the reaction mixture for over night and then add water (400 mL). Extract the aqueous layer with dichloromethane (3×400 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc-Hexane) to give 0.92 g (9.0%) of 1-(8-Methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one as a colorless oil.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[CH3:47][O:48][C:49]1[CH:54]=[C:53]([NH:55][NH2:56])[CH:52]=[CH:51][N:50]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:55]([C:53]3[CH:52]=[CH:51][N:50]=[C:49]([O:48][CH3:47])[CH:54]=3)[N:56]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: COc1cc(NN)ccn1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
500 mg (1.16 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 305 mg (1.74 mmol) of 2-methoxypyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 18 mg (3% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].Cl[CH2:30][C:31](Cl)=[O:32].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[C:31](=[O:32])[CH2:30][O:28][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OCC2=O)cc1

Procedure:
Prepared by analogy to Example 74a by reaction of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (diastereomer B), chloroacetyl chloride and sodium hydride, and purification of the base on a silica gel column using toluene/ethyl acetate=6:4 as eluant.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH2:10]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH2:11][CH2:12][CH3:13]>ClCCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N+:16]1[CH:17]=[CH:18][N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]=1
Reactant: CCCCn1ccnc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCCCn1cc[n+](C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The procedure of Example 2 was followed. 3 g of trimethyloxonium tetrafluoroborate in suspension in 10 ml of 1,2-dichloroethane was added to 2.7 ml of N-butylimidazole in 10 ml of 1,2-dichloroethane. The mixture was stirred for 4 hours at room temperature. The remaining solvent was evaporated off under vacuum using a vane pump. A colorless liquid was obtained.
Reaction SMILES: S([CH:5]([CH2:17]C(OCCCCCCCC)=O)[C:6]([O:8]CCCCCCCC)=[O:7])(O)(=O)=O.[Na].[O-2].[Zn+2:31].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>C1(C)C=CC=CC=1>[C:6]([O-:8])(=[O:7])[CH:5]=[CH2:17].[Zn+2:31].[C:32]([O-:36])(=[O:35])[CH:33]=[CH2:34]
Reactant: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Reactant: C=CC(=O)O
Agent: [Na]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]

Procedure:
U.S. Pat. No. 5,789,616 disclosed a process comprising adding at the first an anionic surfactant, sodium dioctyl sulfosuccinate, in toluene, following with adding successively zinc oxide, fatty acid and acrylic acid, and, after completion of the reaction, drying by distillation at a reduced pressure, and pulverizing and sieving the thus produced crude product to yield a modified zinc acrylate powder having a particle size characterized in that 64% of particles<44 μm, 54% of particles<10 μm, and 41% of particles<5 μm, while the part that had a particle size of>105 μm and must be removed by sieving was estimated to be 31%. The anionic surfactant, i.e. sodium dicotyl sulfosuccinate, used in this technique to be added at the first stage of the reaction might cause the swelling of the content in the reaction mixture such that in the subsequent addition of acrylic acid, might lead to local thickening and hence difficulty for stirring, and therefore, the reaction could be completely only through slow addition of raw material and postponing the reaction time. This might be the cause that made the zinc acrylate powder thus produced coarser and the particle size distributions non-uniform. On the other hand, it had an advantage that the trouble of sticking the wall of the reactor and the drying tank in the course of drying could be avoided.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:29])[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[C:19]([Cl:27])[C:18]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:29])[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19]([Cl:27])[C:18]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (2S,4R)-2-(3-chloro-2-fluoro-5-methoxycarbonyl-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, 0.3 mmol) in THF/MeOH/H2O 2:1:1 (4 mL) was added LiOH (7 mg, 0.3 mmol). The reaction mixture was stirred for 4 h at ambient temperature and the solvent was removed in vacuo to give the title compound which was used without further purification. MS (LC/MS): 319.0 [M−100]+. tR (HPLC conditions c): 4.40 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H](O[C:37]2[CH:42]=[C:41]([N+:43]([O-])=O)[CH:40]=[C:39](F)[CH:38]=2)C1)=O)(C)(C)C>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[NH2:43][C:41]1[CH:42]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cc(N)cc(F)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(N)cc(F)c2)C1
Product: Nc1ccccc1
Reaction time: 8 h

Procedure:
3-(5-Amino-3-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. Four cylinders charged with (S)-3-(3-fluoro-5-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (50 g), 10% Pd(OH)2/C (5.0 g) and MeOH (300 mL) were subjected to hydrogenation under 50 psi H2. The mixture was stirred vigorously overnight. The mixture was filtered through a pad of diatomaceous earth and rinsed with methanol. The alcoholic solutions were combined and concentrated to give the aniline (S)-3-(5-amino-3-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as syrup in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:14][C@H:13]3[N:15]([CH3:16])[C@H:10]([CH2:11][CH2:12]3)[C@@H:9]2[C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:14][C@H:13]3[N:15]([CH3:16])[C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[CH:4][CH:3]=1
Reactant: CN1[C@H]2CC[C@@H]1[C@H](c1nnc(-c3ccccc3)o1)[C@@H](c1ccc(Cl)cc1)C2
Solvent: ClC(Cl)Cl
Product: CN1[C@H]2CC[C@@H]1[C@@H](c1nnc(-c3ccccc3)o1)[C@@H](c1ccc(Cl)cc1)C2
Product: Cl

Procedure:
Further elution gave as a second fraction 0.1 g (13%) of white solid which was characterized to be 3β-(4-Chlorophenyl)-2α-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane: 1H NMR (CDCl3) 1.76 (m, 3 H), 2.06 (s, 3 H), 2.45 (s, 3 H), 3.36 (m, 2 H), 3.51 (m, 1 H), 3.65 (m, 1 H), 7.21 (m, 4 H), 7.47 (m, 3 H) 7.91 (m, 2 H); mp 170-171° C.; Anal calcd for C22H22CIN3O; C=69.55; H=5.84, N=11.06; Cl=9.33; found C=69.49, H=5.85, N=11.01; Cl=9.41; [α]D+33.06° (c=0.18, CHCl3).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]2[CH2:25][CH2:24][NH:23][CH2:22][C@@H:21]2[OH:26])=[CH:17][CH:16]=1>>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][C@H:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([CH3:14])=[CH:16][CH:17]=3)[C@H:21]([OH:26])[CH2:22]2)(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C[C@@H]2CCNC[C@@H]2O)cc1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Product: Cc1ccc(C[C@H]2CCN(CCS(=O)(=O)c3ccc(O)cc3)C[C@H]2O)cc1
Yield: 31 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3R,4R)-4-(4-methyl-benzyl)-piperidin-3-ol in 31% yield as a white foam.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[S:13](=[O:17])(=[O:16])([OH:15])[OH:14]>O>[S:13]([O-:17])([O-:16])(=[O:15])=[O:14].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: O=S(=O)(O)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)[NH+]1O
Product: O=S(=O)([O-])[O-]
Reaction time: 0.5 h

Procedure:
To a glass 0.5L reaction bottle are added 10.0 g (58 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 2.85 g (29 mmol) sulfuric acid, 200 mg 5% Pt on C and 100 mL water. Catalytic hydrogenation is carried out at 50 psi for 30 minutes at room temperature. Catalyst is removed by filtration through a pad of Celite. Removal of water yields the product as an pale yellow solid.