Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[F:4][C:5]([F:26])([F:25])[C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]=2[CH2:23][NH2:24])[CH:9]=[CH:10][CH:11]=1.O.O=[CH:29][C:30]([OH:32])=[O:31]>ClCCl.CO>[F:26][C:5]([F:4])([F:25])[C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]=2[CH2:23][NH:24][CH2:29][C:30]([OH:32])=[O:31])[CH:9]=[CH:10][CH:11]=1
Reactant: O=CC(=O)O
Reactant: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CNCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
In a reactor equipped with a filter and an emptying system and placed on a vortex, were introduced 0.33 g (0.656 mmol) of cyanoborohydride resin. The resin was swelled in 3 ml of dichloromethane, the mixture was stirred at r.t. for 10 min and then dichloromethane was removed by filtration. The operation was repeated a second time and then a mixture of 0.2 g of (3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl) methanamine and 0.055 g (0.596 mmol) of 2-oxoacetic acid hydrate solubilised in 3 ml of methanol was added. The mixture was stirred under a slow vortex at r.t. for 24 h. The resin was removed by filtration, washed with 15 ml of methanol, 15 ml of dichloromethane and then again 15 ml of methanol. The obtained filtrate was concentrated in vacuo and the residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol/aqueous ammonia (20% by mass), 80/20/2, v/v/v). 0.049 g (yield=22%) of 2-(((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)amino) acetic acid were obtained as a white solid. LC-MS: m/z=374 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.76 (d, J=6.7 Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.69 (dd, J=8.3, 7.1 Hz, 2H), 7.53-7.42 (m, 1H), 7.16 (td, J=6.8, 1.0 Hz, 1H), 4.17 (s, 2H), 3.31 (s, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)[CH2:3]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 90.5 %

Procedure:
To a mixture of trans-4-(3-hydroxy-cyclopentylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile (500 mg, 2.0 mmol) in anhydrous DMF (15 mL) was added, at RT, under argon atmosphere, imidazole (680 mg, 10.0 mmol) followed by tert-butyldimethylsilylchloride (750 mg, 5.0 mmol) and the resulting mixture was stirred at RT for 64 h. The reaction mixture was quenched with NH4Cl (sat'd aq, 20 mL) and was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 95/5) to give 660 mg of 4-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbonitrile as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:3].[NH2:12][C:13]1[CH:20]=[C:19](F)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>CCO>[NH2:12][C:13]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])([OH:11])[CH2:10][CH2:9]2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN(C)CC1(O)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)CC1(O)CCN(c2cc(N)ncc2C#N)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-[(dimethylamino)methyl]-4-piperidinol (1.0 g, 4.33 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 593 mg, 4.33 mmol) and triethylamine (3.62 ml, 26.00 mmol) was heated at 80° C. in a septum sealed reaction vessel under argon for 28 h. The reaction mixture was cooled, EtOH (5 ml) added and heated at 80° C. for 18 h. The reaction mixture was then evaporated, partitioned between aqueous NaHCO3 solution and DCM, extracted 5× with DCM containing 10% MeOH, the combined DCM layers dried over MgSO4 and evaporated. The residue was triturated with Et2O (20 ml) and DCM (1 ml) to give the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 5.82 (s, 1H), 4.70 (s, br, 2H), 3.65-3.58 (m, 2H), 3.27-3.20 (m, 2H), 2.38 (s, 6H), 2.26 (s, 2H), 1.68-1.62 (m, 4H). (UPLC-MS 6) tR 0.25; ESI-MS 276.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.O=S(Cl)[Cl:15]>C(Cl)Cl>[ClH:15].[Cl:15][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: FC(F)(F)c1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of (5-(trifluoromethyl)pyridin-2-yl)methanol (0.400 g, 2.26 mmol) in CH2Cl2 (4.4 mL) was cooled to 0° C. and SOCl2 (0.494 mL, 6.77 mmol) was added as a CH2Cl2 solution (2.2 mL). The reaction was allowed to gradually warm to ambient temperature over 1 hour and then stirred for an additional 1 hour. The reaction was concentrated and dried under vacuum to provide the desired product (0.520 g, 99%) as dark oil that was used directly in the subsequent step.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:16])(=O)/[CH:10]=[CH:11]\[C:12]([NH2:14])=[O:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1(=[O:13])[NH:14][C:9](=[O:16])[CH:10]=[CH:11]1
Reactant: NC(=O)/C=C\C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C=Cc1ccccc1
Solvent: O
Product: O=C1C=CC(=O)N1

Procedure:
5.0 g of Styrene/maleamic acid and 0.5 g of anhydrous sodium acetate were added to 50 mL of acetic anhydride in a round bottom flask equipped with an inert gas inlet tube, magnetic stirrer and a heating bath. The resulting solution was heated and maintained at 80°-85° C. under nitrogen for 3 hr. The cooled solution was poured in a slow stream into a well stirred beaker of 400 ml cold (5°-10° C.) water. The resulting solid was collected by suction filtration, washed with four portions of acidic (1 mL acetic acid per 200 mL of water) ice water and vacuum dried. Nearly quantitative yields of product were obtained.
Reaction SMILES: [CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([OH:36])=[O:35].C(N(CC)CC)C.O.O.O.C([O-])(=O)C.[Na+:51]>CC(C)=O>[CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([O-:36])=[O:35].[Na+:51]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1

Procedure:
The ceftriaxone acid was dissolved in aqueous acetone using triethylamine. To the clear solution obtained, sodium acetate trihydrate (13 g) was added and. charcoalized. To the filtrate, acetone (720 mL) was added over 1-2 h and filtered to get ceftriaxone sodium. The wet material of ceftriaxone sodium thus obtained was dissolved in water (120 mL) followed by addition of acetone (222 mL). The solution was cooled to −5 to −15° C. and the impurity separated as a sticky mass. The clear solution was separated and the temp raised to 18-22 C. Acetone (624 mL) was added under stirring over 1 h, filtered and washed with acetone. Drying under vacuum afforded pure ceftriaxone sodium (19.2 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH:10]O>C(O)(=O)C>[CH:1]1([C:4]2[CH:5]=[N+:6]([O-:10])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cncc(C2CC2)c1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc(C2CC2)c1
Yield: 67.1 %

Procedure:
1.93 g of 3-cyclopropylpyridine (synthesized according to a method disclosed in Tetrahedron Lett. 2002, 39, 6987-6990) was dissolved in 15 mL of acetic acid, then 2.4 g of hydrogen peroxide solution (31%) was added thereto, and heated overnight under reflux. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and water in the subsequent order. The organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and 1.47 g of 3-cyclopropylpyridine 1-oxide [121-1] was obtained as a brown oily product.
Reaction SMILES: [Cl:1][C:2]1([Cl:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([Cl:9])[Cl:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC1(C)C(CO)C1(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2C(C)(C)C2(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.9 %

Procedure:
A solution of 33.8 g of 2,2-dichloro-3,3-dimethylcyclopropane methanol in 200 ml of pyridine was cooled to 0° C., and 38.2 g of p-toluenesulfonyl chloride was added portionwise. The reaction mixture was left to stand for 12 hours in a refrigerator (0° C.), and then poured into 1 liter of ice water. The crystals precipitated were collected by filtration, washed with water, dried in the air, and washed with hexane to give 62 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl p-toluenesulfonate, the desired compound shown above. The melting point of the product was 96.5° to 97.5° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])C.[NH:14]1C=C(CC(O)=O)C=[N:15]1.O.NN>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])=[C:10]([CH3:11])[NH:9][N:8]=1
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Reactant: O=C(O)Cc1cn[nH]c1
Agent: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(C)c1CC(=O)NN
Yield: 68 %

Procedure:
As described for example 112a, (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (Rainer, Georg. 4-Pyrazoleacetic acid derivatives. U.S. (1979), U.S. Pat. No. 4,146,721) in butanol was reacted with hydrazine hydrate (3 equivalents) and the resulting mixture was heated under reflux for 6 h. Evaporation of all volatiles afforded the title compound as a colourless oil (yield: 68%). MS: m/e=183.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[H-].[Na+].I[CH3:27].O>CN(C)C=O>[CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON=C(C)c1ccc(S(=O)(=O)N(C)Cc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
0.4 g (1.2 mmol) of the compound from Example 2 was added to a slurry of 0.04 g (1.32 mmol) of NaH (95% pure) in 50 ml of dimethylformamide (DMF), and the mixture was then stirred at 20-25° C. for 10 min. A solution of 0.17 g (1.2 mmol) of iodomethane in 10 ml of DMF was then added dropwise, and the combined reaction solution was stirred at 20-25° C. for about 18 hours, poured into water and then extracted with MtBE. The the organic phases were washed with water and then dried. Removal of the solvent gave 0.3 g of the title compound as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CCN([CH2:16][CH3:17])CC>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:7]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:16][CH3:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Product: CCCCCC/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 181.8 %

Procedure:
1-bromo-4-nitrobenzene (2.01 g, 10 mmol), 1-ocetene (7.8 mL, 50 mmol), and Pd(OAc)2 (50 mg, 0.2 mmol) were stirred for 10 min under nitrogen atmosphere. Then tri-o-tolylphosphine (24 mg, 0.8 mmol) was added to the mixture and stirred for 10 min. Et3N (5.5 mL, 40 mmol) was then added to the mixture. The mixture was heated to 110° C. for 18 h. Water was added to the mixture and extracted with EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE as eluent to give compound the title compound (2.121 g, 90%). 1H NMR (300 MHz, CDCl3) δ 8.097 (d, 2H), 7.235 (d, 2H), 6.442 (s, 1H), 5.976-5.377 (m, 1H), 2.231-2.052 (m, 2H), 1.710-1.246 (m, 8H), 0.850 (t, 3H).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=1.C(O)(=O)C>C(Cl)Cl>[ClH:19].[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:55][CH2:56][CH2:57][C:58]4[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCCc1ccncc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCc1ccncc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 156.3 %

Procedure:
1,1'-(Azodicarbonyl)dipiperidine (1.06 g, 4.2 mmol) in methylene chloride (15 ml) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol), (prepared as described for the starting material in Example 24), tributylphosphine (848 mg, 4.2 mmol) and 4-(3-hydroxypropyl)pyridine (322 mg, 2.4 mmol) in methylene chloride (15 ml) and the mixture stirred for 3 hours at ambient temperature. Acetic acid (1 26 mg, 2.1 mmol) was added and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was triturated with ether, the resulting solid collected and dissolved in methylene chloride (20 ml). 5M Hydrogen chloride in isopropanol solution (0.7 ml) was added, the solution was diluted with isopropanol (5 ml) and concentrated by evaporation to a total volume of 4 ml. Ether was added and the resulting soild was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline hydrochloride (520 mg, 73%).
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH2:63]>C1COCC1>[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH:63][C:56]([C:53]1[CH:52]=[CH:51][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=1)=[O:58]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Yield: 99.8 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) followed by N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil. The oil was purified via silica gel flash chromatography using 140:10:1 (CHCl3/MeOH/NH4OH) as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide (0.95 g, 100% yield) as a yellow oil. Recrystallized from diethyl ether to obtain 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide (0.49 g) as a white solid that was collected by filtration.
Reaction SMILES: [CH3:1][NH:2][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:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[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:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:38]([N:2]([CH3:1])[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:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[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)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CNCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CN(CCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1)C(=O)c1ccccc1

Procedure:
Acylation of tert-butyl (3RS,4RS)-4-[4-(3-methylamino-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride analogously to the procedure described in Example 22(k) gave tert-butyl (3RS,4RS)-4-[4-[3-(benzoyl-methyl-amino)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 609 (M+H)+.
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[CH:11]=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:2][CH3:3])[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyltriphenylphosphonium bromide (4.69 g) was dissolved in anhydrous THF (70 mL) and the mixture cooled to 0-5° C. n-BuLi (5.05 mL of 2.5 M in hexane) was added dropwise and the resulting mixture was stirred at room temperature for 3 h. The mixture was cooled to −78° C. and a solution of 3,5-dimethoxybenzaldehyde (2 g) in anhydrous THF (14 mL) was added. The mixture was allowed to warm up to room temperature then stirred overnight. The mixture was concentrated, and the residue was taken up with AcOEt, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane and AcOEt 10:1) to give 3,5-dimethoxy-1-(1-propenyl)benzene as a mixture of cis and trans isomers (2.15 g).
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].C=O.[C:14](=O)([O-])[O-].[Na+].[Na+]>CO.O.[Pd]>[CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH3:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C(=O)O)CCCCN1
Agent: [Pd]
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC1(C(=O)O)CCCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-ethylpiperidine-2-carboxylic acid (320 mg, 1.65 mmol) in MeOH (4.0 mL) and water (4.0 mL) was added paraformaldehyde (372 mg, 4.13 mmol) and Pd/C (10%) (88 mg, 0.83 mmol). One equivalent of sodium carbonate (175 mg, 1.65 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for overnight. LC/MS indicated complete conversion of starting material. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with MeOH (2×30 mL). The filtrate was concentrated in vacuo to give the crude product. The crude solid was suspended in methanol (50 mL) and the resulting suspension was filtered and the filtrate was concentrated to give 2-ethyl-1-methylpiperidine-2-carboxylic acid (202 mg, 71.4%) as a solid. LC/MS: 172 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 3.58 (td, J=12.80, 3.51 Hz, 1 H), 3.09-3.20 (m, 1H), 2.81 (s, 3H), 2.17-2.29 (m, 1H), 1.54-1.84 (m, 7H), 0.98 (t, J=7.40 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11]/[CH:12]=[CH:13]\[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Cl)Cl>>[CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11][C@H:12]1[CH2:28][C@H:13]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C\C[C@@H](O)COCc2ccccc2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2C[C@@H](O)COCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of the commercially available (S,S) dioxaborolane ligand (7.37 g, 27.3 mmol) in DCM (20 mL) was added. The mixture was stirred for 10 minutes. The precipitate dissolves yielding a clear solution. A solution of the alkene from step B of this example (8.53 g, 22.7 mmol) in DCM (20 mL) was added. The solution was warmed to 0° C. and stirred for 24 hours. The solution remains clear after stirring for 24 hours. The reaction was quenched after 24 hr by addition of 50 ml of sat'd aq. NH4Cl. The mixture was placed in a separatory funnel, 250 ml DCM and 200 ml 10% HCl (aq) added, shaken, and the layers separated. The aqueous layer was re-extracted with DCM (2×150 ml), the organic layers combined, transferred to a Morton flask. 2N NaOH (300 ml) and 50 ml of 30% H2O2 were added. The biphasic solution was stirred vigorously for 12 hours. The layers were separated and the aqueous phase was re-extracted with DCM (2×150 ml), the organic phases were combined, washed with 10% HCl (aq, 250 ml), 1N Na2S2O3 (250 ml), sat'd NaHCO3 (250 ml), brine (250 ml), dried over MgSO4, filtered and stripped. The material was purified by chromatography on SiO2 eluting with 30% EtOAc:Hexanes. The desired product is obtained as a mixture with the minor diastereomer and the residual SM. The desired diastereomer was isolated by Chiralpak IA stationary phase chromatography.