Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-])(=[O:13])=[O:12])[CH3:10].P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:12])=[O:13])[CH3:10]
Reactant: Cc1ccc(C)c(C(C)S(=O)(=O)c2cccc[n+]2[O-])c1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: Cc1ccc(C)c(C(C)S(=O)(=O)c2ccccn2)c1

Procedure:
A mixture of 4.7 g (0.017 mole) of 2-[1-(2,5-Dimethylphenyl)-ethylsulfonyl]-pyridine-N-oxide, 60 ml of chloroform, and 7.5 g (0.055 mole) of PCl3 were placed in a 100 ml round bottom flask equipped with a magnetic stirrer and reflux condenser. The mixture was refluxed for one hour, and then the solvent was removed under reduced pressure using a rotovap. To the residue was added 25 ml of ethanol, followed by a second evaporation. The residue crystallized to give a white solid, which was recrystallized from ethanol. Obtained were 3.0 g of product having a melting point of 95-96° C. The IR, NMR and mass spectra were consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>>[CH3:12][C:7]1([CH3:13])[C:8]([CH3:11])([CH3:10])[O:9][B:5](/[CH:4]=[CH:3]/[CH2:2][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)[O:6]1
Reactant: CC1(C)OB(/C=C\CCl)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Yield: 24.8 %

Procedure:
Following the procedure outlined for Example 488, (Z)-2-(3-chloroprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (210 mg, 1.1 mmol) was reacted with tert-butyl piperidin-4-ylcarbamate (640 mg, 3.2 mmol) to afford the desired product (100 mg, 30%) as a brown solid: ESI MS m/z 367 [C14H27BN2O2+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:18])=[O:17])[CH3:14].[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([CH2:32][N+:33]([O-:35])=[O:34])[CH2:18][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:17])[O:15][CH2:13][CH3:14])=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: CCOC(OCC)P(C)(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(Cl)cc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 1.16 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 7.2 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 2.0 g of ethyl(diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 1.75 g of 4-chloro-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-chlorophenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.2 and +41.8 ppm (CDCl3).
Reaction SMILES: [CH2:1]([C@H:4]([CH:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH:10]=[CH2:11])[C:5]([OH:7])=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.CCCCCC>CN(C=O)C>[CH2:1]([C@H:4]([C@H:8]([CH2:9][CH:10]=[CH2:11])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC=C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CC[C@H](C(=O)OC(C)(C)C)[C@@H](CC=C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R)-2-allyl-3-(tert-butoxycarbonyl)hex-5-enoic acid, Intermediate S8E (1.8 g, 7.08 mmol) (anti:syn 4:1) in DMF (20 mL) at room temperature was added potassium carbonate (1.956 g, 14.16 mmol), followed by (bromomethyl)benzene (1.010 mL, 8.49 mmol). The reaction mixture was stirred at room temperature for 3 h and filtered to remove solid material. The filtrate was diluted with EtOAc and water. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered, and concentrated to give a crude material. This crude material was purified with ISCO 80 g column, 60 mL/min. 0-20% EtOAc/hexane in 25 min to afford (2R,3S)-1-benzyl 4-tert-butyl 2,3-diallylsuccinate, Intermediate S8F (1.5 g, 4.35 mmol, 61.5% yield) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ 7.43-7.31 (m, 5H), 5.81-5.62 (m, 2H), 5.17-5.08 (m, 2H), 5.08-4.96 (m, 4H), 2.84-2.63 (m, 2H), 2.45-2.23 (m, 3H), 2.18 (d, J=1.5 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH2:16]([O:23][CH2:24][C:25]([NH:27][NH:28][C:29]([C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:16]([O:23][CH2:24][C:25]1[O:30][C:29]([C@H:31]2[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:33][CH2:32]2)=[N:28][N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(COCc1ccccc1)NNC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](c2nnc(COCc3ccccc3)o2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hexachloroethane (205 mg, 0.87 mmol), triethylamine (0.29 ml, 2.08 mmol), and the compound (152 mg, 0.35 mmol) obtained in Step 1 above were added to a dichloromethane (9 ml) solution of triphenylphosphine (273 mg, 1.04 mmol) under ice cooling and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane:methanol [10:1 (v/v)], washed with 10% aqueous citric acid solution, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=2:1→1:1 (v/v)] to give 125 mg (86%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(O)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 4-methyl-3-(trifluoromethyl)phenol (5 g) and triethylamine (4.75 mL) in THF (40 mL) was added acetic anhydride (3.48 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.04 g).
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:7]=1[O:8][CH2:9][CH2:10][S:11][C:12]1[CH:32]=[CH:31][C:15]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.C(=O)([O-])[OH:39].[Na+]>>[Cl:5][C:6]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:7]=1[O:8][CH2:9][CH2:10][S:11]([C:12]1[CH:32]=[CH:31][C:15]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1)=[O:39]
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(SCCOc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: COc1cc2nccc(Oc3ccc(S(=O)CCOc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Nitric acid (0.5 ml) was added to 4-(4-{[2-(2,4-dichlorophenoxy)ethyl]sulfanyl}phenoxy)-6,7-dimethoxyquinoline (20 mg), and the mixture was stirred at 0° C. for one hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (19 mg, yield 92%).
Reaction SMILES: COOB([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)O.C1(P(C2CCCCC2)[C:19]2[C:24]([O:25][CH3:26])=[CH:23][C:22](OC)=[CH:21][C:20]=2OC)CCCCC1.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][C:6]1[C:37](=[O:40])[O:38][CH:8]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:7]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COOB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)c(P(C2CCCCC2)C2CCCCC2)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1=C(C)C(=O)OC1c1ccccc1
Yield: 100 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 4. The difference is that 3-methyl-4-chloride-5-phenyl-2(5H)— furanone (42.0 mg, 0.2 mmol), methoxyphenyl boronic acid (46.5 mg, 97%, 0.3 mmol), palladium acetate (2.3 mg, 0.01 mmol), dicyclohexyl(2,4,6-trimethoxyphenyl)phosphine (7.3 mg, 0.02 mmol), potassium carbonate (82.3 mg, 0.6 mmol) are reacted in 1 mL of toluene at 110° C. for 35 minutes and 3-methyl-4-(methoxyphenyl)-5-phenyl-2(5H)— furanone is obtained. The yield is 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:15]([C:12]2[N:11]=[N:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]=2[CH3:14])=[O:17])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2nnn(Cc3ccc(F)cc3)c2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[(4-fluorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.85 mmol), 3,4-bis(methyloxy)aniline (0.156 g, 1.2 eq), HATU (0.485 g, 1.5 eq) and DIPEA (240 μL, 1.5 eq) in DMF was stirred at room temperature overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM to give after precipitation from ether, the title compound as a white solid (180 mg, 57%). HRMS calculated for C19H19FN4O3 (M+H)+371.1519, found: 371.1500, Rt: 2.78 min. MP: 119.7° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18](Cl)[C:9]=2[C:8]1=[O:22].[F:32][C:33]1[CH:38]=[CH:37][C:36](OB(O)O)=[CH:35][CH:34]=1>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[C:9]=2[C:8]1=[O:22]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Product: CSc1nc2c(c(-c3ccc(F)cc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 91.2 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 2.43 g) was reacted with 4-fluorophenylboric acid (840 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (2.49 g, 91%).
Reaction SMILES: [N:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:9][OH:10].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].O>CN(C=O)C>[CH2:15]([O:8][CH2:7][C:6]1[N:1]=[C:2]([CH2:9][OH:10])[CH:3]=[CH:4][CH:5]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: OCc1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCc1cccc(CO)n1
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with allyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz) 6.04-5.93 (1H, m), 5.38-5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15-4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([O:24]CC)=[O:23])=[N:10]1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([OH:24])=[O:23])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(I)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1

Procedure:
The ester (10 g, 19.9 mmoles) obtained from step C was taken in 500 ml 1 neck flask and to it 300 ml of 7:2:1 mixture of THF-methanol-water along with solid lithium hydroxide (2.5 g, 104.6 mol) was added. The mixture was refluxed for 12 hours. The solvents were removed totally and to the residue 200 ml of DCM was added. To that 100 ml of water was added and the mixture was acidified to pH ˜2 using concentrated HCl. The organic layer was separated, washed with 100 ml of brine, dried over sodium sulphate and concentrated to give the acid. This was taken directly to the next step (9.4 g, 100%).
Reaction SMILES: [C:1](=[O:62])([O:51][C:52]1[C:57]([O:58][CH3:59])=[CH:56][CH:55]=[CH:54][C:53]=1[O:60][CH3:61])[O:2][C@H:3]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=1)[C@@H:4]([N:6](C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([F:27])=[CH:20][C:19]=1[O:28][CH3:29])[CH3:5].[ClH:63]>>[Cl-:63].[F:49][C:47]([F:48])([F:50])[C:39]1[CH:38]=[C:37]([C@@H:3]([O:2][C:1]([O:51][C:52]2[C:57]([O:58][CH3:59])=[CH:56][CH:55]=[CH:54][C:53]=2[O:60][CH3:61])=[O:62])[C@@H:4]([NH2+:6][CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[C:21]([F:27])=[CH:20][C:19]=2[O:28][CH3:29])[CH3:5])[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](OC(=O)Oc1c(OC)cccc1OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cl
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C[NH2+][C@@H](C)[C@H](OC(=O)Oc1c(OC)cccc1OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]

Procedure:
A solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl 2,6-dimethoxyphenyl carbonate (125.7 mg, 0.141 mmol) in HCl saturated EtOAc (4 mL) was stirred at 25° C. for 5 h. The reaction mixture was concentrated in vacuo to afford (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-1-{[(2,6-dimethoxyphenoxy)carbonyl]oxy}-N-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-aminium chloride, as a colorless oil/glass. LCMS calc.=792.2; found=792.2 (M+H)+.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40].O>C(Cl)Cl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Oc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex. 2, Step 1 (320 mg, 0.72 mmol) in 10 ml CH2Cl2 was cooled to 0° C. Triethylamine (100 μl, 0.72 mmol) was added followed by 1-propanesulfonyl chloride (81 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added, the mixture extracted with CH2Cl2 (3×20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2) afforded 220 mg (56%) of the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#C[Si](C)(C)C)ccc2NC1C(F)(F)F
Yield: 38.4 %

Procedure:
The ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 160, Step 1) (750 mg, 1.89 mmol), trimethylsilylacetylene (925 mg, 9.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol), copper(I)iodide (9.5 mg, 0.05 mmol), and triethylamine (953 mg, 9.44 mmol) were mixed at room temperature for 2 h in acetonitrile (10 mL). The resulting black heterogeneous mixture was poured into ethyl acetate(50 mL) and extracted with water (2×25 mL), 1 N aqueous hydrochloric acid (25 mL), and saturated aqueous ammonium chloride (2×25 mL). The organic layer was dried over sodium sulfate and solvent removed at reduce pressure. The product was purified by flash chromatography (0–25% ethyl acetate/hexanes, silica gel). A black semisolid was isolated which upon trituration with hexanes afforded ethyl 6-trimethylsilylethynyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid(267 mg,38%): mp 117–119° C. 1H NMR (CDCl3, 300 MHz) 7.65 (s, 1H), 7.24–7.32 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.08–5.18 (m, 1H), 4.66 (brs, 1H), 4.24–4.64 (m, 2H), 1.34 (t, 3H, J=7.1 Hz) 0.22 (s, 9H). ESHRMS m/z 368.1306 (Calc'd for M+H 368.1293).
Reaction SMILES: [C:1]1([C:7]([C:28]2NN=[N:30][N:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>CCOCC.CO>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[C:1]1([C:7]([C:28]2[O:35][C:33]([CH3:34])=[N:30][N:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C2CCN(CCC(c3ccccc3)(c3ccccc3)c3nnn[nH]3)CC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nnc(C(CCN2CCC(c3ccccc3)CC2)(c2ccccc2)c2ccccc2)o1

Procedure:
2.0 Parts of 5-[1,1-diphenyl-3-(4-phenylpiperidino)propyl]-1H-tetrazole hemimethanolate, 6.21 parts of acetic anhydride and 20 parts by volume of pyridine are heated together to reflux for 1 hour and 20 minutes. The mixture is then cooled and stripped in vacuum. The resulting residue is taken up in ether. The ether solution is washed with sodium hydroxide, dried over sodium sulfate and then stripped in vacuum to give a gum. 1.74 Parts of this gum dissolved in 6 parts by volume of methanol and 0.35 part of oxalic acid dissolved in 4 parts by volume of methanol are mixed together. This solution is diluted with ether to just below the point of cloudiness. The crystals which form are filtered off and dried in vacuum to provide 5-[1,1-diphenyl-3-(4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxadiazole oxalate, melting at 180° - 190° C., having the following formula ##STR9##
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])[CH3:3].[Li+].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.CI>C(=O)=O.CC(C)=O.C1COCC1>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][C@@H:11]([CH3:21])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:1])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)[C@H](C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a 250 mL RB flask was added dimethyl N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-glutamate (4 g, 14.53 mmol) and cool in Dry Ice/Aceton −78° C. bath. By cannulation was added by drop wise 1M LiHMDS in THF (30.5 mL, 30.5 mmol. After addition the mixture was let stir at −78° C. for 0.5 hours. Then methyl iodide (1.817 mL, 29.1 mmol) was added as rapidly as possible, and the solution was stirred at −78° C. for 4.5 hours. The reaction was then quenched with 1N HCl solution (40 mL), and extracted with EtOAc (3×50 mL). The organics were combined and washed with saturated NaHCO3, brine, then dried over Na2SO4 and concentrated to give a red amber color oil. The oil was then purified on a Biotage SNAP 50 g column with a gradient of 0 to 35% gradient EtOAc in Hexane over 35 minutes. The fractions with product were combined to isolate the title compound (1.37 g) as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 1.08 (d, J=7.1 Hz, 3H), 1.38 (s, 9H), 1.71 (ddd, J=13.6, 8.3, 5.1 Hz, 1H), 1.94 (ddd, J=13.9, 10.1, 6.1 Hz, 1H), 2.43-2.49 (m, 1H), 3.60 (s, 3H), 3.62 (s, 3H), 4.01 (ddd, J=9.9, 8.4, 5.2 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H).