Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][CH:2]1O.C1(P(=[CH:32][C:33]([O:35][CH3:36])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(O)C.[C].[Pd]>[OH:3][CH2:4][CH2:5][C:6]1([CH2:1][CH2:2][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OC1CC2(CCCCC2)CCO1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCCC1(CCO)CCCCC1
Yield: 34 %

Procedure:
To a solution of 3oxaspiro[5.5]undecan-2-ol (460 mg) in dichloromethane (15 mL) was added methyl triphenylphosphoranylideneacetate (1.36 g). After stirring the solution under reflux for 3 hours, methyl triphenylphosphoranylideneacetate (1.36 g) was further added thereto. The solution was stirred under reflux for 14 hours. The solution was concentrated under reduced pressure, and the resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give a mixture of an unsaturated ester derivative and 3-oxaspiro[5.5]undecan-2-ol (520 mg) To a solution of the resulting mixture in ethanol (30 mL) was added 10% palladium-carbon (60 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 63 hours. The catalyst was filtered off, concentrated under reduced pressure and the resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (210 mg) 1HNMR (CDCl3) δ: 1.23-1.48 (m, 12H), 1.52-1.68 (m, 4H), 2.29 (t, 2H, J=7.2 Hz), 3.62-3.71 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([N:12]([CH3:25])[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[C:15](=[O:24])[N:16]([CH3:23])[C:17]3=[O:22])=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([N:12]([CH3:25])[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[C:15](=[O:24])[N:16]([CH3:23])[C:17]3=[O:22])=[O:11])=[CH:4][CH:3]=1)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc(N)cc3)c2C1=O
Reactant: CCCCCC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(NNC(=O)N(C)c2cccc3c2C(=O)N(C)C3=O)cc1
Reaction time: 2 h
Yield: 30.5 %

Procedure:
1-p-Aminophenyl-4-methyl-4-(2-methyl-1,3-dioxoisoindolin-4-yl)semicarbazide (1.5 g, 4.5 mmole) and pyridine (1 ml) were dissolved in 30 ml of acetonitrile under nitrogen and cooled to +5° C. in an ice bath. Hexanoyl chloride (0.6 g, 4.5 mmole) in 5 ml of acetonitrile was added dropwise. The mixture was stirred 11/2 hours at ice-bath temperature. The resulting solid was filtered to give 0.6 g of product, m.p. 115°-118° C. Recrystallization from acetonitrile and ethyl acetate gave 0.32 g (16% yield) of product, m.p. 147°-149° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C:24]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:9]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>CCOC(C)=O>[CH3:30][C:24]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([C:10]3[CH:9]=[C:8]([C:3]4[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:31](=[O:33])[CH3:32])=[CH:35][CH:36]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(c1cc(-c2cccc(-c3ccccc3Br)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1

Procedure:
Prepared according to the general procedure Coupling-1 using bromide from step 1 and 4-acetylbenzeneboronic acid as starting material. Flash chromatography (Hex:EtOAc; 50:50) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[CH2:5][O:6][C:7]1[CH:21]=[CH:20][C:10]2[CH:11]=[C:12]([CH:14]([NH:16][C:17](=[O:19])[CH3:18])[CH3:15])[O:13][C:9]=2[CH:8]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C(O[K])(C)(C)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:28]1([C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=2[O:25][CH2:26][CH3:27])[CH2:5][O:6][C:7]2[CH:21]=[CH:20][C:10]3[CH:11]=[C:12]([CH:14]([NH:16][C:17](=[O:19])[CH3:18])[CH3:15])[O:13][C:9]=3[CH:8]=2)[CH2:30][CH2:29]1
Reactant: OB(O)C1CC1
Reactant: CCOc1ccc(COc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOc1ccc(COc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1C1CC1
Yield: 60.1 %

Procedure:
A solution of N-(1-{6-[(3-bromo-4-ethoxybenzyl)oxy]-1-benzofuran-2-yl}ethyl)acetamide (100 mg, 0.231 mmol) obtained in Example 175, cyclopropylboronic acid (58.9 mg, 0.693 mmol), tert-butoxy potassium (77.6 mg, 0.693 mmol), tricyclohexylphosphine (6.50 mg, 0.0231 mmol) and palladium(II) acetate (2.60 mg, 0.0115 mmol) in toluene (4 mL) was stirred under argon at 100° C. overnight. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) and triturated with a small amount of hexane and diisopropyl ether to give the title compound (54.6 mg, yield 60%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br.Cl>CS(C)=O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6-Bromo-2-nitropyridin-3-ol (10.8 g, 49.1 mmol) was dissolved in dimethylsulfoxide (DMSO) (30 mL). Potassium carbonate (13.6 g, 98.6 mmol) and bromoacetic acid methyl ester (7.0 mL, 74 mmol) were added and the reaction mixture was stirred at 60° C. for two hours. Then, the reaction mixture was cooled to room temperature and neutralized with 1N HCl(aq). The aqueous solution was extracted twice with ethyl acetate, and the combined organic extracts were washed with brine. The product was purified by column chromatography (SiO2, EtOAc/hexanes) to afford (6-bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester. Yield 10.9 g (37.5 mmol, 76%). LCMS (ESI): calc. C8H7BrN2O5=290, 292; obs. Low ionization.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](Cl)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:35]([C:30]2[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=3)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:36])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a mixture of 4-aminophenylacetic acid ethyl ester (3.41 g), triethylamine (3.2 mL) and methylene chloride (30 mL) was added dropwise a solution of the 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride (5.40 g) obtained in Example 1-d) in methylene chloride (10 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. After addition of 1N hydrochloric acid, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and then concentrated to give the title compound (8.12 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C@H:15]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[NH:16]C(OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:9]1=[O:41])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CO>[H][H].[C].[Pd]>[C:6]([OH:42])(=[O:5])[CH3:7].[C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C@H:15]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[NH2:16])[C@@H:10]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:9]1=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@@H](N)Cc1ccc(O)cc1
Yield: 176.2 %

Procedure:
A mixture of 1.3 g of (S)-4-(N-benzyloxycarbonyl-L-tyrosyl)-3 -methoxycarbonylmethyl-2-oxopiperazine- 1-acetic acid tert-butyl ester thus obtained, 300 mg of 10% palladium-carbon, 180 mg of acetic acid and 20 ml of methanol was stirred for 30 minutes in hydrogen streams. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to afford 1.0 g of (S)-4-L-tyrosyl-3-methoxycarbonylmethyl-2-oxo-piperazine-1-acetic acid tert-butyl ester acetate as a colorless oily product. This product can be used in the subsequent reaction without purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].[O:31]1CCC[CH2:32]1>CCCCCC.[Cl-].[Na+].O.C(O)(=O)C.CN(C)C=O>[Cl:21][C:22]1[C:29]([CH:32]=[O:31])=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(F)c(C=O)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution (300 mL) of diisopropylamine (12.4 mL) in tetrahydrofuran was added dropwise 1.6 mol/L solution (55.4 mL) of n-butyllithium in hexane at −78° C., and the mixture was stirred at 0° C. for 1 hr. To the prepared lithium diisopropylamide was added dropwise a solution (70 mL) of 2-chloro-4-fluorobenzonitrile (12.0 g) in tetrahydrofuran at −78° C. After the reaction mixture was stirred at the same temperature for 1 hr, N,N-dimethylformamide (6.90 mL) was added thereto. The reaction mixture was stirred for 30 min, and acetic acid (20 mL) was added thereto. The temperature of the mixture was raised to room temperature, saturated brine was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=30:1→1:1) and recrystallized from a mixed solvent of isopropyl ether and hexane to give the title compound as a yellow solid (yield: 5.94 g).
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:24][C:23]([F:25])([F:26])[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:13]=1)=[O:27]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1(O)CCCCCC1
Product: O=C(NCCCc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-ethynylcycloheptanol with bromide 10 following the method used to prepare Example 7. Purification by flash chromatography (20% EtOAc-hexanes) gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (1.78 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ9.40 (s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.22 (m, 3H), 5.26 (s, 1H), 3.16 (q, J=6.0 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.91-1.97 (m, 2H), 1.73-1.79 (m, 4H), 1.45-1.63 (m, 8H).
Reaction SMILES: CO.C[O:4][C:5](=[O:33])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH3:13])[C:7]=1[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>CCOCC>[CH2:26]([N:14]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:7]1[C:8]([CH3:13])=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[C:5]([OH:33])=[O:4])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)c(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)ccc(Cl)c2C)cc1
Yield: 92.6 %

Procedure:
In the same manner as described in Example 19, except a mixture of MeOH and ThF was used instead of MeOH, 0.506 g (1.1 mmol) of the product of Example 98 provided 0.454 g (93%) of the desired carboxylic acid as a white solid after triion with ether. Electrospray Mass Spec 446.1(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 36 h
Yield: 33 %

Procedure:
A solution is prepared of 1 g (4.9 mM) of 2-nitro-5-bromopyridine and 917 mg (4.9 mM) of N-Boc-piperazine in 10 ml of dimethylformamide and 1.02 g (7.4 mM) of potassium carbonate are added. The reaction mixture is agitated at 120° C. for 36 hours and then cooled. 50 ml of water are then added and extraction is carried out with ethyl acetate. The organic phase obtained is washed with water, dried and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a toluene/isopropanol mixture (98/2; v/v). The product sought after is thus obtained as a yellow solid (yield=33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:18]([CH2:29][CH3:30])[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:15])([F:16])[F:14])[CH:5]=[CH:4][C:3]=1[N:18]([CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCN(C(=O)CCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Agent: B
Solvent: C1CCOC1
Product: CCN(CCCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 10 h
Yield: 90.9 %

Procedure:
A solution of 70 mg (0.15 mmol) of N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamide in 3 mL of THF was treated with 1 mL of 1M BH3THF-complex in THF and stirred for 10 hours at 80° C. in a sealed tube. Evaporation of the solvent and column chromatography on silica gel with CH2Cl2/n-heptane 1:1 yielded 60 mg (91%) of 2-{3-chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, colorless oil, MS: 440 (MH+, 1Cl).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]1[C@H:24]2[C@H:20]([CH2:21][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:23]2)[CH2:19][CH2:18]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.Cl>C(O)C>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:22]1[CH2:23][C@H:24]2[C@H:17]([NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH2:8])[CH2:18][CH2:19][C@H:20]2[CH2:21]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Agent: Cl
Solvent: CCO
Product: CC(C)C[C@H](N)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N2-(tert-Butyloxycarbonyl)-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Step A (0.731 g, 1.469 mmol) in ethanol (5 mL) was treated with HCl (4 N in dioxane, 10.0 mL, 40.0 mmol). The reaction was stirred at room temperature for 2 hours and the solvent removed in vacuo. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with 3×50 mL of dichloromethane. The solvent was removed in vacuo to give N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=7.6, 1H), 7.75 (s, 1H), 7.63-7.54 (m, 2H), 7.44 (dd, J=6.9, 14.6, 1H), 4.44-4.33 (m, 1H), 3.62-3.53 (m, 2H), 3.45 (d, J=13.5, 1H), 2.84 (dd, J=2.5, 8.9, 1H), 2.52 (dd, J=7.2, 14.0, 1H), 2.50-2.43 (m, 1H), 2.42-2.37 (m, 1H), 2.32 (dd, J=2.8, 9.0, 1H), 2.23 (dd, J=7.2, 8.8, 1H), 2.09 (td, J=6.0, 12.0, 2H), 1.94-1.81 (m, 4H), 1.61-1.50 (m, 2H), 1.39 (ddt, J=6.3, 8.7, 12.6, 1H), 0.90 (d, J=6.4, 3H), 0.84 (d, J=6.3, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH-:16].[Na+]>O.[Zn]>[Cl:13][C:5]1[C:4]([Cl:14])=[CH:3][C:2]([Cl:1])=[C:7]([C:8]([OH:9])=[O:16])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: [OH-]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Na+]
Agent: [Zn]
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 88534.9 %

Procedure:
This compound was prepared by modifications to the literature method of Syn. Lett., 1990, 339. A mixture of 3,4,5,6-tetrachlorphthalic anhydride (19) (Aldrich Chemical Co., 100 g, 0.35 mmol) and NaOH (50.0 g, 1.25 mmol) in water (1000 mL) was stirred at 50-60° C. (bath) for 45 min under a nitrogen atmosphere. Zinc dust (70.0 g, 1.07 mmol) was then added portionwise over 10 min, and the mixture was stirred at 70-80° C. for a further 6 h. The reaction was cooled to room temperature and filtered through a bed of Celite, and the filter and residue was washed successively with 0.1N NaOH (2×100 mL) and H2O (2×100 mL). The combined filtrate was acidified with conc. HCl to pH≦1, and the colourless precipitate was collected by filtration and washed with 0.1N HCl (3×100 mL). The damp solid was stirred with EtOAc (600 mL) and acidified with conc. HCl until all the solids had dissolved. The EtOAc layer was separated and the aqueous portion further extracted with the same solvent (2×100 ml, The combined EtOAc solution was dried (Na2SO4), filtered, and evaporated under reduced pressure give 3,4,6-trichlorophthalic acid (20) (83.5 g, 89%) as a colourless solid; m.p. (without recrystallisation) 151-153° C. (lit. m.p. 150-153° C.), 1H NMR identical to literature.
Reaction SMILES: Cl.[C:2]1([C:8]([C:25]2[O:29][C:28]([C:30]([O:32]CC)=[O:31])=[N:27][N:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[K+]>[C:2]1([C:8]([C:25]2[O:29][C:28]([C:30]([OH:32])=[O:31])=[N:27][N:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nnc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2ccccc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1nnc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2ccccc2)o1

Procedure:
Thus 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile described in U.S. Pat. No. 3,318,869 is reacted with sodium azide in DMF to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. This tetrazole is reacted with ethyl chloroglyoxylate in pyridine at -6° C to provide ethyl [1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylate hydrochloride. This ester is hydrolysed in aqueous potassium hydroxide to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylic acid. Heating this acid for 15 minutes in an oil bath at 130°-140° provides 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole. The hydrochloride salt melts at 233°-234.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:45]=1)=[CH:6][C:7]1[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C([Li])CCC.C(N)(C)(C)C.[C:56]([NH:60][Si:61](C1C2C(=CC3C(CCCCCCCCCCCCCC)(CCCCCCCCCCCCCC)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:63])[CH3:62])([CH3:59])([CH3:58])[CH3:57]>C(OCC)C>[C:56]([NH:60][Si:61]([CH:45]1[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH:3]=[C:2]1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH3:63])[CH3:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3[Si](C)(C)NC(C)(C)C
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)(C)N
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C([Si](C)(C)NC(C)(C)C)C(C)=C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
In a 250 mL round flask, 2-methyl-9,9-ditetradecyl-3,9-dihydrocyclopenta[b]fluorene (4.9 g, 8.0 mmol) was dissolved in 100 mL of anhydrous diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (1.6M hexane solution, 5.5 mL) was slowly injected thereto, followed by stirring at room temperature for 12 hours. After volatile materials were removed by vacuum, 100 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (2.9 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 250 mL round flask, and dissolved in 100 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (1.8 g, 24.1 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of n-hexane was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, to thereby obtain 5.5 g of a mixture of N-tert-butyl-1-(9,9-ditetradecyl-2-methyl-3,9-dihydrocyclopenta[b]fluoren-3-yl)-1,1-dimethylsilanamine and N-tert-butyl-1-(9,9-ditetradecyl-2-methyl-1,9-dihydrocyclopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (ratio=˜1:1), (yield: 92.7%), as high viscous material.