Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:25]([C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:26]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COCCCN
Product: COCCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 3-methoxy-propylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10]([NH:12][C@@H:13]([CH:21]([CH3:23])[CH3:22])[CH2:14][O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:11])=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:9]1[CH2:8][C:5]2=[CH:4][CH:3]=[C:2]([CH:7]=[CH:6]2)[NH:1][C:18](=[O:19])[CH2:17][CH2:16][O:15][CH2:14][C@H:13]([CH:21]([CH3:23])[CH3:22])[NH:12][C:10]1=[O:11])([CH3:29])([CH3:31])[CH3:30]
Reactant: CC(C)[C@@H](COCCC(=O)O)NC(=O)[C@@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COCCC(=O)Nc2ccc(cc2)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 1 h

Procedure:
The 3-{(S)-2-[(R)-3-(4-aminophenyl)-2-tert-butoxycarbonylaminopropionylamino]-3-methylbutoxy}propionic acid (˜225 mg) obtained as crude product in 7-1 D was dissolved in 225 ml of DMF. 70.0 mg (0.51 mmol) of HOAt, 0.26 ml (1.5 mmol) of N,N-diisopropylethylamine and 195.4 mg (0.51 mmol) of HATU were successively added to this solution, and the mixture was stirred at room temp. for 1 h. The reaction mixture was concentrated in vacuo. The residue obtained in this way was taken up in CH2Cl2, washed with sat. NaHCO3 solution, dried over MgSO4 and freed of solvent in vacuo. The ring-closed compound obtained in this way was employed crude in the next stage. Yield: 215.0 mg.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cc(C)n1
Yield: 45.4 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (99 mg, 45%). MS (ISP) 437.2 [(M+H)+]; mp 236° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:56]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][Br:56])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A 200 mL round bottomed flask was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (3.03 g, 6.18 mmol), anhydrous THF (75 mL), and then triphenylphosphine (3.24 g, 12.4 mmol) and CBr4 (4.10 g, 12.4 mmol). The yellow mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was concentrated. The residue was diluted with EtOAc (500 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a solid. The crude product was purified using a Biotage medium pressure chromatography system (EtOAc:hexanes 10:90) to give a yellow oil (2.95 g, 86%), MS (ES) m/e 572 (M+NH4).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=3)=[CH:12][C:3]1=2.C(=O)([O-])[O-].[K+].[K+]>CO>[C:19]([C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:25])([CH3:1])[C:3]=3[CH:12]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4,4-dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.7 g, 2 mmol) and potassium carbonate (2 g, excess) in anhydrous methanol was stirred at rt under nitrogen for 4 hours. The mixture was treated with ice-water (100 mL) and extracted with ethyl acetate (2×80 mL). The organic layers were washed with brine and dried with MgSO4. The solvent was removed and the title compound was obtained as a off-white solid (0.4 g, 72%): mp 171-172° C.; 1H-NMR (DMSO-d6) δ10.3, (s, 1H), 7.78 (bs, 1H), 7.72-7.69 (m, 1H), 7.6-7.57 (m, 2H), 7.49-7.43 (m, 2H), 6.97 (d, 1H, J=7.98 Hz), 4.25 (s, 1H) , 1.67 (s, 6H); MS (EI) m/z 277([M+], 100%); Anal. Calc. For C18H15NO2.0.2 EtOAc: C, 76.56, H, 5.67, N, 4.75. Found: C, 76.34, H, 5.4, N, 4.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Yield: 73 %

Procedure:
To a suspension of 3-chloro-4-(piperidin-4-yloxy)nitrobenzene (1.00 g) obtained in reference example 8 in dichloromethane (20 ml) were added successively methanesulfonyl chloride (0.33 ml) and triethylamine (1.09 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.96 g, yield: 73%) as a colorless amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][C:29]#[N:30])=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26](/[C:28](=[CH:13]/[C:12]3[CH:15]=[CH:16][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:10]([O:17][CH3:18])[CH:11]=3)/[C:29]#[N:30])=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: COc1cc(C=O)ccc1OCCCCCCO
Reactant: N#CCc1ccc2c(c1)OCO2
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCO
Yield: 85 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(6-hydroxyhexyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared from 4-[(6-hydroxyhexyl)oxy]-3-methoxybenzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 85% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:25]=[CH:24]3)([OH:20])[C:16]([F:19])([F:18])[F:17])[N:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:18][C:16]([F:17])([F:19])[C:15]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[N:25]=[CH:24]2)([C:13]1[N:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=1)[OH:20]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1nc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a chilled (0° C.) solution of 1-[2-(tert-butyldimethylsilanyloxymethyl)thiazol-4-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (300 mg, 0.558 mmol) in 15 mL of THF was added tetra-n-butylammonium fluoride (0.670 mL, 1 M solution in THF, 0.67 mmol). The mixture was warmed to room temperature. After 30 minutes, the mixture was quenched with 50 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on SiO2 (0-50% ethyl acetate in hexanes) to afford 230 mg (97%) of the title compound. MS m/z 424.71 (MH+).
Reaction SMILES: CSC.[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH3:11])[CH:10]=1.ClC(O[C:16]1[CH:21]=[CH:20]C=CC=1)=O.C1([Mg]Br)CC1>O1CCCC1.[Cu](I)I>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH3:11])[C:10]=1[CH:20]1[CH2:21][CH2:16]1
Reactant: Cc1cncc(Br)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: I[Cu]I
Agent: Br[Mg]C1CC1
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cncc(Br)c1C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of copper iodide (1.082 g, 0.0056 mol), dimethyl sulphide (2.78 mL, 0.0380 mol) and 3-bromo-5-methylpyridine (1.0 g, 0.0056 mol) in anhydrous tetrahydrofuran (25 mL) at room temperature was added phenyl chloroformate (0.764 mL, 0.0060 mol) and the mixture was stirred for 40-50 min. To this suspension at −25 to −20° C. was added cyclopropyl magnesium bromide (12.13 mL, 0.0060 mol, 0.5M solution in tetrahydrofuran) over 30-40 min. The mixture was stirred at this temperature for 30 min. and then warmed slowly to room temperature over 1.0-1.5 h. The reaction mixture was quenched with 20% ammonium chloride (25 mL), followed by extraction of the aqueous layer with ethyl acetate (50 mL). The organic layer was washed with 20% ammonium chloride (25 mL), then saturated aqueous sodium chloride solution (25 mL), and dried over anhydrous sodium sulphate. Silica gel chromatography using 0-5% ethyl acetate-hexane gradient yielded crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][O:31][S:40]([C:37]4[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=4)(=[O:42])=[O:41])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCl solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%—>60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10](Cl)=[O:11].CO.[Cl-].[NH4+]>O1CCCC1.C1(S[Cu])C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: [Li]C(C)(C)C
Agent: [Cu]Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)C(C)(C)C)cc1C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A suspension of 25.9 g. (0.15 mole) of phenyl thio copper in 1 liter dry tetrahydrofuran is cooled to -20° C. and treated by the dropwise addition of 120 ml. t-butyl lithium (0.149 mole, 1.24 M in pentane) for about 20 minutes maintaining the temperature at -20° C. The resulting green solution is stirred at -20° C. for 5 minutes and then cooled to -72° C. and treated by the dropwise addition of 17.8 g. (0.107 mole) 3,4-dimethyl-benzoyl chloride in 50 ml. tetrahydrofuran for about 20 minutes. The mixture is then stirred at -22° C. for 11/2 hours and then treated with 100 ml. methanol and allowed to warm to room temperature and then hydrolyzed by the addition of 250 ml. saturated ammonium chloride. The resulting solids are filtered and washed with tetrahydrofuran. The filtrate is dried over anhydrous magnesium sulfate, filtered and evaporated and the oil distilled to give 3',4' -dimethylpivalophenone; (b.p. 73°-76° C. at 0.1 mm).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([OH:44])([C:40]([F:41])([F:43])[F:42])[C:36]([F:39])([F:37])[F:38])=[C:29]([CH3:48])[CH:28]=3)[CH2:49][CH3:50])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 45-(1); 44.9 mg, 0.071 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (20 mg, 48%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][CH:14]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Step A To a solution of N-Boc-1,4-phenylene diamine (Aldrich, 1.00 g, 4.82 mmol) in CH2Cl2 (12 ml) were added N,N-diisopropylethylamine (1.26 g, 9.76 mmol) and ethyl bromoacetate (Aldrich, 813 mg, 4.87 mmol). The mixture was allowed to stir at rt overnight and then taken up in EtOAc (300 ml) and washed with sat. aqueous Na2CO3, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give ethyl 2-(4-(tert-butoxycarbonylamino)phenylamino)acetate as a light brown oil (1.33 g, 94%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1>>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1cccc(F)c1
Product: CCOC(=O)C1CCN(c2cccc(C#N)c2)CC1

Procedure:
According to a similar manner to that in Reference Example 17, the title compound was synthesized from 3-fluorobenzonitrile and ethyl isonipecotate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:3][CH2:4][C:5]([NH:43][CH:40]1[CH2:41][CH2:42][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:23]3[N:22]([CH3:21])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH:32]=2)[CH2:38][CH2:39]1)=[O:7])[CH3:2]
Reactant: Cn1c(-c2cccc(N3CCC(N)CC3)c2)nc2ccccc21
Reactant: CCOCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCC(=O)NC1CCN(c2cccc(-c3nc4ccccc4n3C)c2)CC1
Temperature: 70 °C
Yield: 435 %

Procedure:
Method N—Step e To a solution of ethoxyacetic acid (0.05 mL, 0.49 mmol) in acetonitrile (3 mL) was added CDI as a stock solution (0.80 g, 0.49 mmol) and the resulting suspension was stirred at room temperature for 3 h. {1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-ylamine hydrochloride (0.13 g, 0.41 mmol) and DIPEA (0.07 mL, 0.41 mmol) were added and the resulting solution heated at 70° C. overnight. The reaction was then cooled to room temperature, the solvent removed under reduced pressure. The crude product was redissolved in dichloromethane (4 mL) and washed with saturated Na2CO3 solution (2 mL) and water (2 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: dichloromethane:MeOH, gradient from 100% dichloromethane to 95% dichloromethane:5% MeOH) to afford 0.70 g (44%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C@@H:9]([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C>[CH2:1]([N:8]([C@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[C@@H:9]([CH3:18])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
tert-Butyl (3S)-3-[benzyl-[(1S)-1-phenylethyl]amino]butanoate (24 g, 67.9 mmol) is dissolved in anhydrous THF (237 mL) and cooled to 0° C. under an argon atmosphere. 1 M Lithium aluminum hydride in THF (237 mL, 237 mmol) is added dropwise over 10 min. The reaction mixture is stirred at 0° C. for 1 h and then at 60° C. for 1 h. The mixture is cooled to room temperature (RT) and diluted with diethyl ether (500 mL). The reaction is quenched with a mixture of CELITE® and Na2SO4.10 H2O (1:1) is added portionwise over 15 min. The mixture is filtered and concentrated under a vacuum to afford the title compound as a colorless oil (17.54 g, 90%). LC-ES/MS m/z 284 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([OH:20])[C@H:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C@:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:26]#[C:25][C@:27]2([OH:35])[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([OH:20])[C@H:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CC(C)O[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)O[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1O
Temperature: 75 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A mixture of 464 mg of 2-benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)-3-iodopyridine, 176 mg of (3R)-3-ethynyl-3-quinuclidinol, 122 mg of tetrakis(triphenylphosphine)palladium (0), 10 mg of cuprous iodide, 0.44 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 168 mg of the target compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C@@H:12]([OH:23])[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1COCC1.CCN(CC)CC>CCOC(C)=O.CCCCCC.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCOc1ccc2c(c1)[C@@H](O)C=C2c1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Temperature: 40 °C

Procedure:
A 100 mL three-necked flask was charged with (S)-3-(1,3-benzodioxol-5-yl)-6-propoxy-1H-inden-1-ol (1.9 g, 6.13 mmol), anhydrous THF (40 mL), Et3N (2.0 mL, 14.4 mmol) and Pd(dppe)Cl2 (130 mg, 0.227 mmol) under nitrogen. The mixture was warmed to 40° C. and after 6 h, cooled to room temperature, diluted with EtOAc/hexane solution (1:3, 60 mL) and filtered through SiO2. The filtrate was concentrated in vacuo affording (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one as a yellow solid (1.85 g, 95%, 94% e.e.); mp 63.0-65.0 ° C.; Chiralpak AD column (93:7 IPA/hexane, 1 mL/min, 254 nm): 14.107 min (90.11%), 15.805 min (2.90%).1H NMR δ7.25-7.1 (m, 3H), 6.75 (d, J=7.9 Hz, 1H), 6.6 (dd, J=1.7, 8.0 Hz, 1H), 6.5 (d, J=1.7 Hz, 1H), 5.9 (s, 2H), 4.4 (dd,J=3.5, 7.8 Hz, 1H), 3.95 (t, J=6.5 Hz, 2H), 3.2 (dd, J=7.8, 19.3 Hz, 1H), 2.6 (dd, J=3.5, 19.1 Hz, 1H), 1.8 (quintet, J=7.8 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H).