Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[C:5]([C:15]([O:17]CC)=[O:16])[CH:4]=[CH:3]1>Cl>[O:1]=[C:2]1[NH:7][C:6]([C:8]([F:14])([F:13])[C:9]([F:10])([F:11])[F:12])=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[CH:3]1
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)C(F)(F)F
Agent: Cl
Product: O=C(O)c1ccc(=O)[nH]c1C(F)(F)C(F)(F)F

Procedure:
A suspension of ethyl 6-oxo-2-(pentafluoroethyl)-1,6-dihydropyridine-3-carboxylate (0.300 g) in concentrated hydrochloric acid (10 mL) was heated at reflux for 20 h. The reaction mixture was cooled and a colourless solid filtered off (0.30 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1([N+:27]([O-])=O)[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21][CH2:20]1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn]>[CH2:1]([O:8][C:9]1[C:10]([C:30]([F:31])([F:33])[F:32])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1([NH2:27])[CH2:20][O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24]1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(c2ccc3c(C(F)(F)F)c(OCc4ccccc4)ccc3c2)([N+](=O)[O-])CO1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(C)OCC(N)(c2ccc3c(C(F)(F)F)c(OCc4ccccc4)ccc3c2)CO1
Temperature: 23 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
5-(6-(benzyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-2,2-dimethyl-5-nitro-1,3-dioxinane (2.00 g, 0.00433 mol) was dissolved in acetic acid (20 mL, 0.4 mol), followed by zinc (2.834 g, 0.04334 mol) in small portions at 23° C. The reaction mixture was then allowed to stir at 23° C. for 4 hours. Excess of acetic acid was removed, and the residue was treated with DCM, and filtered. The organic layer was then treated with NaOH (2N, 2 mL), and separated. The organic layer washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4. Removal of the solvent gave a pure product (1.88 g, 100%). MS (ES, to M+1): 432.30.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:7]#[N:8])[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O.[C:14]1(C)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C.C(#N)CCC.C1(C)C(C)=CC=CC=1>[NH2:6][C:4]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:1]=[CH:2][C:3]=1[C:7]#[N:8]
Reactant: Cc1ccccc1
Reactant: N#CC(=CN)C(N)=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCC#N
Product: N#Cc1cnc2ccccc2c1N

Procedure:
The present invention relates to a process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising combining an amine compound with cyanoacetic acid and an acid catalyst to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline in an alcoholic solvent and a trialkylorthoformate to yield a 3-amino-2-cyanoacrylamide, and then combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 4-amino-3-quinolinecarbonitrile.
Reaction SMILES: [Mg].I[CH2:3][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:9][C:10]1[C:11](=[O:22])[O:12][CH2:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1>O1CCCC1.C(OCC)C>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][C@@:10]1([CH3:9])[C:11](=[O:22])[O:12][CH2:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:15]1
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Reactant: CC(C)(C)CCI
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)CC[C@]1(C)N[C@@H](c2ccccc2)COC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of Rieke Magnesium (343 mg, 14.1 mmol) in tetrahydrofuran (13.7 ml) was added to a solution of 1-iodo-3,3-dimethylbutane in diethylether (50 ml) over a period of twenty minutes and the reaction was stirred for 40 minutes at room temperature. The Grignard reagent solution and (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) were used according to the method of Preparation 1 to generate the title compound. The total amount of compound synthesised was 0.394 g.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[N:23][N:22]=[N:21]1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-Methyl-4-nitro-benzamide (2.25 g, 12.5 mmol, 1 eq.) and PCl5 (2.60 g, 12.5 mmol, 1 eq.) were melted together under house vacuum connected to a NaOH trap behind a safety shield. Melting occurred at 100° C. Heated at 130° C. for 1 hour then purified by kugelrohr distillation at 0.1 mmHg at 130° C. CAUTION: THE EXPLOSIVE PROPERTIES OF THIS COMPOUND ARE UNKNOWN). The iminoyl chloride (12.5 mmol 1 eq.) in DMF 10 ml was added to NaN3 in 10 ml of DMF at 25° C. and stirred overnight. Worked up by adding EtOAc then rinsing 3× with H2O. The organic layer was dried over MgSO4, then stripped to obtain yellow solids which were purified over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc. Obtained 1.21 g of yellow solids as product. NMR (300 MHz, CDCl3) δ 8.46 (d, 2H, J=7 Hz), 8.02 (d, 2H, J=7 Hz), 4.27 (S, 3H).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:44]=[C:45]([N:49]=[C:50]=[O:51])[CH:46]=[CH:47][CH:48]=1.[C:52]([O:56][CH2:57][CH:58]([OH:61])[CH2:59][CH3:60])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>>[C:52]([O:56][CH2:57][CH:58]([O:61][C:50](=[O:51])[NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([S:42][CH3:41])[CH:44]=1)[CH2:59][CH3:60])(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)OCC(O)CC
Reactant: CSc1cccc(N=C=O)c1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Product: C=CC(=O)OCC(CC)OC(=O)Nc1cccc(SC)c1
Temperature: 60 °C

Procedure:
0.05 g of 2,6-di-tert-butyl-4-methylphenol, 0.02 g of Desmorapid Z, 26.7 g of 3-(methylthio)phenyl isocyanate were initially introduced into a 250 ml round-bottomed flask and heated to 60° C. Thereafter, 23.3 g of 2-hydroxybutyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled offat 5 mbar and cooling was effected. The product was obtained as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11](C#N)=[CH:10][CH:9]=1.[F:20][C:21]([F:33])([F:32])[O:22]C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([O:22][C:21]([F:33])([F:32])[F:20])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Yield: 68.8 %

Procedure:
The title compound was prepared by coupling reaction of Step 2 of Intermediate 4 (9.5 g, 37.312 mmol) with 4-(trifluoromethoxy)phenyl boronic acid (9.5 g, 32.523 mmol) in the presence of Pd[(C6H5)3P]4 (1.5 g, 1.301 mmol) and sodium carbonate (20.6 g, 195.13 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 yielded 7.3 g of the desired compound as a pale yellow solid; IR (KBr) 3088, 1658, 1646, 1513, 1269, 1160 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.42-7.4 (m, 4H), 7.53 (d, J=4.8 Hz, 1H), 8.01 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 327.16 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)=[C:15]([F:37])[CH:14]=1)=[O:11])[C:6]([OH:8])=[O:7])(=O)C.C1COCC1.[OH-].[Na+]>>[F:37][C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][C@H:5]([OH:4])[C:6]([OH:8])=[O:7])[CH:18]=[CH:17][C:16]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]1)[N:22]=2
Reactant: CC(=O)O[C@@H](CC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(C[C@H](O)C(=O)O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S)-2-Acetoxy-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid (7.0 mg, 13 μmol) was dissolved in THF (135 μl, 13 μmol) before 0.1 N sodium hydroxide (404 μl, 40 μmol) was added and stirred at ambient temperature for 24 h. The reaction mixture was concentrated to give (2S)-4-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)-2-hydroxy-4-oxobutanoic acid after preparative LC purification. MS (ESI) m/z: Calculated: 476.1; Observed: 477.7 (M++H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:3].CC(C1C=CC=C(C(C)C)C=1NC(=O)CNC(C)(C)CC1C=CC=CC=1)C.FC(F)(F)C(F)(F)C(F)(F)C([O:64][C:65](=O)[C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])=O.C(OC(=O)C)(=O)C>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:65](=[O:64])[C:66]([F:74])([F:75])[C:67]([F:72])([F:73])[C:68]([F:71])([F:70])[F:69])[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(C)(C)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 79 an appropriate amount of the product of Example 4 was substituted for the product of Example 5 and an appropriate amount of heptafluorobutyric anhydride was substituted for acetic anhydride and the general procedure of Example 79 was followed the title compound was obtained. Total yield, 1.33 g (59%).
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC(C3SC=CC=3)=CC=2)C(NO)=O)=CC=1)C#CC.[CH2:29]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH:42]([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[S:54][CH:55]=[CH:56][CH:57]=3)=[CH:49][CH:48]=2)[C:43]([NH:45][OH:46])=[O:44])=[O:41])=[CH:36][CH:35]=1)[C:30]#[C:31][CH3:32]>>[CH2:29]([O:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([CH:42]([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[S:54][CH:55]=[CH:56][CH:57]=3)=[CH:49][CH:48]=2)[C:43]([NH:45][OH:46])=[O:44])(=[O:5])=[O:41])=[CH:38][CH:39]=1)[C:30]#[C:31][CH3:32]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(-c3cccs3)cc2)cc1
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(-c3cccs3)cc2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2ccc(-c3cccs3)cc2)cc1
Yield: 26 %

Procedure:
Starting from a mixture of 2{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]acetamide and 2-{[4-(2-butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]ethanamide (410 mg, 0.96 mmol), and following the procedure as outlined in Example 75, 110 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]acetamide was isolated as a gray solid. mp: 175° C.; Yield: 26%; MS: 442.2 (M+W)+; 1H NMR (300 MHz, DMSO-d6): δ 1.83 (t, 3H), 4.85 (d, J=2.01 Hz, 2H), 5.04 (s, 1H), 7.11 (m, 4H), 7.39 (d, 7.49-7.63 (band, 5H), 9.30 (s, 1H), 10.9 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22]Cl>CN(C)C=O>[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: ClCC=C(Cl)Cl
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(C(F)(F)F)cc1
Yield: 48.9 %

Procedure:
Using 0.45 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 0.28 g of 2-(3,3-dichloro-2-propenyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (55)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][SH:8].C(O)C.Br[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]>O>[CH3:7][S:8][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1OC
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(SC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction mixture containing 21 g. of potassium carbonate, 25 g. of methanethiol, and 30 ml. of ethanol was cooled in an ice-water bath. 33.5 g. of 3-bromo-4-nitroveratrole were added thereto. The reaction mixture was stirred for 1 hour under cooling and was then allowed to warm up to ambient temperature, at which temperature it was stirred for an additional 24 hours. 3 l. of water were then added and the resulting precipitate of 3-methylthio-4-nitroveratrole formed in the above reaction was separated by filtration. The filter cake was recrystallized from a benzene-ethanol solvent mixture to yield yellow crystals melting at 137°-140° C. (weight=22.8 g)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH2:15][CH2:14][O:13]4)[O:10][C:9]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.[CH3:26][N:27](C)C=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[CH:23]([C:9]1[O:10][C:11]2[C:20]([C:21](=[O:22])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:26]#[N:27])=[CH:3][CH:4]=1)=[CH:19][CH:18]=[C:17]1[C:12]=2[O:13][CH2:14][CH2:15][NH:16]1)([CH3:25])[CH3:24]
Reactant: CN(C)C=O
Reactant: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)NCCO3
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(C#N)cc1)NCCO3
Temperature: 180 °C

Procedure:
A mixture of 7-(4-chlorophenyl)-6-isopropyl-2,3-dihydro-1H-1-aza-4,5-dioxa-phenanthren-8-one (71.7 mg, 0.202 mmol), tris(dibenzylideneacetone)dipalladium (0) (92.2 mg, 0.101 mmol), 1,1′-bis(diphenylphosphino)ferrocene (112 mg, 0.202 mmol) and zinc cyanide (24 mg, 0.204 mmol) in N,N-dimethylformamide (2.5 ml) is heated at 180° C. for 40 min under microwave irradiation in an Emrys Optimizer instrument (Biotage AB, Uppsala, Sweden). The mixture is filtered through a short pad of Celite, which is then thoroughly washed through with ethyl acetate. The filtrate is washed successively with water and brine. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (cyclohexane/ethyl acetate gradient) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:37][C:36]3[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=[C:34]([F:33])[CH:35]=3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of a mixture of 4-methyl-2-{5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (40 mg, 0.09 mmol) in 1,2-dichloroethane (2.0 mL) was added 3-fluoro-5-trifluoromethyl-benzaldehyde (19 mg, 0.10 mmol) and sodiumtriacetoxyborohydride (25 mg, 0.12 mmol). The mixture was stirred for 14 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 2-{5-[1-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester and methyl ester. Calcd for C33H34F7NO2 (M+H) 610.62, Found 610.30 (methyl ester) and Calcd for C34H36F7NO2 (M+H) 624.64, Found 624.24 (ethyl ester).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)#[CH:16]>C(N(CC)CC)C.O.[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]3([OH:25])[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: OC1(C#Cc2ccc(-c3ccc(F)cc3)cc2)CN2CCC1CC2
Yield: 16.5 %

Procedure:
A mixture of 4-bromo-4'-fluorobiphenyl (1.0 g), 3-ethynyl-3-hydroxyquinuclidine (600 mg), bis(triphenylphosphine)-palladium (II) chloride (120 mg) and copper (I) iodide (60 mg) in dry triethylamine (15 ml) was stirred at reflux under an atmosphere of argon for 5 hours. The reaction mixture was cooled, diluted with water (60 ml), 2H aqueous sodium hydroxide solution added and extracted with dichloromethane. The mixed layers were filtered through diatomaceous earth and washed with dichloromethane. The organic layer in the filtrate was separated, dried (MgSO4) and evaporated to a residue which was further purified by flash column chromatography on alumina (ICN Alumina N 32-63) using a mixture of 10% ethanol in ethyl acetate as eluent to give a residue which was crystallised from a mixture of 10% ethanol in ethyl acetate to give 3-[2-(4'-fluorobiphenyl-4-yl)ethynyl]quinuclidin-3-ol (210 mg) as a solid, m.p. 232-233° C.; microanalysis, found: C, 78.0; H, 6.4; N, 4.5%; C21H20FN0.O.1H2O requires C,78.07; H,6.26; N, 4.34%; NMR (DMSO-d6): 1.2-1.4(1H, m), 1.5-1.7(1H, m), 1.8-2.01(3H, m), 2.6-2.8(4H, t), 2.8-3.15(2H, d of d), 5.6(1H, s), 7.22-7.4(2H, m), 7.45-7.55(2H, d) and 7.61-7.81(4H, m); m/z 322 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.S(Cl)(Cl)(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Al+3].[Cl-].[Cl-].[Cl-].[CH:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:9](=[O:10])[NH:8][C:6]=2[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=O
Reactant: c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=C1Nc2cc(Cl)ccc2Cc2ccccc21
Reaction time: 4 h
Yield: 14 %

Procedure:
To a mixture of 5-chloro-2-methylphenyl isocyanate (100 μL, 0.73 mmol) in CCl4 (2 mL) was added sulfuryl chloride (118 μL, 0.88 mmol) and 2,2′-azobis(isobutyronitrile) (catalytic amount) and the resulting mixture was refluxed for 20 h. The mixture was allowed to obtain room temperature, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3-solution, dried (Na2SO4) and concentrated. The mixture was taken up in benzene (2 mL) and a mixture of AlCl3 (160 mg, 1.2 mmol) in benzene (1 mL) was added. The resulting mixture was stirred at 80° for 4 h, and then allowed to obtain room temperature. The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1) to give 25 mg (14%) of the title compound (189JO59). 1H NMR (CDCl3) δ 8.18 (bs, 1 H), 7.92 (dd, 1 H, J=1.2, 7.8 Hz), 7.46 (dt 1 H, J=1.4, 7.4 Hz), 7.34 (dt, 1 H, J=1.2, 7.4 Hz), 7.23 (m, 2 H), 7.07 (m, 2 H), 3.92 (s 2 H). MS (ESI) 244 (MH+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)=[CH:12][N:11]=1)[CH2:2]2.[OH:25]O>>[NH:20]1[C:21]2[C:17](=[C:16]([C:13]3[CH:12]=[N:11][C:10]([O:9][C@@H:3]4[CH:4]5[CH2:5][CH2:6][N+:1]([O-:25])([CH2:8][CH2:7]5)[CH2:2]4)=[N:15][CH:14]=3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: c1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)c2cc[nH]c2c1
Reactant: OO
Product: [O-][N+]12CCC(CC1)[C@@H](Oc1ncc(-c3cccc4[nH]ccc34)cn1)C2

Procedure:
The product of Example 12A (10 mg, 0.03 mol) was oxidized with H2O2 (Aldrich, aq., 30%) according to the procedure of Example 23. The title compound was purified by chromatography [SiO2, CH2Cl2:MeOH (v. 5% NH3.H2O), 90:10]. 1H NMR (300 MHz, CD3OD) δ 2.01-2.32 (m, 3H), 2.42-2.64 (m, 2H), 3.41-3.70 (m, 5H), 3.91-4.24 (m, 1H), 5.39-5.59 (m, 1H), 6.55 (d, J=4.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 8.96 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C:2](=[CH2:27])[CH:3]([N:8]1[C:11](=[O:12])[CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:9]1[S:24]([OH:26])=O)[C:4]([O:6][CH3:7])=[O:5].S(Cl)(Cl)=O>>[C:17]1(=[O:18])[N:13]([CH:10]2[C:11](=[O:12])[N:8]3[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:2](=[CH2:1])[CH2:27][S:24](=[O:26])[C@H:9]23)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)O
Solvent: O=S(Cl)Cl
Product: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC

Procedure:
The same procedure was followed as described in Example 1 (L) above except 0.20 g. of methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate was employed as the starting material instead of the corresponding sulfinyl chloride. An nmr spectrum of the product showed the title compound to be the major constituent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([NH2:51])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1>CC(N(C)C)=O>[CH:42]1([NH:51][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:11][C:3]=2[O:2][CH3:1])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1
Reactant: COc1cc(-c2ccncc2)ccc1C(=O)O
Reactant: NC1CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2ccncc2)ccc1C(=O)NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-4-(pyridin-4-yl)benzoic acid (34 mg, 0.15 mmol), dissolved in DMA (0.5 ml) was added a solution of HATU (68 mg, 0.18 mmol) dissolved in DMA (0.5 ml). Then a solution of TEA (55 mg, 0.5 mmol), dissolved in DMA (0.4 ml) was added, followed by a solution of 2,3-dihydro-1H-inden-1-amine (27 mg, 0.2 mmol) dissolved in DMA (0.7 ml). The resulting mixture was shaken for 4 hours at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/methanol and purified by reverse phase HPLC (TFA method) to afford the title compound.