Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:23])=[CH:3][CH2:4][O:5][C:6]1[CH:20]=[C:19]([Cl:21])[C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([Cl:22])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:23][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:22])[C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:19]([Cl:21])[CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 0 °C

Procedure:
A mixture of 0.3 gram (0.0008 mole) of tert-butyl 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)acetate in 3.0 mL of methylene chloride was stirred and cooled to 0° C. Trifluoroacetic acid (3.0 mL, 0.04 mole) was added and the reaction mixture was allowed to warm to ambient temperature where it stirred for two hours. The reaction mixture was concentrated under reduced pressure leaving a residue. The residue was dissolved in methylene chloride and the solution concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride again. The solution was concentrated under reduced pressure to yield a quantitative amount of the subject compound as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH:4]([CH2:35][C:36]1[N:37]=[CH:38][S:39][CH:40]=1)[NH:5][C:6](=[O:34])[C@@H:7]([CH2:15][S:16]([C:19]([CH3:33])([C:21](=[O:32])[N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20])(=[O:18])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:33][C:19]([S:16]([CH2:15][C@@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]([NH:5][CH:4]([C:3]([OH:41])=[O:2])[CH2:35][C:36]1[N:37]=[CH:38][S:39][CH:40]=1)=[O:34])(=[O:18])=[O:17])([C:21](=[O:32])[N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20]
Reactant: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)N(C)CCc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCc1ccccn1)C(=O)C(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)NC(Cc1cscn1)C(=O)O
Reaction time: 3 h
Yield: 124.6 %

Procedure:
A solution of 300 mg of N-[(S)-α-[[[1-methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamoyl]-3-(thiazol-4-yl)-D,L-alanine methyl ester in 2.5 ml of dioxan was treated with a solution of 24.3 mg of lithium hydroxide hydrate in 1 ml of water and stirred at 50 for 3 hours. Subsequently, the solution was partitioned between ethyl acetate and water and the organic phase was extracted three times with water. The aqueous extracts were adjusted to pH 2 with ethyl acetate and with 2N hydrochloric acid and evaporated under reduced pressure. There were obtained 365 mg of N-[(S)-α-[[[1 -methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamoyl]-3-(thiazol-4-yl)-D ,L-alanine as a colourless foam which was used directly in the next step.
Reaction SMILES: [C@H:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CC[CH2:2]1.Cl.Cl.Cl.NC1CCN(C[C@@H]([N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)C)CC1>>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([C@@H:1]([CH3:2])[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:16][CH2:17]2)[CH2:57][CH2:58]1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120, see example 86) and amine 50 analogously to the method described in example 1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CN1CCOCC1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NCC(=O)OCc1ccccc1)C(C)C
Yield: 21.9 %

Procedure:
A solution of 2.12 g (12.6 mmol) of L-valine methyl ester hydrochloride, 2.0 ml (12.6 mmol) of benzyl bromoacetate, and 3.5 ml (31 mmol) of 4-methylmorpholine in 100 ml of dioxane was heated at reflux for 4 h. After being allowed to cool, the solution was concentrated in vacuo and partitioned between ether and water. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate in hexane provided 0.77 g (22%) of the desired compound as a colorless oil (Rf 0.24, 20% ethyl acetate in hexane. 1H NMR δ 0.95 (d, J=7 Hz, 6H), 1.96 (br, 1H), 1.98 (octet, J=7 Hz, 1H), 3.08 (d, J=6 Hz, 1H), 3.43 (AA', 2H), 3.71 (s, 3H), 5.16 (s, 2H), 7.36 (m, 5H).
Reaction SMILES: CO.[CH3:3][NH2:4].[BH4-].[Na+].[Br:7][C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=O)[C:9]=1[CH:24]([CH3:26])[CH3:25]>>[Br:7][C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][NH:4][CH3:3])[C:9]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)c1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(Br)c1C(C)C
Yield: 12.6 %

Procedure:
Using methyl 5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (4.8 g), and a 1.5 mol/L solution (50 mL) of diisobutylaluminum hydride in toluene, tetra-n-propylammonium perruthenate (218 mg), N-methylmorpholine N-oxide (1.6 g) and molecular sieves 4A powder (2.5 g), a procedure as in Reference Example 6 was performed to give crude 5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.83 g) as an oil. Furthermore, using 40% methylamine methanol solution (877 mg), sodium borohydride (474 mg) and crude 5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.83 g), a procedure as in Reference Example 66 was performed to give the title compound as a colorless oil (yield 502 mg, 11%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[K].[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl)=[O:19].O>CN(C)C=O>[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: C#CCc1c(C)nc2c(O)cccn12
Reactant: COC(=O)Nc1cccc(C)c1CCl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.6 %

Procedure:
A mixture of 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[ 1,2-a]pyridine (0.372 g) and potassium carbona (0.276 g) in N,N-dimethylformamide (7.4 ml) was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then 2-methoxycarbonylamino-6-methylbenzylchloride (0.427 g) was added. After being stirred for 2 hours. The mixture was poured into water and the resulting precipitates were collected by filtration. The crude product was purified by column chromatography on silica gel (10 g) with chloroform as eluents to give 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.048 g).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[Cl:18])=O.[OH-].[Na+]>C(O)C>[Cl:18][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:11][C:6]=1[OH:5]
Reactant: CC(C)(C)C(=O)Oc1ccc(Cn2cccn2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cn2cccn2)cc1Cl
Yield: 80.7 %

Procedure:
A mixture of 20.0 g of 2-chloro-4-(1-pyrazolyl)methylphenyl 2,2-dimethyl-propanoate, 50 ml of 20% aqueous sodium hydroxide solution and 300 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was then concentrated under reduced pressure, to which water was added, and the mixture was adjusted to pH 6.0 with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 11.5 g of 2-chloro-4-(1-pyrazolyl)methylphenol as white crystals. Yield, 80.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[N+:12]([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[NH:12][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(Cl)cc1NC(C)=O
Reaction time: 2 h

Procedure:
An argon filled flask was charged with (4-Chloro-2-nitro-phenyl)-acetic acid methyl ester (40 g, 175 mmol), 10% Pd/C (2.5 g), acetic anhydride (64 mL, 677 mmol), water (9 mL) and acetic acid (150 mL). The flask was vacuum flushed with hydrogen gas at 30 PSI and shook vigorously. After 2 hours, more 10% Pd/C (2 g) was added, and the reaction was complete after a total of 4 hours reaction time. The 10% Pd/C was removed by filtration, and the solvent was removed by rotary evaporation.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[N:15]=[C:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH:25]=[C:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20].N1CCCCC1>C(O)C>[NH2:18][C:17]1[O:32][C:31]([CH3:33])=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]([C:24]2[CH:34]=[CH:35][CH:36]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:16]=1[C:14]1[O:13][N:12]=[C:11]([CH2:10][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:9])[N:15]=1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CN(Cc1ccccc1)Cc1noc(CC#N)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)C1=C(C)OC(N)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
To a stirred mixture of 1.21 g of 3-(N-benzyl-N-methylamino)methyl-5-cyanomethyl-1,2,4-oxadiazole prepared in Example 95 and 1.25 g of methyl 2-(3-nitrobenzylidene)acetoacetate in 10 ml of ethanol was added 0.1 ml of piperidine. The reaction mixture was heated under reflux for 3 hours and then concentrated in vacuo. The residue was triturated with 10 ml of ethyl acetate and the insoluble crystals were collected by filtration. Treatment of a solution of this base in chloroform with etherial hydrogen chloride afforded 820 mg of methyl 2-amino-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-6-methyl-4-(3-nitrophenyl)-4H-pyran-5-carboxylate as pale yellow powder, m.p. 201.5° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:21])[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperazine. MS (ESI): mass calcd. for C21H20FN5O, 377.17; m/z found, 378.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.64-8.56 (m, 1H), 8.11 (d, J=1.5, 1H), 8.04-7.93 (m, 1H), 7.53-7.40 (m, 4H), 7.37 (dd, J=8.1, 1.8, 1H), 7.30 (dd, J=12.2, 1.7, 1H), 4.77 (s, 2H), 3.72 (d, J=25.1, 2H), 3.14 (s, 1H), 2.92 (s, 2H), 2.65 (s, 2H), 2.05 (s, 1H).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:34]([F:37])([F:36])[F:35])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]([NH:28][CH2:29][CH2:30][S:31]([CH3:33])=[O:32])=[O:27])=[CH:18][CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.[OH-].[Na+]>C(O)(=O)C.O>[Cl:10][C:8]1[CH:7]=[C:6]([C:11]2([C:34]([F:36])([F:35])[F:37])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]([NH:28][CH2:29][CH2:30][S:31]([CH3:33])(=[O:1])=[O:32])=[O:27])=[CH:18][CH:17]=3)[CH2:12]2)[CH:5]=[C:4]([Cl:3])[CH:9]=1
Reactant: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
H2O2 (0.056 mL, 30% in H2O) was added to a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylsulfinyl)ethyl]-1-naphthalenecarboxamide (i.e. the product of Example 2, 100 mg) in acetic acid (1.0 mL). The reaction mixture was stirred at 60° C. for 4 h, then cooled to room temperature, diluted with water, adjusted to pH 4 with 1.0 M aqueous NaOH solution, and extracted with chloroform. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (100 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.80 (d, 1H), 8.29 (d, 1H), 7.43-7.66 (m, 7H), 6.94 (br t, 1H), 4.24 (d, 1H), 4.04 (q, 2H), 3.40 (t, 2H), 3.01 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=5)[N:20]([CH3:30])[C:19]4=[O:31])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=5)[N:20]([CH3:30])[C:19]4=[O:31])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33])=[O:37])[CH3:40]
Reactant: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 89 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 500.0 mg (1.12 mmol) of Compound 89 obtained in Example 79 was used in place of Compound 24 and ethyl bromoacetate was used in place of methyl iodide. As a result, 530.0 mg (yield: 89%) of Compound 93 was obtained as white crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[CH3:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C(F)(F)F)nc3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 120 mg (0.36 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 214 mg (0.78 mmol) of 5-iodo-2-trifluoromethyl-pyridine in 1.5 mL THF with 0.41 mL 2M isopropylmagnesium chloride. Yield: 81 mg of a white powder. LC-MSD, m/z for C23H16F3N3O2 [M+H]+=424.1; HPLC retention time: 2.2 min.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:10]1([CH2:9][OH:8])[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2c1C=CCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane (see Tetrahedron, 53, 15969-15982 (1990))(1.079 g, 3.740 mmol) in tetrahydrofuran (30 ml) was added a 1.0 M solution (3.74 ml, 3.74 mmol) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at room temperature for 15 min. The reaction solution was concentrated and the obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−1/1) to give the objective substance.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[C:14]1([CH2:24][CH2:25][Mg]Cl)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:24][CH2:25][CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Cl[Mg]CCc1cccc2ccccc12
Product: COC(=O)c1cc2c([nH]1)C(CCc1cccc3ccccc13)CC2

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) and (2-(naphthalen-1-yl)ethyl)magnesium chloride (synthesized in situ) were reacted according to General Procedure 3 to give the exo olefin-containing compound (E)-methyl 6-(2-(naphthalen-1-yl)ethylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. (Note: (2-(naphthalen-1-yl)ethyl)magnesium chloride was synthesized as follows: Activated magnesium turnings (0.306 g, 12.6 mmol; washed sequentially with 3N HCl, water, THF and diethyl ether) was placed in a flask and anhydrous THF (50 mL). 1-(2-chloroethyl)naphthalene ((0.168 M in THF, 75.0 mL, 12.6 mmol) was added dropwise followed by a few grains of I2 (catalytic). The solution was stirred gently at ambient temperature for 30 min. Additional anhydrous THF (25 mL) was added and the solution refluxed for 3 h, and then allowed to cool to ambient temperature). (E)-methyl 6-(2-(naphthalen-1-yl)ethylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 (with 5% Pd/C), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane affording the title compound. 0.051 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.86-2.03 (m, 1H), 2.08-2.29 (m, 2H), 2.55-2.81 (m, 3H), 3.03-3.31 (m, 3H), 3.67-3.86 (m, 3H), 6.54-6.72 (m, 1H), 7.30-7.37 (m, 1H), 7.37-7.45 (m, 1H), 7.45-7.58 (m, 2H), 7.75 (d, J=8.10 Hz, 1H), 7.83-7.93 (m, 1H), 8.01 (d, J=8.25 Hz, 1H), 8.74 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=C(C=CC=1)C(OO)=[O:21].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1[OH:21]
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethoxy)benzaldehyde (1.0 g, 4.542 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (2.04 g, 9.08 mmol). The resulting clear solution was stirred for 16 hours at room temperature. A white precipitate had formed and this was filtered off. The filtrate was evaporated to a white solid, which was diluted with ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate, and evaporated to a white solid. This solid was redissolved in methanol (15 mL), and treated with triethylamine (2 mL, 10 mmol). After stirring for two hours, the solvents were evaporated. The residue was taken up in ethyl acetate (25 mL), and washed with 1N citric acid solution (20 mL) and brine (20 mL) dried over sodium sulphate, and evaporated to an oil. This crude material was then purified by eluting through a short pad of silica with dichloromethane, which afforded the title compound as a clear oil (650 mg, 57%)
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20]C)[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[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>[OH:20][CH2:19][CH2:18][N:6]1[C:5]2[C:22]([O:24][CH3:25])=[CH:23][C:2]([C:26]#[N:27])=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc2nc(-c3ccc(C(C)C)cc3)n(CCO)c12
Temperature: 180 °C

Procedure:
A solution of 1.42 g (3.52 mmol) of 5-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole and 455 mg (3.87 mmol) zinc cyanide in 15 ml DMF is stirred under argon for 10 min at RT. Tetrakis(triphenylphosphine)palladium (214 mg, 0.176 mmol) is added and the reaction is heated to 180° C. for 90 min. After cooling to RT, ice/water is added and the reaction mixture is extracted with ethyl acetate (3×). The organic layer is washed with water, dried (Na2SO4) and concentrated in vacuo and the material is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:15][CH:16]=2)[CH2:11][NH:10][CH2:9]1.[CH2:28]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:15][CH:16]=2)[CH2:11][N:10]([CH3:28])[CH2:9]1
Reactant: C=O
Reactant: Fc1ccccc1C1CNCc2cc(OCCCN3CCCCC3)ncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1Cc2cc(OCCCN3CCCCC3)ncc2C(c2ccccc2F)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A solution of 4-(2-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridine (50.2 mg, 0.136 mmol) in MeOH (5 mL) was treated with paraformaldehyde (62 mg). The mixture was heated at 55° C. for 1 h, cooled to 0° C., and was treated with NaBH4 (66 mg, 1.74 mmol). After 2 h at 0° C., the mixture was diluted with satd. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated. The residue was chromatographed (SiO2; 1-10% 2 M NH3 in MeOH/DCM) to give the title compound (20.4 mg, 39%) as an oil. MS (ESI): mass calcd. for C23H30FN3O, 383.24; m/z found, 384.5 [M+H]+. 1H NMR (CDCl3): 7.69 (s, 1H), 7.23-7.17 (m, 1H), 6.47 (s, 1H), 4.57-4.54 (m, 1H), 4.26 (t, J=6.7, 2H), 3.62 (d, J=15.9, 1H), 3.58 (d, J=15.9, 1H), 2.97 (dd, J=12.0, 5.1, 1H), 2.65 (dd, J=11.5, 7.5, 1H), 2.47-2.36 (m, 9H), 1.98-1.91 (m, 2H), 1.61-1.55 (m, 4H), 1.47-1.39 (m, 2H).