Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 77 %

Procedure:
An 18-mL test tube was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (30 mg, 0.1 mmol, 1 eq. Synthesis of this compound was described in step 1 of EXAMPLE 1) and methyl 2-(4-aminophenyl)acetate (33 mg, 0.2 mmol, 2 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane followed by 1˜3% of MeOH in dichloromethane as eluent to give methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate (31 mg, 77% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][C:13]([CH:11]=[N:1][CH:2]2[CH2:10][CH:9]3[N:5]([CH2:6][CH2:7][CH2:8]3)[CH2:4][CH2:3]2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: NC1CCN2CCCC2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: C(=NC1CCN2CCCC2C1)c1ccncc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
(±)-7-Amino-1,2,3,5,6,7,8,8a-octahydroindolizine (4.91 g (35.0 mmol), prepared as described in 1)) was dissolved in toluene (95 ml). To the solution were added 4-formylpyridine (3.34 ml, 35.0 mmol) and anhydrous magnesium sulfate (3.75 g, 31.2 mmol), and the resulting mixture was stirred at 70° C. for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure, to give the title compound (8.08 g) as a pale yellow oil (yield quantitative).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:4][C:3]([CH3:5])=[CH2:2])=[CH:17][CH:16]=1)[CH3:15]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OCC)cc1
Temperature: 90 °C

Procedure:
3-Chloro-2-methylpropene (2.1 mL, 0.021 mol) is added to a stirred N,N-dimethylformamide solution (30 mL) of ethyl 4-hydroxybenzoate (3 g, 0.018 mol). Potassium carbonate (3.2 g, 0.023 mol) is introduced and the mixture is heated at 90° C. for one hour. The reaction mixture is cooled to room temperature and filtered to remove inorganic salts. N,N-dimethylformamide is removed under reduced pressure, Demineralized water (20 mL) is added to the residue and the aqueous layer is extracted with ethyl acetate (3×20 mL). Combined organic layers are washed with demineralized water (2×15 mL) followed by brine and dried over sodium sulphate. Removal of ethyl acetate under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 90:10) to give 4-(2-methylprop-2-enyloxy)benzoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:21][C:19]1[CH:18]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([CH:20]=1)[O:5][C:4]1[C:3]([CH3:28])=[C:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
1.18 g 3-(3-amino-2-methylphenoxy)-5-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (2.3 mmol, 1 eq.) were dissolved in 9.6 mL pyridine, cooled to 0° C., treated with 292 μL ethyl sulfonyl chloride (3.1 mmol, 1.2 eq.) and stirred at 0° C. for 3 hours. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo to yield 1.6 g of the crude product, which was taken up in toluene and again concentrated in vacuo. The crude product was used in the subsequent transformations without further purification.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([N:23]1[C:27]2=[C:28]([N+:35]([O-:37])=[O:36])[C:29](O)=[C:30]([CH3:33])[C:31](=[O:32])[N:26]2[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:16]([N:23]1[C:27]2=[C:28]([N+:35]([O-:37])=[O:36])[C:29]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:30]([CH3:33])[C:31](=[O:32])[N:26]2[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
Triflic anhydride (2.8 g, 0.010 mol) was added to a stirred solution of 1-benzyl-7-hydroxy-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (2 g, 0.007 mol) and TEA (1.34 g, 0.013 mol) in DCM (40 mL) at −78° C. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was monitored by TLC (100% ethyl acetate). The reaction mixture was partitioned between DCM and water. The organic layer was washed with NaHCO3 solution, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 2.5 g of the product (89% yield).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17](=[O:22])C(Cl)(Cl)Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:25](CC)CC)C.C([O-])(=O)C.[NH4+].O>CS(C)=O>[CH:1]1([C:7]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=3)[NH:16][C:17](=[O:22])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl)C1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1nc(C2CCCCC2)c2cc(Cl)ccc2[nH]1
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of 7.66 g of 2-trichloroacetamido-5-chlorophenyl cyclohexyl ketone in 150 ml of dimethyl sulfoxide was added 4.0 g of triethylamine and 7.71 g of ammonium acetate. The mixture was left at room temperature for 1 day, and poured into 700 ml of water. The resulting precipitate was collected by filtration, washed with water and dried to obtain 5.29 g of 4-cyclohexyl-6-chloro-2(1H)-quinazolinone, which was recrystallized from chloroform to give colorless needles, m.p. 269.5°-270.5°C.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>C1COCC1.C(OCC)(=O)C>[CH2:10]([CH:17]1[CH2:18][CH2:19][C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)([OH:23])[CH2:21][CH2:22]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Fc1cccc(Br)c1
Reactant: CCCCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCC1CCC(O)(c2cccc(F)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
Well-dried magnesium (8.3 g) and THF (20 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 50° C. 3-Fluorobromobenzene (8) (60.0 g) dissolved in THF (300 ml) was slowly added dropwise thereto in the temperature range of 40° C. to 60° C., and the mixture was stirred for another 60 minutes. Then, 4-heptylcyclohexanone (9) (50.0 g) dissolved in THF (150 ml) was slowly added dropwise thereto in the temperature range of 50° C. to 60° C., and the mixture was stirred for another 60 minutes. The reaction mixture obtained was cooled to 30° C., and then poured into a vessel containing an aqueous 1N—HCl solution (900 ml) and ethyl acetate (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving 80.0 g of 4-heptyl-1-(3-fluorophenyl)-cyclohexanol (10). The compound (10) obtained was a yellow oil.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1[CH:28]=O.O>O1CCCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cn1cc2c(C=O)c(Cl)ccc2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1c(Cl)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a suspension of sodium hydride (0.488 g, 12.2 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl diethylphosphonoacetate (2.44 mL, 12.2 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 5-chloro-2-methyl-2H-indazole-4-carbaldehyde (2.16 g, 11.1 mmol) in tetrahydrofuran (10.0 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.54 g, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:30])[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1c(C(=O)OC(C)C)c2cc(Cl)ccc2[nH]c1=O
Product: CCc1c(C(=O)OC(C)C)c2cc(Cl)ccc2[nH]c1=S

Procedure:
150 mg (0.51 mmol) of isopropyl 6-chloro-3-ethylquinolin-2(1H)-one-4-carboxylate (Example 10) are reacted with Lawesson's reagent according to the process described in Example 5 (reaction time 5 hours at reflux temperature) and purified by means of chromatography on silica gel as indicated above (mobile phase: n-heptane/ethyl acetate=2/1).
Reaction SMILES: [O:1]1[CH:6]([CH2:7][NH2:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[O:1]1[CH:6]([CH2:7][NH:8][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCC1COc2ccccc2O1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCC3COc4ccccc4O3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 547 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=O.[C:14]([CH2:16]C(O)=O)#[N:15].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>CN(C)C=O>[CH3:1][C:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][CH2:16][C:14]#[N:15]
Reactant: CC(C=O)CCC(C)CC(C)(C)C
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=CCC#N)CCC(C)CC(C)(C)C
Temperature: 180 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
438 g (2.38 moles) of 2,5,7,7-tetramethyloctanal, 202 g (2.38 moles) of cyanoacetic acid, 350 ml of toluene, 350 ml of dimethylformamide and 28.5 g of ammonium acetate were heated under a water separator for 4 h, while stirring. Thereafter, the toluene was distilled off and the remaining residue was heated for 2 h at 180° C. The cooled residue was poured onto ice water and 10 extracted with diethyl ether. The organic phase was washed in succession with NaHCO: solution and water and then distilled. 450 g (yield: 91% of theory) of 4,7,9,9-tetramethyldec-3-enenitrile of boiling point 83°-88° C./-.3 mbar were obtained. The fragrance note was waxy, floral and fresh.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C@@:7]2([C:13]([O:15]C)=O)[CH2:11][C@@H:10]([OH:12])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=[O:35])[CH:29]=[C:30]([Cl:32])[CH:31]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]2[C:34](=[O:35])[N:33]([C:28]2[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=2)[C:13]3=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@]1(Cc2ccc(Br)cc2)C[C@@H](O)CN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of methyl (4R)-2-(4-bromobenzyl)-4-hydroxy-L-prolinate (0.170 g) (Prep. 3) in 10 mL of DMF was added K2CO3 (0.15 g). The reaction mixture was cooled to 0° C., treated with 3,5-dichlorophenyl isocyanate (0.116 g), then allowed to warm to RT and stirred overnight. The insoluble material was removed by filtration, the DMF evaporated, and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting oily residue was purified over SiO2 isolute column (10 g) (eluent: DCM/acetone-95/5) to afford the above-titled compound (0.100 g) as a white solid. 1H NMR (CDCl3): 7.45 (2H,d), 7.30 (1H,m), 7.10 (2H,d), 6.85 (2H,d), 4.75 (1H,m), 4.10 (1H,dd), 3.45 (1H,d), 3.40 (1H,dd), 3.25 (1H,d), 2.35 (1H, dd), 2.20 (1H,dd).
Reaction SMILES: [C:1]([Si:5]([CH3:43])([CH3:42])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([CH:17]([OH:33])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3O)[CH2:14][CH2:13][O:12][C:11]=2[CH:41]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:43])([CH3:42])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]3[CH:17]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:23]=4)[O:33][C:35]4[C:34](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:15]=3[CH2:14][CH2:13][O:12][C:11]=2[CH:41]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC(c1ccccc1O)=C2C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC1=C2C(c2ccc(OCCN3CCCCC3)cc2)Oc2ccccc21

Procedure:
Following the procedure described in Examples 76, 2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol, the compound prepared as in Example 105 above, was reacted with 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine to yield 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-(4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol as a crude oil. The crude 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin4-yl)-phenol was then further treated with HCl (12N, 4 eq., 0.67 mL) in toluene (100 mL) to generate yield 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine as a crude oil. The crude 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine was then further treated with HF•Pyridine (70% HF, 30% Pyridine, 0.5 mL) in CH3CN (20 mL) at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate:THF (1:1) and then washed with 5% NaHCO3 and brine. The reaction mixture was dried, concentrated and purified by flash chromatograph eluted with 5% MeOH in DCM to yield the title compound as a slightly yellow solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].ClS([N:43]=[C:44]=[O:45])(=O)=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:44]([NH2:43])=[O:45]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[3,5-Bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (40.3 mg, 0.073 mmol) (Example 20) was dissolved in CH2Cl2 (3 mL) and the solution was cooled to −78° C. Chlorosulfonyl isocyanate (32 μL, 0.367 mmol) was added dropwise by syringe. The reaction was stirred at −78° C. for 15 minutes, and then at 0° C. for 20 minutes. The reaction was then poured into H2O (15 mL) and saturated NaHCO3 (15 mL) was added. The mixture was extracted with CH2Cl2 (2×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 50% EtOAc/hexanes afforded N-[3,5-bis(trifluoromethyl)benzyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}urea. Rf=0.24 (40% EtOAc/hexanes). LCMS=593.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.75 (s, 1H), 7.66 (s, 2H), 7.60 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.5, 2.3 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.80 (d, J=15.8 Hz, 1H), 4.53 (s, 2H), 4.48 (d, J=15.8 Hz, 1H), 4.45 (d, J=17.8 Hz, 1H), 4.07 (d, J=17.8 Hz, 1H), 3.69 (s, 3H), 2.87 (m, 1H), 1.20-1.22 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:12]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:42](=O)[CH2:43][CH:44]([CH3:46])[CH3:45]>>[CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=2)[CH:12]=[C:13]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=2)[CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)CC=O
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
Following the procedure of Example 39, step (a), reaction of 2-[5-(3,5-Bis-trifluoromethyl-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester, compound 46a with isovaleraldehyde gave the title compound; Calcd. MW 661.66. Found MH+ 662.4.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][N:21]=1)#[N:19].CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:26][C:25]2[C:20]([C:18]#[N:19])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: N#Cc1ncccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1cccnc1C#N)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine in CH3CN with 2-cyano-3-bromomethyl-pyridine, KI and DIPEA gave 3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridine-2-carbonitrile as a dark red oil. 1H NMR (CDCl3) δ 2.04 (s, 6H), 3.86 (s, 4H), 3.99 (s, 2H), 7.07 (m, 2H), 7.38 (m, 3H), 7.84 (d, 1H, J=9.0 Hz), 8.37 (m, 2H), 8.53 (m, 1H).
Reaction SMILES: [C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[OH:26])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.[I-].[K+]>C1COCC1.CN(C=O)C>[C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[O:26][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([C:28]3[O:27][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)=[CH:37][CH:38]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O[C@@H]1CCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(C(N[C@@H]2CCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of trans-2-triphenylmethylaminocyclopentanol (4.76 g; 13.85 mmol), is added Nail (60%; 0.83 g; 20.78 mmol) in 100 ml THF and 20 ml DMF. This mixture is stirred for 1 hr. and then 4-(benzoxazol-2-yl)benzyl bromide (3.99 g; 13.85 mmol) is added followed by potassium iodide (pinch). The reaction mixture is stirred for 72 hrs., quenched with water, concentrated in vacuo and flash chromatographed using 9:1; hexane:EtOAc to obtain trans-2-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]cyclopentane which is used directly in the next step.