(1R)-2,3-dihydro-1H-inden-1-amine

Condiciones: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: A 500 ml round-bottom flask was charged with 5.0 g (1.0 eq.) (R)-2,3-dihydro-1H-inden-1-amine and 7.5 g (1.0 eq.) dimethyl 2-(3-methoxyallylidene)malonate in 120 ml dry THF. The mixture was heated at 65° C. under N2 for 3 hrs. Then the solvent was removed in vacuo, and the crude mixture was purified by silica gel flash column chromatography to afford (R)-dimethyl 2-(3-(2,3-dihydro-1H-inden-1-ylamino)allylidene)malonate as a yellow solid (11.0 g) in 97% yield. Then the solvent was removed in vacuo the crude mixture was purified by silica gel flash column chromatography

Condiciones: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: To a solution of 4-(3-isopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine (40 mg, 0.15 mmol) in anhydrous DMSO (0.25 mL) is added (R)-indan-1-ylamine (58 uL, 0.45 mmol). The reaction mixture is stirred at 150° C. overnight, diluted with dichloromethane, and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC to provide 20 mg of (R)-indan-1-yl-[4-(3-isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine. (Example 83). washed with water The organic layer is dried over sodium sulfate concentrated in vacuo The crude product is purified by preparative HPLC

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: To a solution of (1R)-indan-1-amine (1.00 g, 7.51 mmol) and triethylamine (1.52 g, 15.0 mmol) in DCM (75 mL) was added allyl bromide (1.36 g, 11.3 mmol) and the mixture was allowed to stir at ambient temperature for 3 days. An additional 1.5 equivalents of allyl bromide and 0.5 equivalents of triethylamine were then added, and the reaction mixture was stirred an additional 24 hours. LCMS analysis now indicates the reaction mixture is a 27:35:38 mixture of starting material:desired product:bis-allylation product. Use this solution as is. the reaction mixture was stirred an additional 24 hours a 27:35:38 mixture of starting material

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.5 mmol) with (R)-1-aminoindan (188 mg, 1.4 mmol) in toluene (5 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give 7-chloro-6-(indan-1-ylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (129 mg, 67%). GC-MS m/z: 408 (M+). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) pre-wash column with methanol dissolved in DCM elute with DCM/2M ammonia in methanol (1:1) concentrate in vacuo]

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: [5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)yl]-acetic acid (50 mg, 0.135 mmol) was dissolved in DMF (2.5 mL) and DIEA (0.1 mL) was added to make a solution. HATU (117 mg, 0.31 mmol) was added and after stirring for two min, (R)-(−)-indanamine (0.1 mL) was added and the mixture was stirred overnight. The solution was poured into EtOAc (50 mL), washed with saturated NH4Cl (1×50 mL), 1 N HCl (1×50 mL), saturated NaHCO3 (1×50 mL), and saturated brine (1×50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to provide a crude brown oil (140 mg). This crude oil was purified by SiO2 column chromatography (40 to 100% EtOAc in hexanes) to produce pure title compound. MS (APCI pos) 484 (M+H). the mixture was stirred overnight washed with saturated NH4Cl (1×50 mL), 1 N HCl (1×50 mL), saturated NaHCO3 (1×50 mL), and saturated brine (1×50 mL) The organic layer was dried with Na2SO4 filtered concentrated in vacuo to provide a crude brown oil (140 mg) This crude oil was purified by SiO2 column chromatography (40 to 100% EtOAc in hexanes)

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: This was prepared by the same procedure as in Example 73 starting from (R)-1-aminoindan (8.02 g, 60 mmole) and succinoyl chloride (2.32 g, 14 mmole), to give the white product, (1.30 g, 26.70%). Melting point: 266-9° C. to give the white product, (1.30 g, 26.70%)

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R)(-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C. The solvent is evaporated to dryness and residue is treated with 50 ml cold water The solid material is filtered dissolved in excess ethanol volatiles are evaporated under reduced pressure to remove water Residue upon treatment with ethanol affords solid material It is filtered dried One more crop of the same material is obtained from the mother liquor

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R)(-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C. The solvent is evaporated to dryness and residue is treated with 50 ml cold water The solid material is filtered dissolved in excess ethanol volatiles are evaporated under reduced pressure to remove water Residue upon treatment with ethanol affords solid material It is filtered dried One more crop of the same material is obtained from the mother liquor

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (R)-(−)-1-aminoindan. Prepared

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (R)-(−)-1-aminoindan. Prepared

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (1.40 g, 3.14 mmol, 1 equiv), ethyl (2Z)-3-amino-5-(4-fluorophenyl)-2-pentenoate (0.744 g, 3.14 mmol, 1 equiv), 4-carboxy-2-nitrobenzaldehyde (0.613 g, 3.14 mmol, 1 equiv), and piperidine (0.155 mL, 1.57 mmol, 0.5 equiv) were combined in toluene (8.0 mL). After 2 h at 90° C., the reaction was cooled to ambient temp. CAN (3.44 g, 6.28 mmol, 2 equiv) and H2O (8.0 mL) were added. After 0.5 h the layers were separated. The aqueous portion was extracted with EtOAc (2×8 mL) and the combined organic portions were concentrated to a brown oil. The crude oil was then treated with 4 N HCl in dioxane (10.0 mL). After 1 h, the mixture was concentrated to a brown oil. A CH2Cl2 solution (8.0 mL) of this crude oil was treated with Et3N (2.18 mL, 15.7 mmol, 5 equiv). After 8 h, the mixture was concentrated to a brown foam. A solution of the crude foam (0.070 g, 0.13 mmol, 1 equiv) in CH2Cl2 (1.0 mL) was treated with (R)-(−)-1-aminoindane (0.035 g, 0.26 mmol, 2 equiv), EDCI (0.038 g, 0.20 mmol, 1.5 equiv), and HOBt (0.027 g, 0.20 mmol, 1.5 equiv). After 12 h at ambient temperature, the reaction was diluted with CH2Cl2 (1.0 mL) and treated with saturated aqueous NaHCO3 (2 mL). The organic portion was the washed with 1N HCl (2 mL) followed by brine (2 mL). Concentration gave a brown oil that was chromatographed radially (SiO2, 1 mm plate, 50% hexanes-EtOAc) to the title compound as a pale yellow foam (0.049 g, 58%): low resolution MS (ES+) m/e 649 (H+); RP-HPLC (Dynamax C-18 25 cm×4.1 mm; 50–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=13.78 min, 97% purity. After 0.5 h the layers were separated The aqueous portion was extracted with EtOAc (2×8 mL) the combined organic portions were concentrated to a brown oil The crude oil was then treated with 4 N HCl in dioxane (10.0 mL) After 1 h the mixture was concentrated to a brown oil After 8 h the mixture was concentrated to a brown foam After 12 h at ambient temperature washed with 1N HCl (2 mL) Concentration gave a brown oil that was chromatographed radially (SiO2, 1 mm plate, 50% hexanes-EtOAc) to the title compound as a pale yellow foam (0.049 g, 58%) RP-HPLC (Dynamax C-18 25 cm×4.1 mm; 50–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=13.78 min, 97% purity

Condiciones: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedimiento: To a stirred solution of 4-[(9aS)-3-(ethoxycarbonyl)-5-oxo-2-(3,3,3-trifluoropropyl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.075 g, 0.162 mmol) in 1 mL of dichloromethane, EDCI (0.037 g, 0.194 mmol), HOBT (0.026 g, 0.194 mmol) and (R)-(−)-1-aminoindane (0.051 g, 0.324 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The mixture was then concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration followed by concentration provided a brown oil which was purified by radial chromatography (ethyl acetate/hexanes (4:1)) to yield 0.046 g (49%) of the desired product as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.86–7.77 (d, 2H, J=8.27), 7.45–7.37 (d, 2H, J=8.28), 7.36–7.29 (d, 1H, J=6.38), 7.28–7.16 (m, 3H), 6.48–6.37 (m, 1H), 5.72–5.64 (q, 1H, J=7.59), 4.71–4.63 (dd, 1H, J=10.34, J=6.21), 4.13–3.96 (m, 2H), 3.72–3.58 (m, 1H), 3.38–3.26 (m, 1H), 3.22–3.08 (m, 2H), 3.07–2.96 (m, 1H), 2.96–2.83 (m, 1H), 2.79–2.56 (m, 3H), 2.55–2.38 (m, 1H), 2.38–2.22 (m, 2H), 1.98–1.84 (m, 1H), 1.45–1.27 (m, 1H), 1.04–0.95 (t, 3H, J=7.07); TLC (EtOAc/Hex(4:1)): Rf=0.3; RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer, 30 minutes; 1 mL/min) tr=11.8 min, 94.1% purity. The mixture was then concentrated redissolved in 1 mL of ethyl acetate The organics were then washed with saturated aqueous NaHCO3 and brine Filtration followed by concentration provided a brown oil which was purified by radial chromatography (ethyl acetate/hexanes (4:1))