(2R)-2-methyl-1-[[(2S)-pyrrolidin-2-yl]methyl]pyrrolidine

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure N and Procedure P starting from 4-(2-Methanesulfonyl-thiazol-4-yl)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 434.12.

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

Procedure: The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 30% DMF/CH2Cl2 using 4-(5-Carbamoyl-thiophen-3-yl)-benzoic acid (360 mg, 1.6 mmol), EDC-HCl (439 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol), DIEA (0.70 mL, 4.0 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (236 mg, 1.4 mmol) to give the title compound (80 mg, 14% yield). MS (ES+) 398.3 (M+H)+

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

Procedure: The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 30% DMF/CH2Cl2 using 4-(5-Carbamoyl-thiophen-3-yl)-benzoic acid (360 mg, 1.6 mmol), EDC-HCl (439 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol), DIEA (0.70 mL, 4.0 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (236 mg, 1.4 mmol) to give the title compound (80 mg, 14% yield). MS (ES+) 398.3 (M+H)+

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

Procedure: The title compound is prepared in a manner substantially analogous to General Procedure D in 6 mL DMF using 4-(5-cyano-thiophen-2-yl)-2-fluoro-benzoic acid (181 mg, 0.73 mmol), EDC-HCl (210 mg, 1.1 mmol), HOBt (149 mg, 1.1 mmol), DIEA (0.31 mL, 1.8 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (101 mg, 0.60 mmol) to give the title compound (30 mg, 12% yield). MS (ES+) 398.3 (M+H)+

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

Procedure: The title compound is prepared in a manner substantially analogous to General Procedure D in 5 mL 50% DMF/dichloromethane using 4-(5-ethanesulfonyl-thiophen-2-yl)-benzoic acid, Lithium salt (118 mg, 0.39 mmol), EDC-HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), DIEA (0.17 mL, 1.0 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (61 mg, 0.36 mmol) to give the title compound (80 mg, 50% yield). MS (ES+) 447.3 (M+H)+

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

Procedure: A 100 mL toluene/EtOH mixture of commercially available 4-carboxy-3-phenyl boronic acid and pinacol is stirred at 75-80° C. for 2 hours, then concentrated, slurried in toluene, concentrated, and dried in vacuo to give 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid that is used without further purification. The title intermediate is prepared in a manner substantially analogous. General Procedure E using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. The crude product is confirmed by NMR and MS (MS+) 417.5 (M+H)+ then used without further purification. is used without further purification (M+H)+ then used without further purification

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

Procedure: The title intermediate is prepared in a manner substantially analogous General Procedure E using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (CAS 180516-87-4). The crude product is confirmed by NMR and used without further purification. used without further purification

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

Procedure: The title intermediate is prepared in a manner substantially analogous General Procedure E using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (CAS 180516-87-4). The crude product is confirmed by NMR and used without further purification. used without further purification

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

Procedure: BOC proline (CAS 15761-39-4) and 2-(R)-Methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to General Procedure D in dichloromethane to give 2(S)-(2(R)-Methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (233179). The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq) is added and then stirred at room temperature for 18 hours. Reaction is concentrated and dissolved in H2O. The pH is adjusted to 8-9 with K2CO3, and the aqueous layer is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4) and concentrated in vacuo to give (2(R)-Methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M Lithium Aluminum Hydride/THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2. A THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. The reaction is stirred at 40° C. for 45 minutes, then at room temperature 18 hours. Reaction is cooled in an ice bath and is quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping reaction temperature less than 15° C. Reaction is stirred overnight, is filtered and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 169.3 (M+H)+ Intermediate is used as such or is purified by SCX chromatography or distillation. the reaction The reaction is stirred at 40° C. for 45 minutes at room temperature 18 hours Reaction is cooled in an ice bath reaction temperature less than 15° C Reaction is stirred overnight is filtered the precipitate is washed three times with THF concentrated

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure F from 2-fluoro-4-(4-methanesulfonyl-benzyloxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 475.2

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure F from 2-fluoro-4-(4-methanesulfonyl-benzyloxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 475.2

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure F from 4-(6-Methyl-pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 412.3