Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([CH3:13])=[CH:12][C:7]=1[CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c(Br)c(=O)n1Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a degassed solution of 3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl2(PPh3)2 (0.11 g) were added. The reaction mixture stirred at room temperature under nitrogen for 1 hour and then heated in an oil bath (65° C.) under nitrogen overnight. The solvents were distilled in vacuo and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). The extracts were concentrated to afford the desired compound (0.432 g, 69%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J=8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z 397.0361/399.0310 (M+H calculated for C20H15N2OFBr requires 397.0346/399.0328). Step 3. Preparation of 3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[N:15]=[C:9]2[CH:8]1[CH2:24][CH2:25][S:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:9]2[CH:8]([CH2:24][CH2:25][S:26][C:27]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:7][CH2:12][CH2:11][N:10]2[CH:13]=1
Reactant: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC2
Yield: 64 %

Procedure:
The product from Step 13.f. (2.50 g, 3.96 mmol) was dissolved in CH2Cl2 (16.0 ml) and treated with Tfa (4.0 ml) at room temperature under N2 for about 3.5 hours. The reaction was then poured cautiously into a saturated NaHCO3 solution (150 ml) and the product was extracted with CH2Cl2 (2×50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 9:1/ hexanes:EtOAc and then 100% EtOAc as eluants. Product fractions were combined and concentrated under reduced pressure to obtain a white foam (1.35 g, 64%) which was used without further purification. Mass spec. 532.4 MH+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][NH:6][CH:5]([C:9]([NH:11][C@H:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH3:13])=[O:10])[CH2:4]2)[CH2:2]1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[CH2:7][CH2:8][C:3]3([CH2:2][CH2:1]3)[CH2:4][CH:5]2[C:9]([NH:11][C@H:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH3:13])=[O:10])=[CH:27][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CC3(CCN2)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CC3(CCN2Cc2ccc(F)cc2)CC3)cc1

Procedure:
The title compound (D126) (30 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-(6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D91) (60 mg) and 4-Fluorobenzylbromide (0.074 ml). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 17.8 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (0.50 g, 0.12 mmol), pivaloyl chloride (0.018 g, 0.14 mmol), TEA (0.038 g, 0.37 mmol) in DCM (10 mL) to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.18 (s, 9H), 4.38 (s, 2H), 7.24-7.63 (m, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.99 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.61 (s, 1H); MS (m/z): 470.25 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][C:24]=1[F:32])#[N:22]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C#N)c(F)c3)ccn2c1=O
Yield: 105.5 %

Procedure:
Methyl 8-(4-cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 4-cyano-3-fluoro-phenyl-boronic acid (85 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (135 mg, 98%). ESI-MS m/z: 377 (M+H)+.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(CC)CC>CCO>[CH3:37][C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][NH:24][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22])=[O:32])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (157 mg, 0.450 mmol) and (R)-2-aminomethyl-1-Boc-pyrrolidine (100 mg, 0.495 mmol) in 3 mL of EtOH containing Et3N (0.095 mL, 0.559 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 232 mg (98%); 1H NMR (CDCl3) 1.47 (brs, 9H), 1.83 (m, 1H), 1.90 (m, 2H), 2.03 (m, 1H), 3.31 (m, 1H), 3.37 (m, 2H), 3.62 (m, 1H), 4.09 (m, 2H), 4.24 (m, 6H), 7.26 (m, 1H), 7.50 (m, 1H), 8.27 (s, 1H), 8.55 (brs, 1H); MS (ESI) 529.38 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[SH:11].[CH3:12][C:13]1[O:17][C:16](C=S=O)=[N:15][N:14]=1.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[S:11][C:16]1[O:17][C:13]([CH3:12])=[N:14][N:15]=1
Reactant: Cc1cccc(C)c1S
Reactant: Cc1nnc(C=S=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(Sc2c(C)cccc2C)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To an NaH slurry (0.15 g, 0.0037 mol, 60% in oil) in dry DMF (5 ml) under a N2 atmosphere was added 2,6-dimethylthiophenol (0.50 ml, 0.00374 mol). The mixture was stirred for 10 min at rt and cooled to 0° C. To the cooled solution was added dropwise via syringe a solution of 5-methyl-2-sulfinylmethyl-1,3,4-oxadiazole (77) (0.5 g, 0.0034 mol) in dry DMF (1.5 ml). The mixture was stirred for 1 h, water was added (15 ml) and the aqueous layer extracted with Et2O (4×20 ml). The combined extracts were washed with water (2×25 ml), saturated NaCl solution (1×25 ml), dried (MgSO4) and solvent removed in vacuo. Chromatography on silica gel using 1/2 ethyl acetate/hexanes gave 2-(2,6-dimethylphenyl)thio-5-methyl-1,3,4-oxadiazole (24) as a white solid (0.372 g, 46%, mp 53°-54° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:19][CH3:20])=[CH:11][C:12]([I:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:19][CH3:20])=[CH:11][C:12]([I:18])=[C:13]([C:14]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:16])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: COc1cc(I)c(C(=O)O)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(I)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-benzyloxy-2-iodo-4-methoxybenzoic acid (reference example 5-2) (1.92 g), piperidine (0.74 mL) and N,N-dimethylforamide (12 mL) was added 1-hydroxybenzotriazole (676 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.44 g) at room temperature. The mixture was stirred at room temperature for 6 hours. After addition of ethyl acetate, the mixture was poured into 2 mol/L hydrochloric acid. The organic layer was washed with water, an aqueous solution of sodium bicarbonate, and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The mixture of the residue, aminopropylsilicagel and dichloromethane was stirred for 30 minutes. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (2.13 g).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[CH:23])[C:17]1=[O:24]>>[O:24]=[C:17]1[C@@H:16]([NH:15][S:10]([C:2]2[S:1][C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)(=[O:12])=[O:11])[CH2:20][CH2:19][N:18]1[CH2:21][C:22]#[CH:23]
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Reactant: C#CCN1CC[C@H](N)C1=O
Agent: Cl
Product: C#CCN1CC[C@H](NS(=O)(=O)c2cc3ncccc3s2)C1=O

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using thieno[3,2-b]pyridine-2-sulfonyl chloride and 3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as starting material. The crude product is isolated as a white solid and used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:23][C:24]1[C:25]([F:39])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([O:23][C:24]1[C:25]([F:39])=[C:26]([C:7]2[N:6]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[N:13]3[C:8]=2[C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc(OCc3ccccc3)c2F)OC1(C)C
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Product: Nc1ncnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 75 °C

Procedure:
A flask was charged with 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095 mmol), 2-(3-benzyloxy-2-fluoro-phenyl)-4,4,5,5- tetramethyl [1,3,2]dioxaborolane (62.5 mg, 0.158 mmol), and sodium carbonate (30 mg, 0.286 mmol) and was evacuated and charged with N2 (3×). This mixture was charged with tetrakis(triphenylphosphine palladium (0) (Pd(PPh3)4 (0)) (36 mg, 0.0318 mmol) and the tube was re-evacuated and charged with N2 (2×). This mixture was then charged with a previously degassed solvent DME/H2O (5:1)(3 mL) and heated to 75° C. for 16 h. The reaction mixture was concentrated in vacuo and dissolved in MeOH/CH3CN (1:1) (5 mL), filtered though a 0.45 μM fritted autovial and submitted for mass directed purification (MDP) resulting in the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:27])[CH:13]=[C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.CO.[Li+].[OH-].Cl>O>[CH:16]1[C:15]2[C:14](=[CH:13][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[O:27])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
8-(2-(9H-fluoren-9-ylidene)acetamido)octanoic acid methyl ester (377 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (345 mg, 95% yield) as a white solid. 1H NMR (DMSO-d6) δ1.23 (m, 2H, CH2), 1.45 (m, 6H, 3×CH2), 1.49 (m, 2H, CH2), 2.18 (t, J=8.0 Hz, 2H, CH2CO), 3.23 (m, 2H, NCH2), 7.08 (s, 1H, ═CH—CO), 7.34 (m, 2H, Ar—H), 7.41 (t, J=8.0 Hz, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.50 (t, J=4.0 Hz, 1H, CONH), 8.67 (d, J=8.0 Hz, 1H, Ar—H). LC-MS (m/z) 364 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[C:38]([NH:41][CH2:42][CH2:43][NH2:44])(=[O:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:38]([NH:41][CH2:42][CH2:43][NH:44][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:31])[CH3:32])[NH:17]1)=[O:36])(=[O:40])[CH3:39]
Reactant: CC(=O)NCCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 83.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with N-acetylethylenediamine (Aldrich) (0.15 g, 1.5 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4.8 mmol) in CH2Cl2 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide as a white solid (0.24 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]1)=[O:9].F[B-](F)(F)F.C([O+](CC)CC)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:38][NH2:39])=O)=[N:34][CH:35]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=3)=[N:38][N:39]=[C:12]2[CH2:11]1)=[O:9]
Reactant: NNC(=O)c1ccc(F)cn1
Reactant: O=C1CN(C(=O)c2ccccc2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in an analogous method to that described in E111. To a solution of 4-[(2-chlorophenyl)carbonyl]-2-piperazinone (I4) (225 mg, 0.943 mmol) in Dichloromethane (5 ml) stirred under argon at room temp was added solid triethyloxonium tetrafluoroborate (179 mg, 0.943 mmol). The reaction mixture was stirred at RT for 2 hr. Solid 5-fluoro-2-pyridinecarbohydrazide (I24) (161 mg, 1.037 mmol) was added and the reaction mixture stirred at RT for 18 hr. The solvent was evaporated in vacuo, and the residue dissolved in n-butanol (5 ml) and stirred at 120° C. for 4 hr. The reaction mixture was cooled to room temperature and partitioned between Dichloromethane (˜25 ml) and saturated brine (˜25 ml). The aqueous phase was extracted with Dichloromethane (2×25 ml) and the combined organic extracts washed with saturated brine (˜25 ml), dried over sodium sulphate, and evaporated in vacuo to afford the crude product as a yellow oil. This was dissolved in 1:1 MeOH:DMSO and purified by Open Access Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo and the residue dried overnight in a vacuum oven at 40° C. to give the required product as a white powder in 126.4 mg.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([C@H:17]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[O:28][CH3:29])[CH3:18])[CH2:16][O:15]1>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:15])([C@H:17]([N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[O:28][CH3:29])[CH3:18])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Product: COc1ncnc2c1ncn2[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 77.4 %

Procedure:
Using 1H-1,2,4-triazole (74 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-9-(9H)-purinyl]ethyl]oxirane (183 mg), Compound 47 (171 mg) was obtained as colorless prisms by the same was as in Example 1.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:32][CH2:33][O:34][CH2:35][CH3:36]>C(O)C>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][C:12]3[CH:17]=[CH:16][C:33]([O:34][CH2:35][CH2:36][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[C:32]([O:11][CH2:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)[CH:13]=3)[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCCCc1ccc(OCCCN2CCCCC2)c(OCCCN2CCCCC2)c1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: c1cc(OCCCN2CCCCC2)c(OCCCN2CCCCC2)cc1CCCCc1ccc(OCCCN2CCCCC2)c(OCCCN2CCCCC2)c1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To all ice cooled (0-5° C.) solution of aqueous concentrated HCl (7.0 mL, of 11 N, 77 mmol, 24 equiv.) in 95% ethanol (21 mL) was added dropwise a solution of 1,4-bis{(3,4-bis[3-(piperidin-1-yl)propoxy]phenyl}-butane (2.50 g, 3.225 mmol) in 95% ethanol (21 mL)*. The solution was allowed to stir at 0-5° C. for three hours and the solvent was removed on a rotary evaporator keeping the temperature of the water bath at 45° C. The hydrochloride salt was dried under high vacuum for 48 hours. The crude product was then crystallized from ethanol: ether to give 2.46 g of the product (83.2% yield) after drying high vacuum for 72 hours. *Note that the starting material 1,4-bis{3,4-bis[3-(piperidin-1-yl)propoxy]phenyl}-butane did not dissolve completely in 95% ethanol at room temperature, so the mixture was heated at 45° C. during which 1,4-bis{3,4-bis[3-(piperidin-1-yl)propoxy]phenyl}-butane dissolved. The solution was cooled to room temperature and added to the ethanolic HCl solution.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8]C)=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12.Cl>O1CCOCC1>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c[nH]c(=O)c32)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A solution of 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (12.4 g, 32.6 mmol) in dioxane (140 mL) was stirred at room temperature. To this solution was added 4M HCl in dioxane (140 mL). The reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with diethyl ether, filtered, and rinsed with additional diethyl ether and dried to provide 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (11.23 g, 30.6 mmol, 94% yield) as a beige solid.
Reaction SMILES: [NH2:1][CH3:2].[F:3][C:4]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:5]=1[CH2:6][O:7][CH2:8][C:9]#[C:10][CH2:11]Br>O1CCCC1>[CH3:2][NH:1][CH2:11][C:10]#[C:9][CH2:8][O:7][CH2:6][C:5]1[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:4]=1[F:3]
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Reactant: CN
Solvent: C1CCOC1
Product: CNCC#CCOCc1cc(Br)ccc1F
Yield: 83 %

Procedure:
A solution of aminomethane (89 ml of a 2 M solution in tetrahydrofuran, 178 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (6.0 g, 17.8 mmol) in tetrahydrofuran (89 ml). The cloudy reaction mixture was stirred for about fifteen minutes, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back-extracted thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 4.24 grams (83%) of the title intermediate as a yellow oil.