Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>O.CCO>[O:15]=[C:13]([CH3:14])[CH2:12][CH:4]1[C:5](=[O:9])[CH2:6][CH2:7][CH2:8][C:3]1=[O:10]
Reactant: CC(=O)CCl
Reactant: O=C1CCCC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)CC1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of KOH (2.54 kg, 2.26 kg corrected for assay, 40.2 moles) in water (4.0 L) was added over 30 mins to a solution of cyclohexane-1,3-dione (4.53 kg, 4.51 kg corrected for assay, 40.2 moles) in EtOH (16.2 L), while maintaining the temperature below 30° C. After stirring for 15 mins at r.t., freshly distilled chloroacetone (4.39 kg, 3.83 kg corrected for assay, 41.4 mol) was then added slowly to the mixture, maintaining a temperature of 25-28° C. The resulting slurry was stirred at r.t. for 19 h. Inorganic by-products were then removed by filtration and were washed on the filter with EtOH (4.5 L). The filtrates were combined to provide 2-(2-oxopropyl)cyclo-hexane-1,3-dione as a solution in EtOH. Assay by GC 26.5% w/w; purity by GC: 82.3 area %). This solution was transferred to a reactor and glycine ethyl ester hydrochloride salt (6.41 kg, 6.17 kg corrected for assay, 44.2 moles) was added at r.t. with stirring followed by sodium acetate trihydrate (6.04 kg, 6.02 kg corrected for assay, 44.3 moles). The mixture was diluted with ethanol (28.9 L) then heated under reflux for 2 h. EtOH was removed in vacuo (−0.850 to −0.900 bar) at 30° C. until 40 L of distillate had been collected. After cooling the residue to 0° C., water (15 L) was added, while maintaining a temperature of 0-5° C. After stirring for a further 1 h at this temperature, the solid that separated out was collected by filtration and was then dried in vacuo at 35° C. with a nitrogen bleed to give the title compound as a solid; 6.7 kg; assay by 1H NMR: 86.6% w/w; weight corrected for assay: 5.80 kg (61% over 2 steps); purity by GC: 96.0 area %; m/z: 235 (MH+); 1H NMR: (CDCl3) 1.27-1.32 (3H, t), 2.10-2.17 (2H, m), 2.19 (3H, s), 2.42-2.46 (2H, t), 2.65-2.69 (2H, t), 4.21-4.28 (2H, m), 4.51 (2H, s) and 6.27 (1H, s).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:32]C(=O)C)[CH:24]=2)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.CO.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:6]=[C:7]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])[CH:24]=2)([C:19]([F:20])([F:21])[F:22])[C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc(C(c2ccc([N+](=O)[O-])c(NC(C)=O)c2)(C(F)(F)F)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(C(c2ccc([N+](=O)[O-])c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
160 g (0.31 mol) of 2,2-bis-(3-acetamido-4nitrophenyl) hexafluoropropane are heated under reflux for 15 minutes in a solution of 65 ml of water, 570 ml of methanol and 25 g of sodium hydroxide. The hot solution is diluted with 1,300 ml of hot water and then cooled to 0°-5° C. The solid is filtered off with suction, washed with water, dried at 80° C. and recrystallized from toluene. Yield 115 g (0.27 mol); yellow solid; m.p. 257°-259° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)C)=O)[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1.[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([NH2:33])=[CH:28][N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[Cl:18][C:17]1[C:4]2[N:3]=[C:2]3[N:33]([C:29]4[CH:28]=[N:27][C:26]([N:25]([CH3:24])[CH3:34])=[CH:31][C:30]=4[CH3:32])[C:8](=[O:10])[CH2:7][N:6]3[C:5]=2[C:14]([CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:15][CH:16]=1
Reactant: Cc1cc(N(C)C)ncc1N
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1cnc(N(C)C)cc1C
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.62 g, 4.53 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (2.06 g, 4.85 mmol), p-toluenesulfonic acid monohydrate (922.9 mg, 4.85 mmol) and xylene (8.0 mL) was stirred at 150° C. for 3 days. After cooling, the reaction mixture was diluted with water and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with 1N hydrochloric acid (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give a mixture containing the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was washed with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (49.7 mg, 0.121 mmol, 2.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]1[CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Temperature: 25 °C

Procedure:
To a solution of (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid in THF at 0° C. was added BH3-DMS. The reaction was allowed to warm to rt overnight, and then quenched by the careful addition of MeOH. The reaction was concentrated in vacuo to give (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate as a near colorless oil which was used without further purification. (2R,3S)-tert-Butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate was converted to the title compound following the same general protocol for Mitsunobu reaction with phthalimide followed by hydrazine cleavage as described for Example 32 Part V and Part VI.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N>CO.CCOC(C)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Br:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Reactant: BrBr
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: Brc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g, 2.1 mmol) in 10 ml of ACOH was added Br2 (0.057 ml, 1.1 mmol) in a portion. The resulting reaction mixture was stirred for 1 h at 25° C. Concentration of reaction mixture in vacuo yields a brown oil which was subjected to column chromatography (30% NH3 sat'd MeOH/EtOAc) to provides 0.28 g (1.5 mmol, 71%) of the desired product. The product obtained was recrystallized from MeOH to afford 0.22 g (56%) of the product as a light brown solid: mp 320-321° C.; Anal. Calc. for C10H9N5Br2 requires C, 33.45; H, 2.53; N, 19.51. Found: C, 33.93; H, 4.05; N, 19.01.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]2[C@:10]([N:14]([CH3:16])[CH3:15])([CH2:11]2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:15][N:14]([CH3:16])[C@:10]12[CH2:11][C@H:12]1[CH2:13][NH:8][CH2:9]2
Reactant: CN(C)[C@]12C[C@H]1CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@@]12CNC[C@@H]1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of (1R,5S)-3-benzyl-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.28 g, 1.29 mmol) in MeOH (20 mL) was added 20% Pd(OH)2 (30 mg). The mixture was stirred at rt under H2 overnight and filtered. The filtrate was concentrated in vacuo to give the crude product (1R,5S)—N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.16 g), which was used for the next step without further purification. To a solution of (1R,5S)—N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine in acetone (5 mL) was added anhydrous K2CO3 (0.35 g, 2.54 mmol, 2.0 eq) and 1-bromo-3-chloropropane (0.20 mL, 1.91 mmol, 1.5 eq) in turn. The reaction mixture was heated at 65° C. for 4 h, and then cooled to rt. To the reaction mixture was added water (5 mL) and the mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (30:1 (v/v) CHCl3/CH3OH) to give the title compound as colorless oil (103 mg, 40%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 203.2 (M+1).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:11])=[CH:15][CH:16]=1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a solution of tert-butyl N-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-L-phenylalaninate (570 mg) in ethanol (3.00 mL) and tetrahydrofuran (3.00 mL) was added 10% palladium-carbon (138 mg) under an argon atmosphere, and then followed by stirring at room temperature overnight under a hydrogen atmosphere. The reaction suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(tert-butoxycarbonyl)-L-phenylalaninate (431 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.[CH:17]1([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])[CH2:19][CH2:18]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:17]1([C:20]([C:21]2[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:22]=2[CH3:23])=[O:25])[CH2:19][CH2:18]1
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccco2)c1C(=O)C1CC1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
To a stirred solution of 60 mg (0.26 mmol) (2-amino-5,6-dihydro-4H-cyclopenta [b]thiophen-3-yl)-furan-2-yl-methanone (the preparation of which is described in example 18) in 2 ml acetic acid was added 43 mg (0.34 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 17 mg (21%) cyclopropyl-(4-furan-2-yl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (%): 324 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:26][C:27]3[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[CH:35][CH:36]=3)[C:11](=[O:13])[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)OC)c2)c1=O

Procedure:
200 mg (0.75 mmol) of methyl [3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate [preparation according to WO 2007/134862 Example 222A] were suspended in 7.5 ml of acetone, 365 mg (1.12 mmol) of cesium carbonate and 223 mg (0.97 mmol) of methyl 3-bromomethylbenzoate were added and the mixture was heated at the boil for 1 h. After cooling, the mixture was filtered through Extrelut and the filter cake was rinsed with acetone. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). The target compound was obtained as a colorless foam (165 mg, 53% of theory).
Reaction SMILES: [NH2:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:18][CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: CC(C)(Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1

Procedure:
Using a method similar to example 2, using 6-[4-(2-amino-2-methyl-propyl) phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.96 minutes, Purity: 100%; mass spectrum (ion spray): m/z=376.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.BrC1C2N([C:38](=[O:41])NN=2)C(C)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]2[N:12]([C:38](=[O:41])[NH:15][N:14]=2)[CH:13]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Yield: 88 %

Procedure:
The title compound (190 mg, 88% yield) as a yellow foam was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (200 mg, 0.61 mmol) in a manner analogous to that in which 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=3.83 min, [M+H]+=356.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH:29]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:29]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(c5ccccc5)c5ccccc5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
In DMF (3ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the solution were added 1-benzhydrylpiperazine (127mg) and potassium carbonate (268mg). The mixture was stirred at room temperature for 24 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropylether to give N-[4-(4-benzhydryl-1-piperazinyl-methyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 43) (140mg) as colorless crystals.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:6])[CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](Cl)=[O:26]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25]([N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([CH3:6])[CH3:5])=[O:26]
Reactant: CCOC(=O)CNC(C)C
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)c1cc(Cl)cc(Cl)c1)C(C)C
Temperature: 25 °C

Procedure:
A 250 milliliter round-bottom, 3-neck flask was equipped with a condenser, a thermometer, a dropping funnel, and a Teflon® spin-bar magnet for stirring. The outlets were protected from moisture by calcium chloride drying tubes, and the flask was immersed in an ice-water cooling mixture. The flask was charged with an 80 milliliter dichloromethane solution containing 0.015 mole (2.2 grams) of the ethyl N-isopropylaminoacetate (described above) and 0.015 mole (1.5 grams) of triethylamine. The solution was stirred while cooling in an ice-water bath. A 20 milliliter solution of dichloromethane containing 0.015 mole (3.14 grams) of 3,5-dichlorobenzoylchloride was added dropwise over a period of 1.0 hour with stirring and the stirring was continued for several hours followed by allowing the mixture to warm to room temperature. The reaction solution was washed four times with water (25 milliliters) to remove the triethylamine hydrochloride. The washed organic solution was filtered to remove the phase water and concentrated first by rotary evaporation (house vacuum, water bath to 65° C.) to 4.9 grams of a dull yellow syrup (nD20 1.5257) and then, using a vacuum pump (<1 mm, oil bath to 50° to 60° C.) for 1.0 hour, to 4.5 grams (94 percent crude yield) nD20 (1.5280) ethyl N-3,5-dichlorobenzoyl-N-isopropylaminoacetate. It had a mass spectra (m/e) of molecular weight of 317, an infrared spectra (neat) mull technique with ester C=O band at 1745 centimeters-1 and amide (C=O) band at 1635 centimeters-1. It had the following nuclear magnetic resonance values δ (CDCl3) of 1.1 (doublet, 6H, (CH3)2C--), 1.3 (triplet, 3H, CH3--), 3.7-4.5 (4.0 broad singlet, 4.2 quartet, (overlap), 5H, CH2N, CH2, CH (heptet obscured)), and 7.3-7.5 (multiplets, 3H, aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][C@@H:23]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1([C@H]([C@@H](C2C=CC=CC=2)O)O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][C@H:23]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@@H]2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide was prepared in a similar manner as 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (Example 47) starting with (R,R)-hydrobenzoin (Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59, 8302).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[O:25]1[C:29]2([CH2:34][CH2:33][CH:32](CS([O-])(=O)=O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[O:25]1[C:29]2([CH2:34][CH2:33][CH:32]([N:23]3[CH:24]=[C:20]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([S:11]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)(=[O:12])=[O:13])[CH:7]=4)[CH:21]=[N:22]3)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1
Reactant: O=S(=O)([O-])CC1CCC2(CC1)OCCO2
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c2ccc(F)cc21
Yield: 59 %

Procedure:
Following the general method as outlined in Intermediate 16, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 600 mg; 1.76 mmol) and 1,4-dioxaspiro[4.5]decan-8-ylmethanesulfonate (498 mg; 2.11 mmol), 500 mg (59%) of the title compound was obtained as a white solid after purification by reverse phase flash chromatography.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:28][N:29]([C:37]2([CH2:40][OH:41])[CH2:39][CH2:38]2)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:9]=1[Br:42].F[B-](F)(F)F.[CH3:58][O+](C)C>C(Cl)Cl>[CH3:52][Si:2]([CH3:1])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:49])([CH3:48])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:28][N:29]([C:37]2([CH2:40][O:41][CH3:58])[CH2:39][CH2:38]2)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:9]=1[Br:42]
Reactant: CC(C)(C)OC(=O)N(Cc1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1(CO)CC1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(N(Cc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
To tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(1-(hydroxymethyl)cyclopropyl)carbamate (0.19 g, 0.23 mmol) in DCM (2.5 ml) was added protonsponge (70 mg, 0.33 mmol) followed by trimethyloxoniumtetrafluoroborate (48.2 mg, 0.33 mmol) at room temperature and the resulting mixture was stirred at room temperature for 16 h, at which time LC/MS confirmed full conversion of starting material to product. Reaction mixture was quenched with sat. NH4Cl and diluted with DCM (25 ml). Organics were separated and washed with brine (5 ml) and dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with DCM/MeOH (0-50%) gave slightly impure desired tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(1-(methoxymethyl)cyclopropyl)carbamate (97 mg, 50%).