Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:13]([CH:14]=[CH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH:11]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:10]1[OH:30].S(=O)(=O)(O)[OH:32].C(OCC)C.O>CN(C)C=O.[O-2].[O-2].[O-2].[Cr+6]>[O:30]=[C:10]1[CH:11]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:12][CH:13]([CH:14]=[CH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:32])=[O:1]
Reactant: O=S(=O)(O)O
Reactant: CCCCCC(=O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(=O)C=CC1CC(OC2CCCCO2)C(=O)C1CCCCCCC(=O)O
Reaction time: 1.5 h

Procedure:
Chromium trioxide (4.0 g.) (dried over phosphorus pentoxide) was added portionwise to a stirred solution of 2-(7-hydroxyheptyl)-3-(3-oxooct-1-enyl)-5-(2-tetrahydropyranyloxy)cyclopentanol [2.12 g.; prepared as described in Example 2(f)] in dry dimethylformamide (30 ml.), while maintaining the temperature at between 5° and 15° C. A solution of concentrated sulphuric acid (1.4 ml.) in dimethylformamide (40 ml.) was then added and the mixture was stirred at between 5° and 15° C. for a further 90 minutes. Diethyl ether was then added, followed by a minimum quantity of water to produce two readily separable layers. The ethereal layer was separated and stirred with an aqueous 2N sodium carbonate solution. This aqueous layer was then separated, washed with diethyl ether, and then treated with a further quantity of diethyl ether and acidified to pH 4 by the dropwise addition of concentrated hydrochloric acid. The resulting ethereal layer was separated, and the remaining aqueous layer was extracted with a further quantity of diethyl ether. These last two ethereal solutions were then combined, dried over magnesium sulphate, and evaporated to dryness, to give crude 7-[2-oxo-5-(3-oxooct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (1.03 g.), νmax 1720 cm-1, 1700 cm-1, 1670 cm-1, 1625 cm-1 985 cm-1, which was used as starting material in the following preparation (h) of 7-[2-hydroxy-5-(3-hydroxyoct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid, without further purification being necessary.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)C>[CH3:17][C:16]1[N:5]2[CH2:6][C:7]3[C:8]4[C:9]([NH:14][CH:15]=3)=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]2=[N:20][N:19]=1
Reactant: CC(=O)NN
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Solvent: CCO
Product: Cc1nnc2n1Cc1c[nH]c3cccc-2c13

Procedure:
Alternatively the title compound is prepared as follows. A suspension of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (9.0 g) in dry ethanol (140 ml) is treated with acetylhydrazine (5.0 g). The mixture is heated at reflux for 2 days. Ethanol is partially removed by distillation and ether-hexane added. The solid is collected from methanol to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:11]4[N:19](C5CCCCO5)[C:18]5[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=5[N:12]=4)[CH2:6][CH:7]([O:8]2)[CH:3]1[O:4]3>Cl.C1COCC1.CO>[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:11]4[NH:19][C:18]5[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=5[N:12]=4)[CH2:6][CH:7]([O:8]2)[CH:3]1[O:4]3
Reactant: CCCn1c(=O)c2c(nc(C34CC5OC(C3)C(O4)C5O)n2C2CCCCO2)n(CCC)c1=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CC5OC(C3)C(O4)C5O)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
To a solution of 8-(4-hydroxy-2,6-dioxa-tricyclo[3.3.1.03,7]non-1-yl)-1,3-dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione (0.065 mmol, 0.030 g) in 1:1 THF/MeOH (6 ml) was added 1N HCl (3 drops). The reaction was stirred at room temperature 4 h and then concentrated to dryness. The residue was purified by reverse phase HPLC, providing product (0.0094 g, 38%). 1H NMR (400 MHz, d6-DMSO): 0.80-0.89 (m, 6H), 1.48-1.56 (m, 2H), 1.60-1.70 (m, 2H), 1.9-2.09 (m, 2H), 2.2-2.25 (m, 1H), 3.78-3.82 (m, 2H), 3.89-3.91 (m, 2H), 3.99 (s, 1H), 4.21 (br s, 1H), 4.51 (br s, 1H), 4.80 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21]O)[C:16]2[C:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:25]=[C:26]([Cl:27])[C:15]=2[N:14]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:13]2=[N:14][C:15]3[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:16]=3[N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(C(F)(F)F)cc3Br)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 863.4 %

Procedure:
To a solution of 4-[2-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 57; 109.2 mg, 0.205 mmol) in pyridine (0.5 mL) was added methanesulfonyl chloride (79.3 μL, 1.03 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting crude mesylate (MS Calcd.: 609; Found: 610 (M+H)) was subjected for the next step without further purification. To the crude material in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (56.7 mg, 0.410 mmol). The reaction mixture was stirred at 80° C. for 4 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×35) The combined organic layer was washed with water (×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 0-20% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound as a colorless powder (810.1 mg, 1.77 mmol, 71% (2 steps)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]2.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)N1CCCc2cc(-c3cnccc3Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cnccc3-c3ccc(F)cc3)cnc21
Temperature: 100 °C
Yield: 74.6 %

Procedure:
6-(4-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (50 mg, 0.15 mmol), 4-fluorophenylboronic acid (42 mg, 0.30 mmol) and 2.0 M Na2CO3 aqueous solution (0.15 mL, 0.30 mmol) are dissolved in 1.0 mL of 1,4-dioxane. The Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (7.7 mg, 0.011 mmol) is added. The mixture is heated at 100° C. for 3.5 hrs and then it is cooled down to room temperature. 30 mL of DCM and 20 mL of water are added and the organic layer is separated. The aqueous layer is extracted with DCM (2×20 mL) and all the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 39 mg of the titled compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:36]=[CH:37][C:38](/[CH:41]=[CH:42]/[CH2:43][CH2:44][O:45][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:39][CH:40]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCO)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCOS(C)(=O)=O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-hydroxybut-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.2 mmol) in dichloromethane (50 mL) and triethylamine (3.6 mmol) at room temperature, add methanesulfonyl chloride (1.56 mmol) dropwise over 5 minutes. Stir at room temperature for 1 hour, then dilute the reaction with dichloromethane (100 mL). Wash the organics with water (2×100 mL) followed by brine (100 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield the title compound as a light yellow foam (0.84g, 1.2 mmol). Use this material in the next step (Scheme II, step B) without further purification.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)([CH3:4])=[O:3].C(O)(C(F)(F)F)=O>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CP(C)(C)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP(C)(=O)CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-[(dimethylphosphoryl)methyl]piperazine-1-carboxylate (1.01 g, 3.66 mmole) was dissolved in 7 mL of anhydrous dichloromethane. At 0° C., 7 mL of TFA:DCM=1:1 solution was added in 3 portions. The reaction mixture was stirred at this temperature for 15 minutes before another 3.5 mL of TFA was added, and then continued to stir at room temperature for 2 hours. Volatile components were evaporated and yield light yellow oil. The crude mixture was directly carried into next step. MS (LC/MS): 199.2 [M+Na]
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O>N1C=CC=CC=1>[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])(=[O:14])=[O:13]
Reactant: C=CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
29.3 millimoles of 3-buten-1-ol are added to a solution of 525 millimoles of p-toluenesulphonyl chloride in 200 ml of anhydrous pyridine cooled to 0° C. The mixture thus obtained is kept stirred overnight at −5° C. It is then added with stirring to a mixture of 200 g of water and ice. An oily product is extracted from the aqueous mixture by 3 ether washes, each of 300 ml. The ether fractions are washed twice with 300 ml of a cold solution of hydrochloric acid (HCl:water being 1:1 by weight) to remove pyridine, and then with 300 ml of water, and are then dried over potassium carbonate and sodium sulphate and decolorized with active carbon. The suspension is filtered and the ether is evaporated from the filtrate at reduced pressure to leave an oily product. The oily product is then washed with cold pentane to remove the impurities and obtain γ-butenyl 1-tosylate.
Reaction SMILES: C1C2CCCC2CN1N.COC(=O)CCC1C(=O)N(N)C(=O)NC=1.[CH2:25]1[CH:29]2[CH2:30][CH2:31][CH2:32][CH:28]2[CH2:27][N:26]1[NH:33][C:34]([C:36]1[CH:37]=[N:38][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44](F)[CH:43]=2)=[N:40][CH:41]=1)=[O:35]>>[CH2:27]1[CH:28]2[CH2:32][CH2:31][CH2:30][CH:29]2[CH2:25][N:26]1[NH:33][C:34]([C:36]1[CH:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N:38][CH:37]=1)=[O:35]
Reactant: O=C(NN1CC2CCCC2C1)c1cnc(-c2cccc(F)c2)nc1
Agent: COC(=O)CCc1c[nH]c(=O)n(N)c1=O
Agent: NN1CC2CCCC2C1
Product: O=C(NN1CC2CCCC2C1)c1cnc(-c2ccccc2)nc1

Procedure:
Following procedures similar to those of Example 64 but substituting hexahydro-cyclopenta[c]pyrrol-2-ylamine for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid methyl ester, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide (39%) as a solid. MS: 309 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.20-1.90 (m, 6H), 2.40-3.50 (m, 6H), 6.94 (s, N—H), 7.52 (s, 3H), 8.50 (s, 2H), 9.08-9.38 (d, 2H).
Reaction SMILES: Br[CH:2]=[C:3]([CH3:11])[CH:4]=[CH:5][O:6][Si](C)(C)C.C([Li])(C)(C)C.[CH2:17]1[CH2:25][O:24][C:19]([CH3:23])([CH2:20][CH:21]=O)[O:18]1.Cl>CCCCC.C(OCC)C.O>[CH2:17]1[CH2:25][O:24][C:19]([CH3:23])([CH2:20][CH:21]=[CH:2][C:3]([CH3:11])=[CH:4][CH:5]=[O:6])[O:18]1
Reactant: CC(C=CO[Si](C)(C)C)=CBr
Reactant: CC1(CC=O)OCCO1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C=CCC1(C)OCCO1)=CC=O
Temperature: -70 °C
Reaction time: 1.67 h
Yield: 54.7 %

Procedure:
Anhydrous ethyl ether (11 cc) and 1-bromo-2-methyl-4-trimethylsilyloxy-1,3-butadiene (0.9 g) are introduced under an argon atmosphere into a 50-cc round-bottomed flask. This is cooled to -70° C. and then a solution (3.25 cc) of 1.65M tert-butyllithium in pentane is added over 10 minutes. The mixture is stirred at -70° C. for 100 minutes and 3,3-ethylenedioxybutanal (0.4 g) is then added in solution in anhydrous ethyl ether (4 cc). The temperature is allowed to rise to -30° C. and stirring is performed for 30 minutes. Further stirring is performed for 20 minutes at -20° C. and then the mixture is cooled to -60° C. N Hydrochloric acid (11.5 cc) is added over 20 minutes. The temperature is allowed to rise to about 20° C. After the reaction mixture has been taken up with ether and water and the organic phases have been dried over magnesium sulphate, and after flash chromatography, 7,7-ethylenedioxy-3-methyl-2,4-octadienal (0.33 g) is obtained, its characteristics being as follows:
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:39])([CH3:40])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Product: COc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (85 mg, 0.25 mmol) (Example B.7) according to general procedure II. Obtained as a yellow solid (61 mg, 42%). MS (ISP) 585.3 [(M+H)+]; mp 192-195° C.
Reaction SMILES: C1CO[C:3]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11]C3CCCCO3)[CH2:9][C:8](=[O:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[O:2]1.C(O)(=O)C.C1COCC1>O>[OH:11][C@@H:10]1[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C@H:6]1[CH2:5][CH2:4][C:3](=[O:2])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)OC(C)C)OCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OC(C)C
Temperature: 50 °C
Yield: 64.4 %

Procedure:
The compound (5-a)(0.311 g) was dissolved in the solvent mixture (acetic acid:THF:water=2:1:1)(5 ml) and the solution was maintained at 50° C. for 3 hours. The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (6-a)[yield:0.156 g(66%)].
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[NH2:18][C:19]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[C:26]2[C:21](=[CH:22][C:23]([C:36](O)=[O:37])=[CH:24][CH:25]=2)[N:20]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:18][C:19]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[C:26]2[C:21](=[CH:22][C:23]([C:36]([NH:1][CH:2]([CH2:8][C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[C:3]([N:5]([CH3:6])[CH3:7])=[O:4])=[O:37])=[CH:24][CH:25]=2)[N:20]=1
Reactant: CN(C)C(=O)C(N)Cc1nc2ccccc2s1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4nc5ccccc5s4)C(=O)N(C)C)ccc23)CC1
Yield: 49.9 %

Procedure:
A solution of 2-amino-3-(benzo[d]thiazol-2-yl)-N,N-dimethylpropanamide (12.1 mg, 52.2 μmol), 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 34.8 μmol) from Example 21 Step 4, N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.2 mg, 55.7 μmol), N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (12.1 μl, 69.6 μmol) was stirred at 25° C. for 60 min The reaction was purified by prep RP-HPLC (pH=10) to afford the desired compound (0.009 g, 49%) as an amorphous white solid. Analytical LCMS (M+H)+: m/z=519.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc3ccccc23)CC1
Yield: 68 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: Cl.C([O:4][C:5](=[O:24])[C@@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)C.C(OC(=O)[C@H](C)C[C@H:31]([N:45]1[C:49](=O)[CH2:48][CH2:47][C:46]1=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C>C(OC(C)C)(=O)C>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]([CH2:9][C@H:8]2[NH:22][C:5](=[O:4])[C@@H:6]([CH3:23])[CH2:7]2)=[CH:11][CH:12]=1.[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]2[N:22]([CH2:31][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N1C(=O)CCC1=O
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a mixture of (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-b, R1=R2=H, R3=Et) [9:1 diastereoisomer mixture [(2S,4S): (2R,4S)]] (840 mg) in isopropyl acetate (10 ml) triethylamine (418 mg) is added. The mixture is then stirred at 55° C. for 1 h and then filtered. The filtrate is heated at reflux for 24 hours. To the mixture is added saturated ammonium chloride solution and the phases are separated. The organic layer is concentrated to dryness. The residue is purified by chromatography, eluting first with IPA/Heptane 2:1 then with a mixture 1:1 to afford (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b, R1=H) and (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H). Ratio of diastereoisomers determined by 1H NMR to be 9:1 [(3S,5S): (3R,5S)]. 1H NMR (CDCl3) for (2-b, R1=H): 1.15 (3H), 1.38 (1H), 2.42 (2H), 2.63 (1H), 2.82 (1H), 3.75 (1H), 5.51 (1H), 7.17 (2H), 7.28 (1H), 7.37 (2H), 7.49 (4H). Spectroscopic data for (2-a, R1=H) as in Example 6.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1([C@@H:18]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O>[Br-:1].[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:24]23[CH2:25][CH2:26][CH:27]([CH2:28][CH2:29]2)[C@@H:22]([O:21][C:19](=[O:20])[C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23]3)=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(O)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (256 mg, 1.19 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (400 mg, 1.19 mmol) in EtOAc (15 ml). The resulting reaction was stirred at room temperature for 15 hours. The solvent was removed under vacuum, and the residue was triturated with Et2O to obtain (R)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (655 mg, 100% yield).