Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.[F-].[CH2:5]([N+](CCCC)(CCCC)CCCC)CCC.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][Si](C(C)C)(C(C)C)C(C)C)=[C:25]([F:40])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:5])=[C:25]([F:40])[CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)[Si](Sc1ccc(Br)cc1F)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CSc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Add tetrabutylammonium fluoride trihydrate (546 mg, 1.73 mmol) to a mixture of (4-bromo-2-fluoro-phenylsulfanyl)-triisopropyl-silane (570 mg, 1.57 mmol) and potassium carbonate (650 mg, 4.71 mmol) in 20 mL THF and stir at r.t. for 1 h. Add methyl iodide, stir for 1 h and concentrate to remove THF. Add 20 mL water, extract with diethylether, dry the combined organic extracts over sodium sulfate, filtrate and concentrate under reduced pressure to obtain 4-bromo-2-fluoro-1-methylsulfanyl-benzene (347 mg) as a colorless liquid, which was used for following conversions without further purifications. MS (m/e): 220 [(79Br)M], 222 [(81Br)M].
Reaction SMILES: [CH3:1][C:2]([CH:6]1[CH:15]2[CH2:16][CH:17]=[CH:18][CH:14]2[C:13]2[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=[CH:9][C:8]=2[NH:7]1)([CH3:5])[CH2:3][NH2:4].[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>CN(C)C=O.O.C(OCC)(=O)C>[CH:22]([NH:25][C:26]([NH:4][CH2:3][C:2]([CH3:1])([CH:6]1[CH:15]2[CH2:16][CH:17]=[CH:18][CH:14]2[C:13]2[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=[CH:9][C:8]=2[NH:7]1)[CH3:5])=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)(CN)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)NCC(C)(C)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 49 (57 mg) was dissolved in 2 ml of dimethylformamide, and 0.03 ml of isopropyl isocyanate was added. After 30 minutes stirring at room temperature, the reaction mixture was diluted with water and ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 62 mg of the captioned compound. Its physical properties are shown below.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.Cl.[C:14]1([CH2:20][C@H:21]([N:37]=[N+:38]=[N-:39])[C@@H:22]([OH:36])[C@H:23]([OH:35])[C@@H:24]([N:32]=[N+:33]=[N-:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.C(OCC)C>[C:14]1([CH2:20][C@H:21]([N:37]=[N+:38]=[N-:39])[C@@H:22]([O:36][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:23]([OH:35])[C@@H:24]([N:32]=[N+:33]=[N-:34])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]([C@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-])[C@H](Cc1ccccc1)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 13.5 μL (0.170 mmol) of methanesulfonyl chloride in 300 μL of methylene chloride was slowly added to a cold (0° C.) solution of 80 mg (0.23 mmol) of the subtitled intermediate of Preparation 1D and 32 μL (0.23 mmol) of triethylamine in 0.6 mL of methylene chloride. The reaction mixture was warmed to room temperature, allowed-to react for 15 minutes and then poured into 50 mL of a 3:2 mixture of diethyl ether and 0.1N hydrochloric acid. The resulting layers were separated and the organic layer was washed with a half-saturated sodium bicarbonate solution and then reduced to dryness under reduced pressure to provide a foam. This foam was purified using column chromatography (eluted with a 1:2 ethyl acetate/methylene chloride solution). The fractions containing the desired product were combined and reduced to dryness under reduced pressure to provide 100 mg of a 60:40 mixture of the desired subtitled intermediate and the starting material, 1,6-diphenyl-2(S),5(S)-diazido-3(R),4(R)-dihydroxyhexane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=O>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH2:17][C:18](=[CH2:20])[CH3:11]
Reactant: CC(C)=O
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)COc1cc(C)cc(C)c1C
Yield: 75 %

Procedure:
To a solution of 100 g of 2,3,5-trimethylphenol in 500 ml of acetone was added 75 g of anhydrous potassium carbonate. After refluxing for 45 hours, the reaction mixture was filtered, concentrated under reduced pressure and diluted with diethyl ether. The mixture was extracted three times with 300 ml of 20% aqueous solution of sodium hydroxide. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford the compound of methallyl 2,3,5-trimethylphenyl ether(105 g, yield 75%) as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].[Br:15]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][Br:15]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
Into a stirring solution of methyl-2-methyl-6-nitrobenzoate (3.9 g, 20 mmols) in 50 mL CCl4 anhydrous, N-bromosuccinamide (3.56 g, 20 mmols), and benzoylperoxide (25 mg, 0.10 mmols), was added. The reaction mixture was heated under reflux for about 24 hours. TLC developed in EtOAc/Hex 1:9 mixture showed formation of new product. The CCl4 was evaporated and on leaving a viscous product at RT, light yellow crystals of product were separated. The product was purified by flash silica gel column eluted with Hex/EtOAc. 9:1 mixture to give 3.0 g light yellow crystals (70%). A small portion of dibrominated product was also separated. 1H NMR in CDCl3 confirmed the product as methyl-2-bromomethyl-6-nitrobenzoate.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O)C.[NH3:25]>O1CCOCC1>[C:4]([CH2:6][C:7]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:3])[NH2:25]
Reactant: CCOC(=O)Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)Cc1cc(OCCN2CCOCC2)ccc1C(=O)O

Procedure:
A solution of 2-ethoxycarbonylmethyl-4-(2-morpholin-4-yl-ethoxy)-benzoic acid (2.65 g, 10.0 mmole) and saturated ammonia in dioxane (15 mL) in a pressure bottle is stirred and heated using an oil bath at 95° C. overnight. This mixture is cooled and followed by Ic/ms, reaction not complete. The dioxane is evaporated and replaced with 15 mL of 7M ammonia in methanol and heated overnight in a pressure bottle using an oil bath at 70° C., still a small amount of starting material left. The solvent is removed in vacuo and used as is in the next step MS (ESI): m/z 309.3 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]1[NH:12][N:11]=[C:7]([NH2:8])[CH:6]=1
Reactant: NN
Reactant: CC1CC1C(=O)CC#N
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@H]1c1cc(N)n[nH]1
Yield: 79 %

Procedure:
The crude 3-(2-methylcyclopropyl)-3-oxopropanenitrile was dissolved in ethanol (50 mL) and hydrazine hydrate (0.83 mL, 17 mmol) was added. The solution was maintained at reflux for 10 hours and then the solvent evaporated under vacuum. The residue was redissolved in methylene chloride and washed several times with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to give compound trans 5-(−2-methylcyclopropyl)-1H-pyrazol-3-amine (1 g, 79%, three step).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][C:4]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([Li])CCC.[F:41][C:42](=[C:45]([CH:53]1[CH2:55][CH2:54]1)[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[CH:43]=O>O1CCCC1>[Cl:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([CH:53]2[CH2:55][CH2:54]2)=[C:42]([F:41])[CH:43]=[CH:7][C:6]2[CH:27]=[CH:28][C:3]([F:2])=[C:4]([O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=2)=[CH:51][CH:50]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -57.5 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A mixture of (4-fluoro-3-phenoxybenzyl)triphenyl phosphonium bromide (41.77 g, 0.077 mol) in tetrahydrofuran is cooled to -55 to -60° C., treated dropwise with a 2.5M solution of butyllithium in hexanes (32.15 mL, 0.080 mol), warmed to and stirred at room temperature for 2 hours, cooled to -55 to -60° C., treated dropwise with a solution of 2-fluoro-3-cyclopropyl-3-(p-chlorophenyl)acrylaldehyde (15.7 g, 0.070 mol) in tetrahydrofuran, warmed to and stirred at room temperature overnight, and quenched with ethyl acetate and 2N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:9) gives the title product as an oil (26.0 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 0 °C
Yield: 90.6 %

Procedure:
4-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (58 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), piperazine-1-carboxylic acid tert-butyl ester (34 mg), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 635.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][C:38]([NH2:44])=[CH:39][CH:40]=2)[CH2:35]1>CC(O)C.Cl>[F:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:38]3[CH:37]=[C:36]4[C:41]([CH2:42][CH2:43][N:34]([CH3:33])[CH2:35]4)=[CH:40][CH:39]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5cccc(F)c45)n3)cc2C1
Yield: 59 %

Procedure:
To the solution of N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (0.080 g) in i-PrOH (5 mL) was added 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (0.041 g) and 2 drops of concentrate hydrochloric acid. The reaction was microwaved in a sealed tube at 180° C. for 10 min. The i-PrOH was removed by rotary evaporation and the residue was treated with sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL), and dried (Na2SO4). Concentration and purification with column chromatography afforded the title compound as a white solid (0.060 g, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.63 (s, 2H), 3.17 (s, 2H), 3.84 (s, 2H), 6.80 (s, 1H), 6.89 (dd, 1H, J=4.94, 3.11 Hz), 6.95 (d, 2H, J=3.66 Hz), 6.99-7.05 (m, 1H), 7.08 (d, 1H, J=7.68 Hz), 7.18 (s, 1H), 7.24-7.30 (m, 2H), 7.35-7.37 (m, 1H), 7.58 (d, 1H, J=1.10 Hz), 8.05 (t, 1H, J=1.83 Hz), 8.44 (d, 1H, J=5.12 Hz), 8.72 (d, 1H, J=6.95 Hz), 9.39 (s, 1H), 10.32 (s, 1H). ES-LC/MS m/z=590 [M+H]+.
Reaction SMILES: N1C2=CC=CC=CC2=NC=1N1CCN(C=O)CC1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[CH:36][CH:37]=1)[N:25]=[C:26]([N:28]1[CH2:33][CH2:32][N:31](C=O)[CH2:30][CH2:29]1)[N:27]=2>>[ClH:19].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[CH:36][CH:37]=1)[N:25]=[C:26]([N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)[N:27]=2
Reactant: O=CN1CCN(c2nc3ccc(Cl)ccc-3n2)CC1
Agent: O=CN1CCN(c2nc3cccccc-3n2)CC1
Product: Cl
Product: Clc1ccc2nc(N3CCNCC3)nc-2cc1

Procedure:
In the same manner, but replacing 4-(cycloheptimidazol-2-yl)-1-piperazinecarboxaldehyde with an equivalent amount of 4-(6-chloro-cycloheptimidazol-2-yl)-1-piperazinecarboxaldehyde, there was obtained 6-chloro-2-(1-piperazinyl)cycloheptimidazole hydrochloride: mp 210° C. (crystallized from methanol-acetone) and nmr (DMSO-d6) δ 3.30 (4H), 4.07 (4H), 7.73 (d, 2H), 8.27 (d, 2H) and 9.65 (1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:43]1([O:49][C:50]([O:52][CH:53]([O:55][C:56](=[O:77])[C@@:57]([CH2:75][OH:76])([CH3:74])[CH2:58][C@H:59]([NH2:73])[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)[CH3:54])=[O:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([O:49][C:50]([O:52][C@H:53]([O:55][C:56](=[O:77])[C@@:57]([CH2:75][OH:76])([CH3:74])[CH2:58][C@H:59]([NH:73][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:63][CH:62]=2)[CH3:54])=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CC(OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,2,3-Triazole-4-carboxylic acid (45.2 mg, 400 μmol), DIPEA (209 μL, 1.2 mmol) and HCTU (165 mg, 400 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (193 mg, 400 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The products were purified and separated by preparative HPLC, then lyophilized to yield to yield compound ZC (20 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O7, 579.27. found 579.6, and compound ZD (15 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O7, 579.27. found 579.6.
Reaction SMILES: [CH2:1]1COCC1.[CH2:6]([CH:13]([NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[C:14](=[O:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Mg]Cl.O>C(OCC)(=O)C>[CH2:6]([CH:13]([NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[C:14]([OH:16])([CH3:1])[CH3:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)=O)ccc1-n1cnc(C)c1
Agent: C[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NC(Cc2ccccc2)C(C)(C)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (1.0 mL) solution of (E)-N-(1-benzyl-2-oxopropyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (12.0 mg), methyl magnesium chloride (3MTHF solution, 198 μL) was added at −78° C., the reaction solution was allowed to be warmed to room temperature and agitated for further 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate ethanol=10:1), and 6.8 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH2:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C=O)C>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH:26][C:30](=[O:32])[CH3:31])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CN)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNC(C)=O)C1=O

Procedure:
To a solution of 53 mg (0.123 mmol) of (3SR,5RS,6SR)-3-allyl-1-((RS)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Step B) in DMF (307 μL) was added acetic anhydride (116 μL, 1.229 mmol) at 25° C. After being stirred at 25° C. for 14h the reaction was quenched (H2O) and extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Separation by reversed phase HPLC (50 to 80% AcCN/H2O in 25 min, 2 injections, tR=15.683 min) provided the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+].[OH2:21].[CH3:22]O>>[OH:1][CH:2]1[C:14]2[C:9](=[N:10][C:11]([O:21][CH3:22])=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O
Reactant: CO
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Agent: [BH4-]
Agent: [Na+]
Product: COc1nc2c(nc1C#N)C(O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a suspension of 1 (150 mg, 0.646 mmol) in MeOH (6.5 ml), cooled at 0° C., NaBH4 (24 mg, 0.646 mmol) was added. After 30 min, water (5 ml) was added, MeOH was evaporated and the residue was extracted with CH2Cl2 (3×5 ml). The organic layers were dried over Na2SO4, filtered and evaporated. EtOH was added and the precipitate was collected by filtration affording 2 (82 mg, 53%) as white solid.
Reaction SMILES: FC1C=CC(F)=CC=1C([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36]CN(C)CC=C)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=O.ClCCCOC1C=C(NC2N=C(C3C(C4C=[C:77]([NH:81][C:82](=O)[C:83](F)(F)F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=CC=1.[CH3:88]NC>>[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:83][CH2:82][N:81]([CH3:88])[CH3:77])[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CNC
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCCl)c3)n2)c1)C(F)(F)F
Reactant: C=CCN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5cc(F)ccc5F)c4)nn4ccccc34)n2)c1
Product: CN(C)CCCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1

Procedure:
The title compound may be prepared by treating N-(3-{3-[2-({3-[(3-chloropropyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide with dimethylamine to give product.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:54]1([C:59]2[CH:67]=[CH:66][C:62]([C:63](O)=[O:64])=[CH:61][CH:60]=2)[CH:58]=[CH:57][N:56]=[CH:55]1>CN(C=O)C.O>[N:54]1([C:59]2[CH:60]=[CH:61][C:62]([C:63]([NH:11][CH2:12][C:13](=[O:14])[N:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]3)=[O:64])=[CH:66][CH:67]=2)[CH:58]=[CH:57][N:56]=[CH:55]1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.8 %

Procedure:
DIPEA (247.2 mg, 0.33 mL, 1.9 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (164.3 mg, 0.46 mmol) in DMF (2 mL). HOBT (63.1 mg, 0.46 mmol) and EDCI (179.2 mg, 0.93 mmol) were then added at room temperature. After 2 minutes, 4-imidazol-1-yl-benzoic acid (80 mg, 0.42 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 69 mg (33.4% yield) 4-imidazol-1-yl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 94.26%. 1H NMR (DMSO-d6): δ 8.8-8.7 (s, 1H), 8.4 (s, 1H), 8.1-8.0 (d, 2H), 7.9-7.7 (m, 5H), 7.7-7.62 (m, 1H), 7.62-7.5 (t, 1H), 7.2-7.1 (s, 1H), 4.3-4.1 (d, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.24-3.0 (m, 2H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]1([C:24]([Cl:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[ClH:26].[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([N:12]([CH3:13])[C:24]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)=[O:25])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CNC1CCN(C2CCCCC2)C1
Solvent: c1ccccc1
Product: CN(C(=O)c1cccc2ccccc12)C1CCN(C2CCCCC2)C1
Product: Cl

Procedure:
To 18.8 gm. (0.11 mole) of 1-cyclohexyl-3-methylaminopyrrolidine in dry benzene was added dropwise with stirring 19.0 gm. (0.10 mole) of 1-naphthalenecarbonyl chloride in dry benzene. The crystalline product which separated was collected and recrystallized from benzene to give 27.5 gm. (74%) of product which melted at 219°-221° C.