Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([CH3:22])=[N:20][CH:19]=[C:18]([C:23]2[N:24]=[C:25]([N:32](C(OC(C)(C)C)=O)[C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:41][CH2:40]4)=[C:35]([O:49][CH2:50][CH2:51][O:52]C4CCCCO4)[CH:34]=3)[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CO.O>C(Cl)Cl>[NH2:8][C:16]1[N:17]=[C:18]([C:23]2[N:24]=[C:25]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:40][CH2:41][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:43][CH2:44]4)=[C:35]([CH:34]=3)[O:49][CH2:50][CH2:51][OH:52])[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[CH:19]=[N:20][C:21]=1[CH3:22]
Reactant: Cc1ncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: Cc1ncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)c(OCCO)c3)n2)nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
To a solution of tert-butyl tert-butoxycarbonyl(6-(8-((tert-butoxycarbonyl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)imidazo[1,2-a]pyrazin-6-yl)-3-methylpyrazin-2-yl)carbamate XXXV (165 mg, 0.18 mmol) in DCM (2.2 mL) was added TFA (1.1 mL, 0.11 mmol). The mixture was stirred at rt for 16 h. The reaction was diluted with 9:1 DCM:MeOH and H2O. The aqueous layer was separated and extracted with 9:1 DCM:MeOH. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of 100% 75/18/7 DCM/Et2O/MeOH—100% 70/20/10 DCM/Et2O/MeOH to provide the desired compound 2-(5-((6-(6-amino-5-methylpyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-(4-(oxetan-3-yl)piperazin-1-yl)phenoxy)ethanol (7, 56 mg, 59%). LCMS-ESI+ (m/z): [M+H]+: 518.2. 1H NMR (300 MHz, d6-DMSO) δ: 9.49 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 8.13 (d, J=1.1 Hz, 1H), 7.85-7.66 (m, 2H), 7.62 (d, J=1.1 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 6.25 (s, 2H), 4.87-4.77 (m, 1H), 4.50 (dt, J=25.2, 6.3 Hz, 4H), 4.04 (t, J=5.1 Hz, 2H), 3.74 (q, J=5.2 Hz, 2H), 3.51-3.39 (m, 1H), 3.10-2.95 (m, 4H), 2.45-2.35 (m, 4H), 2.34 (s, 3H). Alternatively, compound XXXIV could be taken directly to this step and similarly de-protected to provide the 5-chloropyrazine substituted analog.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCCC.C(OCC)(=O)C>ClCCl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: COc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of AuCl3 (7.6 mg, 0.025 mmol) and AgOTf (19.3 mg, 0.075 mmol) was stirred in dichloromethane (2 mL) for 30 min. Anisole (54 mg, 0.5 mmol) and 1-Phenyl-1-cyclohexene (158 mg, 1 mmol) were then added sequentially. The resulting mixture was stirred at room temperature overnight. Evaporation of the solvent under reduced pressure gave 130 mg of crude material. Flash chromatography (heptane:ethyl acetate 95:5) afforded 90 mg of a as a colorless oil. Rf=0.33 (heptane:ethyl acetate 95:5). 1H-NMR (400 MHz, CDCl3): 7.27-7.25 (m, 4H), 7.19 (d, 2H, J=8.8 Hz), 7.12 (m, 1H), 6.81 (d, 2H, J=8.8 Hz), 3.77 (s, 3H), 2.30-2.20 (m, 4H), 1.62-1.44 (m, 6H).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C(Cl)CCl.CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[CH2:35][CH2:36][NH2:37]>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:37][CH2:36][CH2:35][C:28]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[F:26])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: COc1ccc(CCN)c(F)c1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccc(CCNC(=O)c2ccc(N=[N+]=[N-])cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Azidobenzoic acid (1.5 equivalents) was dissolved in THF. EDC (1.5 equivalents), DIEA (1.5 equivalents) and DMAP (0.1 equivalents) were added followed by 2-(2-fluoro-4-methoxy-phenyl)-ethylamine (1 equivalent). The reaction was then allowed to stir overnight at room temperature. EtOAc was added and the reaction was washed with 10% citric acid, 10% sodium bicarbonate and brine. After drying over Na2SO4, solvent was removed and the residue was purified by flash chromatography 20% EtOAc/DCM to yield the title compounds as a white powder.
Reaction SMILES: [CH2:1]([C:9]1([CH2:23]CCCCCCC)[C:21]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)CCCCCCC.C1(C)C=CC=CC=1.[Li]CCCC.CN([CH:46]=[O:47])C>CCCCCC>[CH:46]([C:19]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:23])([CH3:1])[C:21]=2[CH:20]=1)=[O:47]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.77 %

Procedure:
To a dry 500 mL flask equipped with an argon inlet, a rubber septum, and a distillation head was charged 22.54 g (48.0 mmol) of 9,9-dioctyl-2-bromofluorene and 100 mL of toluene. Toluene was then removed by distillation to dry the flask and starting material. The residue was allowed to cool to room temperature and 250 mL of anhydrous ether was added. The resultant solution was then chilled to −78 ° C. and treated dropwise over 15 minutes with 30.6 mL (49.06 mmol) of 1.6M BuLi in hexane. Upon addition of the butyl lithium solution the reaction mixture initially turned purple and subsequently turned red. Anhydrous DMF (8 mL) was added and the resulting mixture was stirred at −78 ° C. for 1 hour and then warmed up to room and stirred for an additional hour. The mixture was quenched with 50 mL of 10% HCl and transferred into a separatory funnel. The organic phase was washed with 10% HCl (1×), water (2×) and brine (1×), and then dried over MgSO4. Solvent removal afforded 12 g of crude product. Purification by column chromatography (gradient from 96:4 heptanes: EtOAc in heptanes to 90:10 heptanes:EtOAc) afforded 10.2 g of 2-formyl-9,9-dimethylfluorene (49.77% yield). EI-MS: 418 (M+), 362,193 (100). 1H NMR (CDCl3) δ 10.09 (s, 1H), 7.87 (m, 4H), 7.41 (b, 3H), 2.05 (m, 4H), 1.30-1.05 (m, 22H), 0.83 (t, 5H), 0.61 (t, 3H). 13C NMR (CDCl3) δ 192.22, 152.11, 151.55, 147.54, 139.53, 135.39, 130.40, 128.78, 127.10, 123.09, 120.98, 120.91, 119.93, 70.98, 55.32, 40.24, 31.88, 29.92, 29.17, 23.78, 22.59, 14.03.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:17][N:18]([CH3:29])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][CH:27]=O)=[CH:21][CH:20]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:27](/[CH:26]=[CH:25]/[C:22]5[CH:23]=[CH:24][C:19]([N:18]([CH3:29])[CH3:17])=[CH:20][CH:21]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:27]1/[CH:26]=[CH:25]/[C:22]1[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH3:29])=[CH:24][CH:23]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: CN(C)c1ccc(C=CC=O)cc1
Product: CN(C)c1ccc(/C=C/c2nc3cc(-c4ccc5nc(/C=C/c6ccc(N(C)C)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 264 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 3-(4-dimethylaminophenyl)acrylaldehyde. [M+H]+ calcd for C34H32N6: 525.27; found: 525.59.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)#[N:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.CC(C)=O.O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]3[N:11]([C:12](=[O:13])[C:3]=2[C:1]#[N:2])[CH:10]=[CH:9][CH:8]=[CH:7]3)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c(=O)n2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(N)cc2)c(C#N)c(=O)n2ccccc12
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 100 mg of 3-cyano-1-ethoxycarbonyl-2-(4-nitrophenyl)-4H-quinolizin-4-one (S-20) in 10 ml of ethanol and 5 ml of acetone was added dropwise a solution of 240 mg of sodium hydrosulfite in 5ml of water during 10 minutes. The reaction mixture was heated under reflux for 1 hour and poured into ice-water. The solution was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from methanol to obtain 40 mg of 2-(4-aminophenyl)-3-cyano-1-ethoxycarbonyl-4H-quinolizin-4-one.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(#N)C.Cl.[CH3:26][O:27][NH:28][CH3:29].[OH-].[Na+]>O1CCOCC1.C(N(CC)CC)C>[CH3:26][O:27][N:28]([CH3:29])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reaction time: 72 h
Yield: 84.3 %

Procedure:
To a solution of 4-(2-Quinolin-2-yl-ethyl)-benzoic acid (530 mg) in dioxane 5 ml/acetonitrile 5 ml was added triethylamine (0.60 ml) and O,N-Dimethyl-hydroxylamine hydrogen chloride (240 mg). After 72 h, the reaction mixture was poured into 1N sodium hydroxide solution and extracted with chloroform, dried magnesium sulfate, filtered and concentrated. Biotage MPLC chromatography eluting with 20-50% ethyl acetate provided the title compound (516 mg, 88%). MS: (M+H m/z=321.1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH2:9][CH:10]3[CH:15]([C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1)[CH2:14][NH:13][CH2:12][CH2:11]3.Br[CH2:19][CH2:20][CH3:21]>>[CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH2:9][CH:10]3[CH:15]([C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1)[CH2:14][N:13]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11]3
Reactant: CCCBr
Reactant: Cc1cc(C)c2c(c1)C1CNCCC1CC2=O
Product: CCCN1CCC2CC(=O)c3c(C)cc(C)cc3C2C1

Procedure:
In an analogous manner to that described in Example 49 b), from (+)-7,9-dimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one by alkylation with bromopropane there was obtained (+)-7,9-dimethyl-2-propyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with fumaric acid into the fumarate (1:1) with m.p. 220.5-226.50°, [α]589=+33.7 (c=0.5, H2O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=S)[NH2:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].IC.C([O-])(=O)C.[NH4+:28]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[NH:28])[NH2:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(N)=S)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CI
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C(=N)N)cc1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
[4-(4-Thiocarbamoylphenyl)butyl]carbamic acid tert-butyl ester (58) (500 mg, 1.6 mmol) and iodomethane (4 mL, 64 mmol) were combined in methylene chloride (8 mL). The solution was stirred at reflux for 3 h, and allowed to stand overnight. The volatiles were removed by evaporation, and the residue was dried under vacuum for 3 h. The resulting crystalline solid was dissolved in ethanol (5 mL), and ammonium acetate (1.1 g, 14.4 mmol) was added. The resulting solution was stirred at reflux for 2 h, and the solvent was evaporated. The residue was taken up in a mixture of methanol and concentrated ammonium hydroxide (20 mL, 10:1), and the solvent was then evaporated. To this residue were added water (20 mL) and concentrated ammonium hydroxide (3 mL). The resulting mixture was stirred for 1 h, cooled in an ice bath, and suction filtered to collect a solid. The solid was dried under vacuum overnight to afford the product 59 (137 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9H), 1.38 (m, 2H), 1.55 (m, 2H), 2.64 (t, 2H), 2.93 (m, 2H), 6.80 (br s, 1H), 7.35 (d, 2H), 7.70 (d, 2H), 9.62 (br s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]([CH:21]([CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8].[CH3:42][NH:43][CH3:44]>C(O)C>[CH3:42][N:43]([CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]([CH:21]([CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCBr
Reactant: CNC
Solvent: CCO
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCN(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-bromohexanoate 10 (3.1 g, 4.9 mmol) in a teflon sealed pressure vessel was added 5.6 M dimethylamine in ethanol (20 mL) and the reaction was heated to 70° C. and stirred overnight. Once complete, the reaction was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (100 mL) and washed with sodium bicarbonate solution (2×50 mL). The ethyl acetate layer was dried on magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% EtOAc) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-(dimethylamino)hexanoate 11 as a pale yellow oil (2.0 g, 69%), 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 6H), 4.93 (m, 1H), 2.27 (m, 10H), 2.00 (m, 12H), 1.63 (m, 6H), 1.51 (m, 6H), 1.28 (m, 25H), 0.90 (m, 9H). Rf 0.3 (10% MeOH—CH2Cl2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:27][CH:28]([N-]C(C)C)[CH3:29].C(Br)C=C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH:22]([CH3:23])[CH3:24])([CH:13]([C:28]([CH3:29])=[CH2:27])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:25])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
A solution of tert-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate (3.65 g, 10.3 mmol) in dry THF (45 mL) is cooled to -78° C. and treated drop-wise with LDA (5.70 mL, 11.3 mmol). After 30 minutes at -78° C., allyl bromide (1.10 mL, 12.4 mmol) is added. The solution is maintained at -78° C. for 3 hours, and is then allowed to slowly warm to room temperature under N2. After 12 hours, the solution is quenched with saturated NH4Cl (10 mL) and diluted with H2O (50 mL). The crude lactem is extracted into EtOAc (3×100 mL). The organic extracts are combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4.72 g of gold oil. The oil is purified by silica gel chromatography (300 g SG, 5% EtOAc/hexane) to yield 2.98 g (73%) of the title compound as a clear, pale gold oil as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:17])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1.O1CCCC1>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15](=[S:27])[NH2:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(N)=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 120 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (10.44 g), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide (14.64 g) and tetrahydrofuran (300 mL) was stirred at room temperature for 2 hrs. To the reaction mixture was added ethyl acetate, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (10.7 g, 96%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propanethioamide from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: Br.[CH3:2][CH:3]([CH3:15])[CH2:4][C@H:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:8])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[CH2:58][CH2:59][CH2:60][NH2:61])=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=2)[CH2:58][CH2:59][CH2:60][NH:61][C:6](=[O:8])[C@@H:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:4][CH:3]([CH3:2])[CH3:15])=[CH:53][CH:52]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCCC1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
(S)-4-Methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide (0.300 g, 1.51 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.787 mL, 4.52 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.571 g, 1.51 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.448 g, 1.51 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.4 g (54%) of the pure titled compound as a white foam; mp 52-70° C. APCI-MS m/z 443.4 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:23]([F:25])[F:24])([CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15]CC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(Br)C1C=CC=CC=1.[CH:34]1([NH:40]C2CCCCC2)CCCC[CH2:35]1>CN(C)C=O>[C:1]([NH:4][C:5]([CH:23]([F:24])[F:25])([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH:34]([NH2:40])[CH3:35])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(=O)NC(CCCNC(=O)OCc1ccccc1)(C(=O)O)C(F)F
Agent: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NC(CCCNC(=O)C(C)N)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 0.5 g of 2-acetylamino-5-benzyloxycarbonylamino-2-difluoromethylpentanoic acid in 4 ml of dimethylformamide is added 0.27 g of benzylbromide and 0.4 ml of dicyclohexylamine. The reaction mixture is stirred for 12 hours and then the precipitate is filtered off. The filtrate is evaporated under reduced pressure, and the residue is partitioned between ethylacetate and water. The organic phase is washed with aqueous hydrochloric acid, water, 5% sodium bicarbonate, water and brine then dried over magnesium sulfate. The solvent is evaporated and the residue heated in 5 ml of trifluoroacetic acid for 1 hour at room temperature. The excess trifluoroacetic acid is then stripped off under reduced pressure. The residue is suspended in 5 ml of ether and a solution of N-benzyloxycarbonyl-O-ethoxycarbonylalanine (0.4 g) and triethylamine (0.2 g) in 5 ml of ether is added. Stirring is continued overnight at room temperature. The solvent is evaporated. The resulting syrupy residue is dissolved in glacial acetic acid, and the solution hydrogenated over Pd/C 10% (30 mg) for 12 hours. The catalyst is then filtered off. The filtrate is concentrated and the residue is purified by ion exchange chromatography on an Amberlite IR 120 acidic column to give 2-acetylamino-5-(2-aminopropionylamino)-2-difluoromethylpentanoic acid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.CS(O[CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)(=O)=O.O>CN(C=O)C.CO>[O:18]1[C:17]2([CH2:22][CH2:23][CH:14]([N:6]3[CH:5]=[C:4]([I:3])[CH:8]=[N:7]3)[CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: Ic1cn[nH]c1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A suspension of sodium hydride (72.6 mg, 1.82 mmol) in DMF (1 mL); was cooled in an ice/water bath and treated with a solution of 4-iodopyrazole (242 mg, 1.21 mmol) in DMF (2 mL) added dropwise under an atmosphere of nitrogen in 5 min. After stirring in the cold for another 30 min, a solution of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (321 mg, 1.33 mmol) in DMF (2 mL) was added dropwise at 0° C. The mixture was warmed to RT and was then immersed in 150° C. oil bath and stirred for 2 h. The mixture was treated with water (15 mL), extracted with EtOAc (3×20 mL). The extracts were washed with water (3×15 mL), brine (15 mL), dried over MgSO4. After concentration in vacuo, a brown solid was obtained. It was dissolved in MeOH and after water was added, a solid formed, which was filtered off to give 266 mg (66%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.49 (s, 1 H), 4.23 (tt, J=4.2, 11.2 Hz, 1 H), 2.34-2.20 (m, 1 H), 2.21-1.96 (m, 4 H), 1.95-1.81 (m, 2 H), 1.82-1.66 (m, 3 H), 1.33-1.22 (m, 2 H); MS (ESI): 334.96 [M+H]+; HPLC tR=3.26 min.