Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][P:6]([O:52]C(C)(C)C)([O:8][CH2:9][O:10][C:11](=[O:51])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[NH:22]2)=[O:20])=[C:14]([O:49][CH3:50])[CH:13]=1)=[O:7])(C)(C)C.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[P:6]([O:8][CH2:9][O:10][C:11](=[O:51])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:46])([CH3:48])[CH3:47])[NH:22]2)=[O:20])=[C:14]([O:49][CH3:50])[CH:13]=1)([OH:52])([OH:7])=[O:5]
Reactant: COc1cc(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)OCOP(=O)(O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a 25 mL pear-shaped flask, (di-tert-butoxyphosphoryloxy)methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (20 mg, 23.8 μmmol, Example 2) was combined with dichloromethane (1 mL) to give a colorless solution which was cooled in an ice-water bath. After 5 min trifluoroacetic acid (744 mg, 0.5 mL, 6.53 mmol) was added over 8 min. The reaction mixture was concentrated and dried in vacuo overnight to give 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid phosphonooxymethyl ester, trifluoro-acetate salt, as off-white solids (19.5 mg, 97%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12].[NH4+].[OH-]>O1CCOCC1.CCO>[Cl:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[CH:5][C:6]=1[I:9]
Reactant: NN
Reactant: Clc1nccc(I)c1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: NNc1nccc(I)c1Cl
Temperature: 80 °C
Yield: 33.9 %

Procedure:
To a solution of intermediate compound D6 (8 g, 29.21 mmol) in 1,4-dioxane (450 ml), was added hydrazine monohydrate (14.169 ml, 175.255 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 16 h. After cooling, NH4OH (32% aqueous solution) was added to the reaction mixture, which was then concentrated in vacuo. The white solid residue thus obtained was taken up in EtOH and heated. The suspension thus obtained was allowed to cool down and the precipitate obtained was filtered off, washed with EtOH and dried in the desiccator to yield intermediate compound D7 (2.67 g, 52%) as a white solid
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[C:20]([C:27]([F:30])([F:29])[F:28])[CH:19]=1>O1CCOCC1>[ClH:24].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[N:4]=2)=[O:23])=[C:20]([C:27]([F:28])([F:29])[F:30])[CH:19]=1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(F)cc3C(F)(F)F)n2)CC1
Product: Cl
Yield: 81.9 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 4-fluoro-2-(trifluoromethyl)benzoyl chloride (165 μL, 1.09 mmol), and 1,4-dioxane (10 mL) to yield 332 mg (82%) of the title compound: mass spectrum (ion spray): m/z=410.8 (M+1); Analysis calc'd for C20H23N4OClF4.1.5H2O: C, 50.69; H, 5.53; N, 11.82. Found: C, 50.66; H, 5.17; N, 12.01. mp 100–2° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (500 mg, 2.18 mmol, Astatec Pharmaceutical Technology Co.) in DMF (10 mL) was added methyl iodide (1634, 2.62 mmol, Sigma-Aldrich) and K2CO3 (904 mg, 6.53 mmol). These ingredients were stirred at a temperature of about 25° C. for 1 h after which the reaction mixture was quenched with water (20 mL), extracted three times with EtOAc (20 mL for each extraction), washed twice with water (20 mL for each wash), washed with saturated aqueous NaCl (10 mL), dried (MgSO4), and concentrated under reduced pressure to provide tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate as an oil. To a mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (2.18 mmol) in dioxane (10 mL) at a temperature of about 25° C. was added 4N HCl in dioxane (10.8 mmol). Then the reaction mixture was stirred at 50° C. for 2 h. Thereafter, the mixture was concentrated under reduced pressure to provide 380 mg of the hydrochloride of methyl 2-(pyrrolidin-3-yl)acetate as a colorless oil (yield 96% for two steps), the identity of which was confirmed using 1H NMR and LC/MS.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[CH2:9][CH2:8]2.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
An oven dried flask was charged with sodium hydride (60 wt %) (173 mg, 4.32 mmol) and THF (15 mL) and cooled to 0° C. Triethyl phosphonoacetate (0.864 mL, 4.32 mmol) was added dropwise and the reaction was then heated to 50° C. for 1 hr. The reaction was then cooled to 0° C., and 5-methoxy-1-indanone (500 mg, 3.08 mmol) was added via cannula in THF (3×5 mL). The reaction was then refluxed for 17 hours. Next, the reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic layer was washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (15 mL) and 10% palladium on carbon (150 mg) was added. The reaction was stirred at room temperature under an atmosphere of hydrogen (balloon) for 17 hours. At this point, the catalyst was removed by filtration, and the filtrate was concentrated. Purification of the residue via flash chromatography on silica gel (0 to 40% ethyl acetate/hexanes) afforded ethyl (5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate. 1H NMR (CDCl3, 500 MHz) δ 7.07 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 6.71 (dd, J=8.2, 2.3 Hz, 1H), 4.18 (m, 2H), 3.78 (s, 3H), 3.53 (m, 1H), 2.95-2.65 (m, 3H), 2.45-2.30 (m, 2H), 1.76 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: NC/C=C/c1ccc(C(O)Cc2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)NC/C=C/c1ccc(C(O)Cc2ccccc2)cc1

Procedure:
1-[4-[(E)-3-Amino-1-propenyl]phenyl]-2-phenyl-1-ethanol (Compound No. 1-6) is treated with acetic anhydride in pyridine to give the titled compound (Compound No. 2-1).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NC(C)(C)C[C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.O>C(O)(=O)C.CO>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31](=[O:32])[NH2:33])=[CH:34][CH:35]=2)=[CH:36][CH:37]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(C(N)=O)cc2)cc1
Temperature: 60 °C
Yield: 174.6 %

Procedure:
A stirred mixture of (S)-(+)-4-(oxiranylmethoxy)-carbazole (7.50 g, 31.3 mmol), 4-(4-(2-amino-2-methylpropyl)-phenoxy)benzamide (17.82 g, 62.67 mmol), acetic acid (0.10 g, 1.7 mmol), water (10 mL) and methanol (260 mL) was heated to 60° C. for 22.7 hrs. The mixture was cooled and concentrated in vacuo to an oil. The concentrate was taken up in ethyl acetate (250 mL) and partitioned with water (100 mL). The organic layer was then extracted with a solution of 25 mL 1N HCl (25 mL) in water (35 mL). A white precipitate formed during the extraction was mostly 4-(4-(2-amino-2-methylpropyl)-phenoxy)benzamide and was removed by filtration of the two phase mixture. The organic layer was extracted two times with a solution of 1N HCl (3 mL) in water (50 mL). The ethyl acetate layer was stripped to an oily residue. The crude product was purified by flash chromatography with 416 g 230-400 silica gel and eluting with ethyl acetate then 10:1-3 ethyl acetate:ethanol gradient. Concentration of the appropriate fractions and drying under vacuum gave 14.31 g (87.2%) of the desired product as a foamy white solid. 1H NMR was consistent with the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]=[CH2:10])=[CH:4][C:3]=1[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C(C)(C)OB[O:52]1.B(O[O-])=O.[Na+]>C1COCC1>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][OH:52])[CH:4]=[C:3]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[C:2]=1[Cl:1]
Reactant: C=Cc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CC1(C)OBOC1(C)C
Agent: O=BO[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCO)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{[(2,3-Dichloro-5-ethenylphenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane (1 eq.) from the previous step, [Ir(COD)Cl]2 (0.025 eq.) and DPPB (0.05 eq.) were combined in THF (0.11 M). To this solution was then added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq.) and the resulting red solution was stirred at RT for 16 h. Finally, sodium perborate (0.1 M aqueous solution, 1 eq.) was added and the now black biphasic solution was vigorously stirred at RT for another 8 h. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a black oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→1:1 (v/v) EtOAc:Hex) afforded the title compound as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:13][C:5]2=[N:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][N:8]([C:7]1[N:6]=[C:5]2[O:13][C:14]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([C:16]([NH:18][CH3:19])=[O:17])[C:4]2=[CH:3][C:2]=1[I:1])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: BrCCCCBr
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(I)cc12
Temperature: 120 °C

Procedure:
To 5-iodo-N-methyl-6-(methylsulfonamido)-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (crude ˜20%) (400 mg, 0.824 mmol) was added 1,4-dibromobutane (1780 mg, 8.24 mmol) and CESIUM CARBONATE (537 mg, 1.648 mmol) and DMF (4 ml) Heated at 120° C. 30 min. Added water and extracted with EtOAc. Conc. on vac to oil. Added 3 mL ACN and 1 mL water. Filtered with 0.45p filter Purified via HPLC C8 40-80% ACN/H2O (0.1% NH4OH) 40 mL/min over 10 min. to give 6-(N-(4-bromobutyl)methylsulfonamido)-5-iodo-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[C:10]([C@@H:12]([O:19]C(=O)C)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][N:26]=2)[C:10](=[O:11])[C@@H:12]([OH:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)O[C@H](C(=O)N(CCc1ccc(C(F)(F)F)cn1)c1ccc(C)c(C)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)cn2)C(=O)[C@@H](O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 116 mg (0.25 mmol) acetic acid (S)-{(3,4-dimethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-carbamoyl}-phenyl-methyl ester in 1.2 mL tetrahydrofuran were added 0.6 mL water and 11.4 mg (0.27 mmol) lithium hydroxide monohydrate. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.098 g (93%) of the title compound as a colorless oil. MS(m/e): 429.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]([OH:26])([CH2:13][C:14]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24]C)([CH3:16])[CH3:15])[C:9]([F:12])([F:11])[F:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl.O>[CH2:1]([C:8]([OH:26])([C:9]([F:10])([F:12])[F:11])[CH2:13][C:14]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[OH:24])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccc1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CC(O)(Cc1ccccc1)C(F)(F)F)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
To a solution of 49 mg (0.13 mmol) of 2-benzyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (Example 4) in 0.5 mL of dichloromethane, 1 mL (1.0 mmol) of 1 M solution of boron tribromide in dichloromethane was added. The mixture was stirred at room temperature for 3 hours and was then cautiously added to cold MeOH and stirred for 20 minutes. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using first hexanes then EtOAc-hexanes (0.5:99.5 to 1:99) to afford 31 mg (65%) of the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)=[C:5]([Cl:13])[S:4][C:3]=1[NH:14][C:15](=[O:32])[CH:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][NH:18]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:18][CH2:17][CH:16]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:15]([NH:14][C:3]1[S:4][C:5]([Cl:13])=[C:6]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[C:2]=1[Cl:1])=[O:32]
Reactant: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CNC(=O)OC(C)(C)C)c2ccccc2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CN)c2ccccc2)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl (3-{[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-phenylpropyl)carbamate (320 mg, 0.646 mmol) in dichloromethane (6.459 ml) at 25° C. was added TFA (0.498 ml, 6.46 mmol). After 30 min, the solution was dry loaded onto silica and neutralized through silica (0-20% MeOH in DCM (1% NH4OH) affording the free base of the title compound. The free base was then dissolved in MeOH (10 mL) and treated with excess 4M HCl in dioxane (2 mL) providing the HCl salt of 3-amino-N-[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]-2-phenylpropanamide (188 mg, 0.414 mmol, 64.0% yield) as an orange solid: LCMS (ES) m/e 395, 397 (M, M+2)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1 H) 8.18 (br. s., 3 H) 7.55 (d, J=1.77 Hz, 1 H) 7.28-7.51 (m, 1 H) 7.41 (d, J=5.05 Hz, 4 H) 6.36 (d, J=6.06 Hz, 1 H) 4.53 (dd, J=9.09, 5.31 Hz, 1 H) 3.81 (br. s., 3 H) 3.48-3.59 (m, 1 H) 3.01-3.17 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].I.[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:8]1=[O:27]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.34 g, 0.63 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.35 g, 0.63 mmol), and N,N-diisopropylethylamine (0.33 g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and a saturated aqueous ammonium chloride solution. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.39 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCCC2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyrrolidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 395.18 g/mol.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[C:11](/[CH3:15])=[CH:12]/[C:13]#[CH:14])[CH:6]=1.C([Li])CCC.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7](/[C:11](/[CH3:15])=[CH:12]/[C:13]#[C:14][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: C#C/C=C(\C)c1cccc(OCOC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C#C/C=C(\C)c1cccc(OCOC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
764 mg (3.78 mmol) of 1-methoxymethoxy-3-((E)-1-methylbut-1-en-3-ynyl)benzene are dissolved in 20 ml of anhydrous THF and the solution is cooled to −78° C. 1.8 ml (4.5 mmol) of a 2.5M butyllithium solution are then added dropwise and the reaction medium is stirred for 30 minutes at this temperature. 0.43 ml (4.5 mmol) of ethyl chloroformate are then added dropwise and then the reaction medium is brought to room temperature and stirred for 2 hours. After treating with a saturated ammonium chloride solution and extracting with ethyl acetate, the organic phase is dried and then concentrated under reduced pressure. After purification by chromatography on a silica column (ethyl acetate 10-heptane 90), a yellow oil is obtained (m=836 mg; Y=81%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:15][C:13]([CH3:16])([CH3:14])[C@@H:11]([N:7]1[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8]1=[O:10])[CH3:12]
Reactant: C[C@H](N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](N1CC[C@](CCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (144 mg, 0.45 mmol) and triethylamine (136 mg, 1.35 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (153 mg, 1.35 mmol) at 0° C., and the reaction mixture was stirred at rt until the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to afford N-(2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)methanesulfonamide (121 mg, 67%). LC-MS Method 1 tR=1.192, min, m/z=401.1; 1H NMR (CDCl3): 0.65 (s, 9H), 1.01-1.07 (d, 3H), 1.96-2.06 (m, 1H), 2.12-2.18 (m, 2H), 2.21-2.28 (m, 1H), 2.57-2.66 (m, 1H), 2.78 (s, 3H), 2.85-2.97 (m, 1H), 3.01-3.12 (m, 2H), 4.31-4.39 (m, 1H), 4.64-4.72 (m, 1H), 6.98-7.07 (m, 2H), 7.19-7.24 (m, 2H).
Reaction SMILES: [Na+].[O:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O-:6])=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:9][CH:8]([CH3:10])[CH2:7][C:3](=[O:2])[C:4]([O:6][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: CC(C)CC(=O)C(=O)[O-]
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)C(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 93.7 %

Procedure:
A mixture of 2-Oxo-4-methyl pentanoic acid sodium salt (10 g, 65.7 mmol) and benzyl chloride (8 g, 63 mmol) in 300 ml DMF was stirred at 40°-50° C. for 5 h. It was filtered, and the filtrate was evaporated under reduced pressure to provide an oil. The oil was dissolved in chloroform, washed with water, dried, filtered, and evaporated to provide the desired product (13 g, 94%). 1H NMR (CDCl3, TMS) δ0.95 (d,6H), 2.15 (m,1H), 2.7 (d,2H), 5.28 (s,2H), 7.4 (m,5H). Mass spectrum: (M+H)+ =221.