Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([CH3:30])[C:17]=1[CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:30])[C:17]=1[CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](Cc1ccc(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
(R)-3-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (19.5 g, 40.2 mmol) in dichloromethane (100.00 ml, 1554 mmol) was added trifluoroacetic acid (30.00 ml, 389 mmol). The reaction mixture was stirred at RT. After 4 h, LC-MS suggested complete removal of protecting group. The solvent was removed and the crude product was dissolved in dichloromethane (300 mL) and washed with aqueous NaHCO3. The solvent was removed to give (R)-3-(2-(acetoxymethyl)-4-amino-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (15.0 g, 38.9 mmol, 97% yield). MS (ESI) 408 (M+H); Rf=1.69.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.O1CCCC1.O>Cl.C(O)(=O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (14 mg, 0.03 mmol), tetrahydrofuran (2 mL), water (0.5 mL) and acetic acid (2 mL). It was stirred at 25° C. for 2 h and after this time concentrated hydrochloric acid (2 drops) was added and the reaction was complete in 20 min. The reaction was worked up and then purified on a Biotage Flash chromatography system (12M column, silica gel, 10% methanol/ethyl acetate) to afford (R)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (4 mg, 31%): [α]30589=−40.0° (c=0.10, methanol); ES-HRMS m/e calcd for C21H29N3O5S (M+H)+ 436.1901, observed 436.1902; 1H NMR (300 MHz, DMSO-d6) δ 1.13 (m, 2H, CH2), 1.36-1.83 (m, 8H, 4×CH2), 2.13 (m, 1H, CH), 3.20 (s, 3H, SO2CH3), 3.66 (m, 2 H, OCH2), 3.86 (m, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 3.99 (t, J=5.7 Hz, 2 H, NCH2), 4.83 (t, J=5.3 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.14 (dd, Jm=1.2 Hz, Jo=8.2 Hz, 1H, Ar), 7.27 (d, Jm=1.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.73 (d, Jo=8.2 Hz, 1H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][O:16]2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH:28][C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC1C=CC([C@H](O)CNC2CC3C(=CC(CC)=C(CC)C=3)C2)=C2C=1NC(=O)C=C2)C1C=CC=CC=1>>[CH2:21]([N:28]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:17][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)[OH:16])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1OCc1ccccc1
Reactant: CC1(NCc2ccccc2)Cc2ccccc2C1
Agent: CCc1cc2c(cc1CC)CC(NC[C@@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Product: CC1(N(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2C1
Reaction time: 24 h

Procedure:
The title compound is prepared from (R)-2-(4-benzyloxy-3-nitro-phenyl)-oxirane (2.52 g) and benzyl-(2-methyl-indan-2-yl)-amine (2.20 g) by an analogous procedure to that used to prepare (S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one in Example 19. The reaction is shown to be complete by TLC after 24 hours. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC silica, n-hexane/ethyl acetate 4:1 Rf=0.30).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[CH:26]([CH:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)=O>>[OH:25][B:13]1[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:26][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:3][CH2:4]2)[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: O=C(C[C@H]1CC[C@H](NCC2CCNCC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and tert-butyl 4-formylpiperidine-1-carboxylate following the procedure in Example 27. Boc group was removed by treatment with 4N HCl in dioxane. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 444 (MH)+.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH2:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O>O.C(#N)C>[C:31]1(=[O:40])[N:17]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]([O:5][CH2:2][CH2:3][CH3:4])=[O:18])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCOC(=O)CC(N)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCOC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid propyl ester hydrochloride (1.50 g, 5.52 mmol) and sodium carbonate (0.59g, 5.52 mmol) in 50 mL of water was added N-carboethoxy-phthalimide (1.21 g, 5.52 mmol) in 12 mL of acetonitrile. The reaction was complete in one hour. The acetonitrile was removed in vacuo and 5 mL of ether was added to the mixture, which was stirred overnight at room temperature. The resulting slurry was filtered and the solid was washed with 60 mL of water. The solid was dried in vacuo (24° C., <1 mm) to afford 1.69 g (83.2%) of propyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder: mp 51.2°-52.8° C.; 1H NMR (DMSO-d6 250 MHz) δ7.86 (m, 4H), 6.92-7.33 (m, 4H), 5.66 (dd, 1H, J1=7.5, 2.5 Hz), 3.90 (t, 2H, J=5 Hz), 3.72 (S, 3H), 3.3-3.63 (m, 2H), 1.42 (hex, 2H, J=7.5 Hz), 0.75 (t, 3H, J=7.5 Hz); 13C (DMSO-d6 ) δ 170.2, 167.5, 158.7, 134.7, 131.0, 130.5, 128.3, 123.2, 113.9, 65.6; 55.0, 49.5, 21.3, 9.98. Anal. Calcd for C19H17NO5 :=C, 68.65; H, 5.76; N, 3.81; Found=C, 68.42; H, 5.49; N, 3.76.
Reaction SMILES: [CH3:1][C:2]12[CH:10]([CH:11]([CH3:16])[CH2:12][CH:13]3[CH2:15][O:14]3)[CH2:9][CH2:8][CH:7]1[CH:6]([OH:17])[CH2:5][CH2:4][CH2:3]2.C(OCC)(=O)C.[CH3:24][Si:25](C1NC=CN=1)([CH3:27])[CH3:26]>O>[CH3:24][Si:25]([O:17][CH:6]1[CH2:5][CH2:4][CH2:3][C:2]2([CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]2[CH:11]([CH3:16])[CH2:12][CH:13]1[CH2:15][O:14]1)([CH3:27])[CH3:26]
Reactant: CC(CC1CO1)C1CCC2C(O)CCCC12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CC1CO1)C1CCC2C(O[Si](C)(C)C)CCCC12C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.4 g of [1R-[1alpha(R*,S*), 3a beta, 4beta, 7a alpha]]-Octahydro-7a-methyl-1-(1-methyl-2-oxiranylethyl)-1H-inden-4-ol and 40 mL of ethyl acetate is added 1.64 g of trimethylsilylimidazole. The mixture was stirred under a dry argon atmosphere at room temperature for 20 minutes then poured into 100 mL of cold water and extracted 3×25 mL of heptane/ethyl acetate (1:1). The extracts were washed with 3×50 Ml of water and dried over anhydrous sodium sulfate. The mixture was filtered and solvent removed in vacuo. Chromatography on silica gel (2.5×100 cm Altex column, 40-60μ silica gel) eluting with hexane/ethyl acetate (6:1) gave 1.81 g (99%) of [1R-[1alpha(R*,S*),3a beta, 4beta, 7a alpha]]-Octahydro-7a-methyl-1-(1-methyl-2-oxiranylethyl)-1H-inden-4-ol trimethylsilyl ether. This material which contained traces of starting material and slowly reverted to starting material on standing was used with no further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nn(CC(=O)N2CCN(c3ccc(Cl)cc3)CC2)c(-c2ccccc2)c1Br

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.7-7.8 (m, 2H), 7.24-7.3 (m, 3H), 6.8-6.92 (m, 2H), 6.74-6.78 (m, 2H), 4.9 (s, 2H), 4.2 (s, 2H), 3.6-3.7 (m, 4H), 2.86-3.04 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 146, 145, 128, 127, 118, 114.8, 60.2, 50.4, 50, 48.8, 46, 42, 22.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:53])[CH:26]([C:28]1[CH:33]=[CH:32][C:31](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:30][CH:29]=1)[CH3:27]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:53])[CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:32][CH:33]=1)[CH3:27]
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.086 g, 0.29 mmol), triethyl amine (3 mL), copper(I)iodide (0.026 g, 0.14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained as a brown oil (0.067 g, 54%).
Reaction SMILES: CN(C=O)C.[OH:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>C(OCC)C.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])([CH3:27])([CH3:26])[CH3:25]
Reactant: C=CC/C(C)=C\C[C@H](O)C(=O)N(C)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC/C(C)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To an anhydrous DMF (250 mL) solution of the alcohol 4 (70.7 g, 329 mmol) was added tert-butyldimethylsilyl chloride (TBSCl, 55 g, 364 mmol) and imidazole (30 g, 441 mmol) at 0° C. The reaction was allowed to warm to room temperature, and was stirred overnight. The reaction progress was followed by TLC (5:1/hexanes:ethyl acetate). The reaction mixture was poured to a 4 L separation funnel containing diethyl ether (1.7 L), and was separated. The organics were washed with water (4×500 mL) and brine (1×250 mL), dried over magnesium sulfate. Filtration and evaporation under vacuum afforded the crude product 5 as yellowish oil (107 g, 99%), which was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[CH2:9][CH2:8]1)=[O:6].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[NH:54][C:55](=[O:63])[C:56]2[CH2:62][O:61][CH2:60][CH2:59][C:57]=2[N:58]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]([NH:51][CH2:52][C:53]2[NH:54][C:55](=[O:63])[C:56]3[CH2:62][O:61][CH2:60][CH2:59][C:57]=3[N:58]=2)=[O:16])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1Cl
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.3 %

Procedure:
A solution of [4-(3-chloro-4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (0.41 g, 1.3 mmol), EDCl (0.25 g, 1.3 mmol), HOBT (0.18 g, 1.3 mmol) and triethylamine (0.56 g, 5.5 mmol) in 10 mL of DMF was stirred at ambient temperature for 20 min., then 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.20 g, 1.1 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide crude product. Purification by flash chromatography gave the title compound (155.2 mg, 0.3 mmol) as a white solid. MS (ESI) m/z 475.4 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.), t=0.97 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.01-2.19 (m, 6H) 2.65 (t, 4H) 3.31 (s, 2H) 3.63-3.80 (m, 3H) 3.93 (t, J=5.56 Hz, 1H) 3.98 (s, 3H) 4.07 (s, 1H) 4.38 (s, 1H) 4.47 (s, 1H) 7.20 (d, J=8.59 Hz, 1H) 7.98-8.02 (m, 1H) 8.03-8.06 (m, 1H) HRMS calculated for C23H28ClN4O5: 475.1748 (M+H). found (ESI, [M+H]+): 475.1755.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:22])[C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:22])[C:16]5=[O:23])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:30]=[N:29]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C1=O
Product: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C1=O
Yield: 33 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 479. Yield 33%. MS (ESI): 468.2. 1H NMR (400 MHz, DMSO) δ 8.17 (d, J=8.2, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.36 (dd, J=8.2, 1.8, 1H), 7.22 (d, J=1.7, 1H), 4.73 (s, 1H), 4.31 (t, J=4.9, 2H), 4.03 (s, 2H), 3.35 (d, J=5.6, 2H), 3.19 (t, J=5.0, 2H), 2.83 (s, 3H), 1.72 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [N:1]([CH:4]([O:8][CH3:9])[C:5](O)=[O:6])=[N+:2]=[N-:3].S(Cl)([Cl:12])=O>>[N:1]([CH:4]([O:8][CH3:9])[C:5]([Cl:12])=[O:6])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: COC(N=[N+]=[N-])C(=O)O
Product: COC(N=[N+]=[N-])C(=O)Cl
Temperature: 80 °C

Procedure:
A solution of 2-azido-2-methoxyacetic acid (4.2 g.) in thionyl chloride (10 ml.) is heated in an oil bath maintained at 80°C. for 20 minutes. After cooling to room temperature, the mixture is evaporated in vacuo to remove excess thionyl chloride and the residue is distilled to yield 2-azido-2-methoxyacetyl chloride (2.26 g.) as a water-white liquid (b.p. 64°-66°C./27 mm.).
Reaction SMILES: C([C:3]1[Se:7][C:6]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)=[N:5]C=1C(N)=O)C.C[O-].[Na+].C1(C)C=CC=CC=1.[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55]>CO>[C@@H:8]1([C:6]2[Se:7][CH:3]=[C:55]([C:54]([O:57][CH3:58])=[O:56])[N:5]=2)[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]1[OH:10]
Reactant: CCOC(C)=O
Reactant: CCc1[se]c([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)nc1C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C

Procedure:
A gummy suspension of 206.3 g (75.1% pure by HPLC; 0.239 mol) of the blocked ethyl ester, IV, in 700 ml of methanol was heated and stirred on the steam bath until solution occurred. The solution was allowed to cool to room temperature during which time a finely dispersed oily suspension formed. To this suspension was added 17.2 g (318 mmol) of sodium methoxide. The addition was slightly exothermic and resulted in a brown solution. The solution was stirred at room temperature overnight. TLC (SiO2, toluene-ethyl acetate, 10:1) indicated that no starting material remained. To the reaction solution was added 100 g of Dowex 50 W×4 resin (H+) (washed with methanol) and the suspension was stirred for one hour. The resin was filtered off, washed well with methanol, and discarded. The filtrate and washings were evaporated under reduced pressure to give a two phase mixture. The upper, more liquid phase (mainly methyl benzoate) was decanted. The remaining brown viscous gum was triturated two times with ether. (The methyl benzoate was combined with the ether triturates and upon standing yielded some desired product as a solid). The brown viscous gum was treated with approximately 1 l of warm ethanol and triturated. A dark brown material was filtered from the suspension. TLC (SiO2; dichloromethane-methanol, 10:1) indicated that the dark brown material was mostly slower moving impurities in the filtrate and was discarded.
Reaction SMILES: ClCCl.[C:4]([OH:12])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.O[C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1>O.C(OCC)C>[C:5]1([C:4]([O:12][C@H:30]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29]2)=[O:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a dichloromethane (100 mL) solution of benzoic acid (4.03 g, 33.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.4 g, 54.0 mmol) was added tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5.62 g, 30.0 mmol). The reaction mixture was stirred for 6 hours at room temperature, diluted with water (200 mL) and charged with diethyl ether (200 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. This crude product was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([C:7](=[N:15][OH:16])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[Br:17][CH2:18][CH2:19][O:16][N:15]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCCBr
Reactant: ON=C(Cc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: BrCCON=C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of the above oxime (5.0 g, 24 mmol), 1,2-dibromoethane (25 ml) and potassium carbonate (10.0 g, 72 mmol) in acetone (25 ml) was heated at reflux for 1 h, then stirred at ambient temperature for 72 h and finally heated at reflux for 4.5 h. Potassium iodide (0.5 g) was added and refluxing continued for an additional 16 h. Water (100 ml) was added and the resulting mixture extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1) to give 3.6 g of 1,2-diphenylethanone O-(2-bromoethyl)oxime.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].O.[OH-].[Na+].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][C:21](Cl)=[O:22])[C:16]([N+:24]([O-:26])=[O:25])=[CH:15][C:14]=1[O:27][CH3:28]>O1CCOCC1>[CH3:28][O:27][C:14]1[C:13]([O:12][CH3:11])=[CH:18][C:17]([CH2:19][O:20][C:21]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1
Reactant: COc1cc(COC(=O)Cl)c([N+](=O)[O-])cc1OC
Reactant: CC(N)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(COC(=O)NC(C)CC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Yield: 36 %

Procedure:
3-Amino-butyric acid (147 mg, 1.43 mmol) was mixed with water (10 mL), dioxane (10 mL) and 2 M NaOH (10 mL). The mixture was cooled to 0° C. and treated with Nvoc-Cl (1.58 mmol). 2 M NaOH was added in small portions (8×1.25 mL) during 75 minutes. The cooling bath was removed and the reaction mixture was left at room temperature o/n. Water (30 mL) was added and the mixture was filtered. The aqueous phase was adjusted to pH=4 with 2 M HCl (aq.) and extracted with diethyl ether (3×50 mL). The solid was dissolved in water (50 mL) and diethyl ether (50 mL). The combined organic phases were dried over MgSO4 and evaporated in vacuo affording 176 mg (36%) pure 3-(4,5-dimethoxy-2-nitro-benzyloxycarbonylamino)-butyric acid. 1H-NMR (CDCl3): 7.72 (s, 1H), 7.02 (s, 1H), 5.51 (s, 2H), 5.40-5.30 (br s, 1H), 4.15 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.60 (d, 2H), 1.31 (d, 3H).