Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:27]([O:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a solution of (S)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.00 g, 4.60 mmol) in DCM (10 ml) were added sequentially triethylamine (1.3 ml, 9.21 mmol), tert-butylchlorodiphenylsilane (1.414 ml, 5.52 mmol) and DMAP (0.56 g, 4.60 mmol) and the resulting mixture was stirred overnight at ambient temperature. The mixture was diluted with water and the aqueous phase was extracted with DCM. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes) to afford the title product (1.0 g, yield: 48%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:16][C:17]3[C:22](=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[C:19]([O:28][CH3:29])[C:18]=3[O:30][CH3:31])[CH2:23]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(c2ccc(O)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
An ethanol (5.0 ml) suspension of ethyl 2-(4-benzyloxyphenyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (105 mg, 0.213 mmols) and 10% palladium-carbon (32 mg) was stirred under a hydrogen pressure of one atmosphere at room temperature for 4 hours. The palladium-carbon was removed by filtration, and the filtrate was concentrated in vacuo to obtain the entitled compound (81.5 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1)[N:6]=[C:7]2O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:7]1[C:8]2[C:3](=[C:2]([Cl:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:4]=[C:5]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC
Product: COc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Chloro-6,7-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (1,5-Dichloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 353 (MH+).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[S:43]([CH3:42])(=[O:45])=[O:44])[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-ethoxymethyl-1-(piperidin-2-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (0.60 g, 1.1 mmol) and triethylamine (0.79 mL, 5.7 mmol) in chloroform (50 mL) was cooled to 4° C. Methanesulfonyl chloride (0.12 mL, 1.5 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Additional methanesulfonyl chloride (2.5 equivalents) was added at 4° C. over the course of several days. The work-up procedure described in Examples 178 to 181 was carried out. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from about 100:0 to 70:30) followed by recrystallization from acetonitrile to provide 0.19 g of 2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-2-yl]methyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 152-154° C.
Reaction SMILES: Br[C:2]1=[CH:3][C:4](=[O:9])[O:5]/[C:6]/1=[CH:7]\Br.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1=[CH:3][C:4](=[O:9])[O:5]/[C:6]/1=[CH:7]\[C:11]1[S:10][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccs1
Reactant: O=C1C=C(Br)/C(=C/Br)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(c2cccs2)/C(=C/c2cccs2)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture containing (Z)-4-bromo-5-(bromomethylene)furan-2(5H)-one (0.503 g, 1.981 mmol), 2-thiopheneboronic acid (0.560 g, 4.377 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.072 g, 1.026×10−1 mmol), tetrabutylammonium iodide (0.072 g, 1.002×10−1 mmol) and cesium fluoride (1.257 g, 8.275 mmol) in toluene (10 mL) and water (10 mL) was stirred at room temperature for 72 h under nitrogen. Brine (50 mL) was added and the product extracted with ethyl acetate (3×50 mL). The organic fractions were combined, washed with brine (3×20 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a dark brown solid. The resulting solid was subjected to recrystallization to give (Z)-4-(thiophen-2-yl)-5-(thiophen-2-ylmethylene)furan-2(5H)-one 19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[OH:12].[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[O:12][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cccc(Br)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(Br)c1OC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl(3-bromo-2-hydroxyphenyl)acetate (18.7 g, 76.3 mmol) in 200 mL of DMF was added K2CO3 (52.7 g, 382 mmol), MeI (14.0 mL, 229 mmol). The mixture was stirred at 50° C. for 3 hours. The reaction solution was diluted with EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography to give methyl[3-bromo-2-(methyloxy)phenyl]acetate.
Reaction SMILES: Cl.Cl.C([CH:5]1[C@@H:14]2[N:9]([CH2:10][CH2:11][C:12]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:13]=32)[CH2:8][CH2:7][C@H:6]1NCCCS(N)(=O)=O)#N.[C:30](N1C=CN=C1)([N:32]1C=CN=C1)=O.Cl>>[CH:5]1[CH:6]([C:30]#[N:32])[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]1[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12]=1[CH:11]=[CH:10]2
Reactant: N#CC1[C@H]2c3oc4ccccc4c3CCN2CC[C@H]1NCCCS(N)(=O)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: N#CC1C=CN2C=Cc3c(oc4ccccc34)C2=C1

Procedure:
In the second step the first intermediate (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]-ethyl]methanesulfon-amide dihydrochloride (compound IV) reacts with 1,1′-carbonyldiimidazole in the presence of a hydrogen chloride acceptor, whereby a cyclic carbamide, the second intermediate (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzo-furo[2,3-a]quinolizine-2-carbonitrile (compound V) is formed.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.[Cu]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(I)cc1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Yield: 35 %

Procedure:
A mixture of N-phenylnaphthalen-1-amine (5.0 g, 22.8 mmol), 4-iodoanisole (8.0 g, 34.2 mmol), copper powder (2.89 g, 45.6 mmol), K2CO3 (12.59 g, 91.2 mmol) and 18-crown-6 (0.607 g, 2.3 mmol) in DMF (200 mL) was degassed and heated to reflux for overnight under argon. After the salt and copper were filtered off, the solution was poured into water (300 mL), and extracted with DCM (2×300 mL). The organic phase was combined and washed with brine, dried over Na2SO4, loaded on silica gel, purified by flash column (5 to 20% DCM in hexanes). The desired fraction was collected, concentrated, and recrystallized in ethyl acetate/methanol to obtain a white solid (Compound 5) (2.59 g, in 35% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:19](#[N:22])[CH:20]=[CH2:21].CO[Na]>CO>[C:19]([CH2:20][CH2:21][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])#[N:22]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Reactant: C=CC#N
Agent: CO[Na]
Solvent: CO
Product: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Yield: 26.2 %

Procedure:
To a solution of compound 75 (10.5 g, 41 mmol) and acrylonitrile (17.4 g, 328 mmol) in absolute CH3OH (100 mL) was added a catalytic amount of CH3ONa (216 mg, 4 mmol) at room temperature with stirring under N2. The mixture was stirred at room temperature for 10 h under N2. The mixture was diluted with aqNaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=5:1) to give compound 76 (3.3 g, 20%) as a light yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH3:21])[CH:3]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[C:39]([N:49]([CH3:63])[C@H:50]([C:60](O)=[O:61])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:39]([N:49]([CH3:63])[C@H:50]([C:60]([NH:1][CH:2]([CH3:21])[CH:3]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])=[O:61])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40]
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OCc2ccccc2)cc1
Reactant: CC(N)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C[C@@H](C(=O)NC(C)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)N(C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a solution of amine 110 (20 mg, 0.062 mmol) in CH2Cl2 (1 mL), cooled to 0° C., NMM (7 μL, 0.069 mmol) and HOBt (25 mg, 0.18 mmol) were added. The solution was stirred at 0° C. for 15 minutes, and a solution of N-Cbz-N,O-dimethyltyrosine (21) (21 mg, 0.062 mmol) in CH2Cl2 (1 mL) was added. Finally a solution of DCC (14.2 mg, 0.069 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred 16 h at room temperature and filtered to remove the precipitate. The filtrate was diluted with CH2Cl2 (10 mL) and washed with 10% KHSO4 (10 mL), 5% NaHCO3 (10 mL) and NaCl (10 mL, sat), dried (Na2SO4), filtered, and concentrated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/3) to yield 111 (26 mg, 70%) as a white foam. Rf 0.36 (AcOEt/Hexanes 1/3). [α]D20=−40.1 (c=0.5, CHCl3). 1H-NMR (500 MHz, CDCl3): 0.09 (s, 6H), 0.95 (s, 9H), 1.14-1.17 (m, 3H), 1.43 (s, 9H), 2.86 (s, 3H), 3.29-3.32 (m, 1H), 3.42-3.48 (m, 1H), 3.60-3.68 (m, 2H), 3.82 (s, 3H), 4.17-4.18 (m, 1H), 4.87-4.89 (m, 1H), 4.95-4.96 (m, 1H), 5.02-5.14 (m, 2H), 5.21-5.22 (m, 2H), 6.34-6.37 (m, 1H), 6.79-6.83 (m, 2H), 6.98-7.00 (m, 1H), 7.01-7.17 (m, 2H), 7.20-7.36 (m, 5H). 13C-NMR (125 MHz, CDCl3): −5.5, 17.9, 18.2, 25.8, 28.3, 33.2, 44.5, 55.12, 62.6, 67.3, 57.1, 66.1, 113.8, 127.5, 127.9, 128.4, 129.8, 158.2, 171.5. IR (neat) 3328.5, 2930.3, 2856.3, 2361.0, 2346.6, 2249.0, 1708.8, 1513.7, 1452.5, 1449.5. HRMS m/z cald for C34H53N5O7Na (M+Na): 666.3550 found 666.3571.
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1>C(OCC)C>[CH3:1][N:2]1[C:10](=[O:11])[C:7]2[C:6](=[CH:5][CH:4]=[CH:9][CH:8]=2)[C:4]21[CH2:9][CH2:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH2:5]2
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CN
Solvent: CCOCC
Product: CCOC(=O)C1=CCC2(CC1)c1ccccc1C(=O)N2C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 44 %

Procedure:
A 40% methanolic solution (20.0 mL) of methylamine was added to a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g) in diethyl ether (100 mL) and stirred at room temperature for 5.5 hours. Drylite (10.0 g) was added thereto followed by stirring at room temperature for 18 hours. After it was filtered, the filtrate was concentrated. The resulting residue was dissolved in toluene (100 mL), then triethylamine (8.20 mL) and 2-iodobenzoyl chloride (10.97 g) were added thereto and the mixture was stirred for 2 days at 80° C. in a nitrogen atmosphere. A saturated sodium bicarbonate solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. It was purified by a silica gel column chromatography (hexane/ethyl acetate=9/1→3/1). The resulting residue was dissolved in acetonitrile (200 mL), then potassium carbonate (10.70 g), tetraethylammonium chloride (6.42 g), triphenylphosphine (2.03 g) and palladium acetate (869 mg) were added thereto and the mixture was stirred for 17 hours at 80° C. in a nitrogen atmosphere. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. It was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1→3/2). The resulting solid was suspended in diisopropyl ether and filtered to give the aimed compound (7.36 g, 44%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)c(F)c1
Yield: 87.3 %

Procedure:
A solution of 23.9 g(16.9 mL, 0.15mol) of 3,4-difluoronitrobenzene and 29.1 g(39.2 mL, 0.23 mol) of N,N-diisopropylethylamine in 285 mL acetonitrile was treated with 19.3 g(19.7 mL, 0.18 mol) of benzylamine, followed by warming at reflux for 5 h. The mixture was concentrated in vacuo and the residue was dissolved in 200 mL ethyl acetate, followed by extraction with water (3×50 mL). Drying (Na2SO4) and concentration in vacuo afforded a yellow solid, which was recrystallized from hot ethyl acetate-hexane to afford 32.25 g(87%) of the title compound as yellow-orange needles, mp 97.5-99° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:23])[C:3]([NH:5][C@@H:6]([CH3:22])[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:11]([NH2:13])=[O:12])=[O:8])=[O:4].[C:24]([NH:41][C@H:42]([C:51](O)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1)([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[NH2:13][C:11](=[O:12])[C@@H:10]([NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:51](=[O:52])[C@@H:42]([NH:41][C:24](=[O:25])[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=1)[CH3:23])[CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
Following the procedure described in Example 7, except using (S)-2-amino-N-((S)-1-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-1-oxopropan-2-yl)propanamide (40 mg, 0.124 mmol), Fmoc-L Tyrosine (52.6 mg, 0.130 mmol), 1-hydroxy-7-azabenzotriazole (9.5 mg, 0.070 mmol), anhydrous DMF (1.2 mL), N-methylmorpholine (16 μL, 0.146 mmol), EDC (28.5 mg, 0.149 mmol) and stirring at room temp for 4 h 15 min, 48.4 mg (47.5%) of the title compound is isolated as an off white solid. Purification is done by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 35% Solvent B to 100% Solvent B over 11 min, ret. T=8.79 min. LC/MS (Condition A): ret. T=3.46 min, (M+H)+ 708.32. Analytical HPLC: (Condition A): >99%, ret. T=21.87 min, (Condition B): >99%, ret. T=22.15 min, (Condition C): >98%, ret. T=13.82 min, (Condition D): >99%, ret. T=12.79 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC/C=C\[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C=C\[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 21 h
Yield: 71.3 %

Procedure:
To a stirred solution of 34.2 (0.050 g, 0.10 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting reaction mixture was stirred for 21 hours, and concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered, and concentrated. The resulting product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 34 (35 mg, 71% yield) as a colorless oil. MS ESI (neg.) m/e: 979.5 (2M−H)+, 489.2 (M−H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Cl-].ClC=[N+](C)C.[Br:16][CH2:17][CH2:18]O.N1C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:17][CH2:18][O:8][C:7](=[O:9])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=C(O)Cc1ccco1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccco1)OCCBr
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 15.12 g of furanacetic acid in 120 ml of methylene chloride is cooled to 0°; 15.6 g of chloromethylene-dimethylammonium chloride are added and the mixture is stirred for 10 minutes while cooling with ice. A solution of 30 g of 2-bromoethanol and 19.4 ml of pyridine in 60 ml of methylene chloride is then added dropwise with stirring and the reaction mixture is left to stand for 20 minutes while cooling with ice and for 1 hour at room temperature. The solution is extracted three times with a 5% aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution, dried over sodium sulphate and distilled under reduced pressure. The 2-furanacetic acid 2-bromoethyl ester is obtained at 76°/0.25 mm; infrared absorption spectrum (in methylene chloride): characteristic bands at 3,44μ, 5,72μ, 6,10μ, 7,49μ, 8,20μ, 8,68μ, 9,31μ and 9,86μ.
Reaction SMILES: CC1(C)[O:6][CH:5]([C@H:7]2[O:16][C@@H:10]3[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@@H:9]3[CH2:8]2)[CH2:4][O:3]1.C([O-])(O)=O.[Na+]>CC(O)=O.O>[CH3:14][C:12]1([CH3:15])[O:11][C@H:10]2[O:16][C@H:7]([C@@H:5]([OH:6])[CH2:4][OH:3])[CH2:8][C@H:9]2[O:13]1
Reactant: CC1(C)OCC([C@@H]2C[C@H]3OC(C)(C)O[C@H]3O2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)O[C@H]2O[C@H]([C@@H](O)CO)C[C@H]2O1
Yield: 62.3 %

Procedure:
A solution of (3aR,5S,6aR)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole (compound 1b, 10.0 g, 40.9 mmol) in 60% HOAc in water (20 mL) was stirred at 40° C. for 16 hours. The reaction mixture was adjusted to pH 8˜8.5 by saturated NaHCO3 solution and extracted with EtOAc. The organic layer was combined and concentrated, the residue was purified by column chromatography on silica gel (eluting with 1:2 EtOAc in petroleum ether) to afford 5.2 g of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol (compound 1c). MS obsd. (ESI+) [(M+NH4)+]: 222.