Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([O:13]C)=[O:12].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([OH:13])=[O:12]
Reactant: C=C(Oc1ccccc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(Oc1ccccc1OC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4 mmol) in THF (30 mL) and water (30 mL) was added lithium hydroxide monohydrate 0.17 g, 4.0 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of concentrated hydrochloric acid (final pH=2), and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.42 (ddd, 1H), 7.22 (dd, 1H), 7.10 (dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H), 4.51 (d, 1H), 3.64 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cc(N)ccc1F
Reactant: CCCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(Nc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 88 h
Yield: 44.8 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methylaniline (0.301 g, 2.404 mmol) in 15 mL of DMF, was added K2CO3 (1.661 g, 12.020 mmol). After stirring at room temperature under N2 for 88 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes afforded the title compound as brown oil (0.273 g, 45% yield). LC-MS: tR=9.9 min; m/z 254 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29][CH3:30])=[O:28])=[CH:19][N:18]=1>>[CH3:30][O:29][C:27]([C:20]1[C:21]([C:23]([F:26])([F:24])[F:25])=[N:22][C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:18][CH:19]=1)=[O:28]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1C(F)(F)F

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and methyl 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylate. The reaction was heated to reflux for 16 h. The title compound was obtained as a pale-yellow solid in 20% yield.
Reaction SMILES: [CH3:1][O:2]C(OC)OC.[CH3:8][C:9]1[NH:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=1>C(O)(C(F)(F)F)=O>[CH:1]([C:10]1[CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:13][C:9]=1[CH3:8])=[O:2]
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C=O)c(C)[nH]1
Reaction time: 0.17 h

Procedure:
Trimethoxymethane (1.18 ml, 10.78 mmol) was added to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 20) (0.5 g, 3.26 mmol) in TFA (2.5 ml) at 0° C. The reaction was stirred at that temperature for 10 mins then quenched with cold water (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and concentrated to give yellow solid which was purified by flash chromatography (10% to 20% EtOAc in hexanes, 0.25 g).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:4][C:3]1=[O:13].CC(C)([O-])C.[K+].[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24]Br>CO>[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24][N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:12])[N:2]([CH3:1])[C:3]1=[O:13]
Reactant: COC(CCBr)OC
Reactant: Cn1c(=O)[nH]c2c(c1=O)CCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COC(CCn1c2c(c(=O)n(C)c1=O)CCCC2)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After suspending 3-methyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione (CAS 85458-77-1) (500 mg) in methanol (10 ml), potassium tert-butoxide (342 mg) was added and the mixture was stirred at room temperature for 30 minutes. After then adding 3-bromopropionaldehyde dimethylacetal (0.57 ml), the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (235 mg).
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([OH:41])=O)=[N:37][CH:38]=1.Cl.[N:43]1([CH2:49][CH:50]([N:54]2[CH:58]=[C:57]([C:59]3[C:60]4[CH:67]=[CH:66][N:65](COCC[Si](C)(C)C)[C:61]=4[N:62]=[CH:63][N:64]=3)[CH:56]=[N:55]2)[CH2:51][C:52]#[N:53])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([N:46]2[CH2:45][CH2:44][N:43]([CH2:49][CH:50]([N:54]3[CH:58]=[C:57]([C:59]4[C:60]5[CH:67]=[CH:66][NH:65][C:61]=5[N:62]=[CH:63][N:64]=4)[CH:56]=[N:55]3)[CH2:51][C:52]#[N:53])[CH2:48][CH2:47]2)=[O:41])=[N:37][CH:38]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCC(CN1CCN(C(=O)c2ccc(Br)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
Triethylamine (72 uL, 0.52 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (39 mg, 0.103 mmol) were added to a solution of 5-bromopyridine-2-carboxylic acid (26 mg, 0.13 mmol) in THF (0.95 mL). After 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (51 mg, 0.086 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (20 mg, 44%). 1H NMR (400 MHz, d6-dmso): δ 12.10 (br s, 1H), 8.81 (s, 1H), 8.70 (dd, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.52 (dd, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.61-3.54 (m, 2H), 3.37-3.28 (m, 2H), 3.24-3.19 (m, 2H), 2.86 (dd, 1H), 2.81 (dd, 1H), 2.63-2.54 (m, 1H), 2.52-2.40 (m, 2H), 2.39-2.31 (m, 1H); LCMS (M+H)+: 520.2/522.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COCCOc1ccc(N)cc1
Product: COCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 86.9 %

Procedure:
Using general procedure A, 4-(2-methoxy-ethoxy)-phenylamine (Ishidate; Maruyoma, Chem. Abstr., 1952, 8810) (1.15 g, 6.84 mmol) and 1-Boc-4-piperidone (1.36 g, 6.83 mmol) afforded 4-[4-(2-methoxy-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (2.08 g, 86%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[O:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:28][CH:25]3[CH2:24][CH2:23][N:22]([CH:19]4[CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)[CH2:27][CH2:26]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
A stirred mixture of 4-cyclopropyl-2-fluoro-1-nitrobenzene (D37, 180 mg, 0.99 mmol), 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (diHCl salt of D9, 280 mg, 1.1 mmol) and N,N-diisopropylethylamine (0.56 ml, 3.3 mmol), in dimethylformamide (5 ml) was stirred at room temperature for 3 hrs, then heated at 90° C. for 18 hrs. The cooled mixture was concentrated under vacuum and the residue treated with dilute K2CO3 solution (20 ml) and extracted with ethyl acetate (3×30 ml). The combined extract was washed with water, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (40 g) eluting with 1-10% methanol/dichloromethane to afford the title compound as an orange solid (200 mg, 59%). M++H=346.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[OH:13][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:7]=1.C(Cl)(=O)OCC>C(N(CC)CC)C>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[C:9](=[O:11])[CH2:10][C:6]([CH3:5])=[N:7]2)=[CH:20][CH:19]=1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccc(CO)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Into 250 ml of anhydrous chloroform were added 5.0 g of 4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and 25 ml of triethylamine and, further under ice-cooling, 12.5 ml of ethyl chlorocarbonate was added dropwise into the mixture. After evaporation of the solvent, the residue was dissolved in 200 ml of THF, the insolubles were filtered off, and then a solution of 2.08 g of NaBH4 dissolved in 60 ml of water was added dropwise into the filtrate, followed by stirring at room temperature for 2 hours. After evaporation of the solvent, water was added to the residue, and the mixture was adjusted with dil. hydrochloric acid to pH 4-5 and then extracted with chloroform. The organic layer was dried, concentrated and purified on silica gel column chromatograph with the use of chloroform-ethanl (100:1) as eluant, followed by recrystallization from chloroform-ethyl ether to give 1.16 g of 1-(4-hydroxymethylphenyl)-3-methyl-2-pyrazolin-5-one as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([OH:20])[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])C>C(=O)([O-])[O-].[Na+].[Na+].ClC(OCC1C=CC=CC=1)=O>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C@@H:9]([OH:20])[CH2:8][N:7]1[C:21]([O:24][CH2:25][C:26]1[CH:6]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:23])=[O:5]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1.2 g (2S,4R,5R)-5-hydroxy-4-(4-methoxy-phenyl)-piperidine-2-carboxylic acid ethyl ester in 40 ml of ethyl acetate, 20 ml of saturated aqueous sodium carbonate solution and 0.42 ml of benzyl chlorformate is stirred for 1 hour at 0° C., diluted with ethyl acetate and the organic phase is dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.3 (EtOAc-heptane 1:1); Rt=4.34.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:8]=2)[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:22])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:8]=2)[O:3]1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Yield: 76.4 %

Procedure:
0.5 g of (RS)-2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptanol dissolved in 35 ml THF were treated with 480 mg of triphenylphosphine, 275 mg of methyl 4-hydroxybenzoate and 0.28 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 30 ml of water and one portion of 30 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), giving 550 mg of (RS)-methyl 4-[2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptyloxy]-benzoate as a pale yellow oil. 1H NMR (CDCl3): 7.95 (d, J=8.8 Hz, 2H), 7.10 (d, J=2.2 Hz, 1H), 6.94 (dd, J=8.3, 2.2 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.3 Hz, 1H), 4.20-4.00 (m, 2H), 3.87 (s, 3H), 3.05-2.90 (m, 1H), 1.95-1.85 (m, 1H), 1.82 (s, 2H), 1.70-1.60 (m, 1H), 1.34 (s, 6H), 1.33 (s, 3H), 1.32 (s, 3H), 1.30-1.20 (m, 6H), 0.90-0.80 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](O)=[O:24].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:23](=[O:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])[CH:5]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: CN(C)c1ccncc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(NC(=O)Cc2ccc(Cl)cc2Cl)c1

Procedure:
To a solution of 1.1 g 3-Amino-4-methoxy-benzoic acid methyl ester and 1 g (2,4-Dichloro-phenyl)-acetic acid in 15 ml CH2Cl2, 2.7 ml NEt3 and 1.24 g BOP-Cl and 10 mg DMAP were added. After stirring over night the solvent was removed under reduced pressure and the residue directly purified by chromatography on silica with ethyl acetate/heptane 1:5->1:1 to yield the ester as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([F:25])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:3]=1.[CH2:34]([Sn](CCCC)(CCCC)C=C)[CH2:35]CC.CC1C=CC(C)=CC=1>C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Si:27]([O:26][C:4]1[CH:3]=[C:2]([CH:34]=[CH2:35])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([F:25])[CH:12]=3)=[N:7][C:6]=2[CH:5]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2oc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)nc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: Cc1ccc(C)cc1
Product: C=Cc1cc(O[Si](C)(C)C(C)(C)C)cc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.63 g, 0.79 mmol) was added into a mixture of 7-bromo-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-1,3-benzoxazole (14.7 g, 26.6 mmol), tributyl(vinyl)tin (10.5 g, 33.25 mmol) and p-xylene (85 mL). The reaction mixture was stirred at 90° C. for 24 h, cooled to room temperature, diluted with ethyl ether (100 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 50/1) gave a white solid (11.8 g, 89% yield, m.p. 93-95° C.); MS m/e 500 (M+H)+.
Reaction SMILES: N[C@H:2]([C:11](NCC(NCC(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CO)=O)CO)=O)[C@H](CC)C)=O)=O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=C[CH:5]=1.C1[C@H]2[O:47]C(C[C@H]2[C@@H](/C=C/[C@@H](O)COC2C=C(C(F)(F)F)C=CC=2)[C@@H]1O)=O.N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CCCCN)=O)CC(C)C)=O)C)=O)CC(=O)O)=O)=O)CC1C=CC=CC=1.C(C[C@H](NC([C@@H](N)CCCN=C(N)N)=O)C(N[C@H](C(O)=O)CCC(O)=O)=O)CCN.N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CCCNC(=N)N)=O)CC1C=CC=CC=1)=O)CO)=O)CC1C=CC=CC=1)=O)CO)=O)=O)CC(=O)N)=O)CC(=O)O)=O)C)=O)CC(=O)N)=O)CCCCN)=O)CC1C=CC=CC=1)=O)CC1C2C(=CC=CC=2)NC=1)=O)CC(=O)O)=O)CC1C=CC=CC=1>>[CH3:7]/[CH:8]=[CH:9]/[CH:4]1[CH2:3][C@H:2]([OH:47])[C@H:11]([OH:12])[CH2:5]1
Reactant: O=C1C[C@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@H]2O1
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: NCCCC[C@H](NC(=O)[C@@H](N)CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Product: C/C=C/C1C[C@@H](O)[C@@H](O)C1

Procedure:
Tyr-Gly-Gly-Ile-Ser-Ser SEQ ID NO. 8 (6 amino acids) TP-2: Phe-Pro-Asp-Ala-Leu-Lys SEQ ID NO. 9 (6 amino acids) TP-3: Phe-Asp-Trp-Phe-Lys-Asn-Ala-Asp-Asn-Pro-Ser-Phe-Ser-Phe-Arg SEQ ID NO. 10.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:36])[N:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=O)(C)(C)C>C(Cl)Cl>[CH2:29]([O:28][N:21]([C:20](=[O:36])[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (25 mL) was slowly dripped into a solution of (4) (7.10 g, 13.93 mmol) in CH2Cl2 (150 mL) which had been cooled to 0° C. The solution was stirred at 0° C. for 30 minutes and at room temperature for 15 minutes. Solvent and excess TFA were removed by rotary evaporation, and the concentrate was cooled to 0° C., treated with saturated NaHCO3 (150 mL) and extracted with CH2Cl2 (4×80 mL). After solvent removal, the crude oil was purified by silica gel column chromatography with 1:1 hexane/EtOAc as the eluant, generating 4.6 g (81%) of (5) as an oil: NMR δ 1.40-190 (m, 8H), 2.30 (t, 2H, J=6), 2.40 (t, 2H, J=6), 2.90 (t, 2H, J=6), 3.63 (t, 2H, J= 6), 4.63 (s, 2H), 4.75 (s, 2H), 4.93 (br s, 1H), 7.27 (s, 5H), 7.33 (s, 5H). Anal. (C24H31N3O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2cccnc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-D), the title compound was prepared as a solid having a melting point of 100-120° C.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]([OH:21])=[O:20])[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[OH:15].[C:22](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:22][O:20][C:19](=[O:21])[CH2:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[C:14]([OH:15])=[C:9]([Br:8])[CH:10]=1
Reactant: CC(=O)O
Reactant: COc1cc(CC(=O)O)cc(Br)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.409 mL, 0.818 mmol) was added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid (150 mg, 0.575 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (158 mg, 99%).