Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C2c2cccc(Cl)c2F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)O)C2c2cccc(Cl)c2F)ccc1Cl
Yield: 85 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 100b (2.0 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.88 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](OB(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1)=[O:30]
Reactant: COC(=O)c1cc(I)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Yield: 57.2 %

Procedure:
Under nitrogen atmosphere, 2-(2-{2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)-5-iodobenzoic acid methyl ester (5.0 g) synthesized in Example 92-1 and 4-fluorophenylboric acid (1.5 g) were dissolved in dioxane (40 mL) and aqueous sodium carbonate solution (2 mol/L, 20 mL), tetrakis(triphenylphosphine)palladium (0.51 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.7 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]2[O:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.I[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Cu]I>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([N:8]2[C:7](=[O:11])[C:6]3[CH:12]=[C:2]([F:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(I)cn1
Reactant: CNc1cc2c(cc1F)C(=O)NCO2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Temperature: 100 °C
Yield: 23.6 %

Procedure:
To 6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.05 g, 0.25 mmol) and 5-iodopyridin-2-amine (0.067 g, 0.304 mmol) in dioxane (1 ml) was added potassium phosphate (0.08 g, 0.377 mmol). The reaction mixture was degassed for 5 minutes and to this was added trans-diamino cyclohexane (0.004 g, 0.03 mmol) followed by copper (I) iodide (0.006 g, 0.03 mmol) and the mixture heated to 100° C. for 1 hour. Water was added and the product extracted with ethyl acetate (3×10 ml), dried over anhydrous sodium sulfate and concentrated. The product was further purified by reverse phase HPLC (C18) to yield pure 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.017 g, 23%). RP-HPLC: 1.5 min; ES-MS (M+H)+=289.1; 1H-NMR (MeOH-d4) δ (ppm): 2.82 (s, 3), 5.4 (s, 2), 6.2 (d, 1), 6.6 (d, 1), 7.3 (d, 1), 7.4 (dd, 1), 7.8 (s, 1).
Reaction SMILES: [CH3:1][C:2]1([CH3:49])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:48])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]#[C:25][C:26]3[CH:27]=[C:28]([S:32]([N:35]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36][C:37]([NH2:39])=[O:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)C.[Pt]=O>[CH3:1][C:2]1([CH3:49])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:48])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([N:35]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36][C:37]([NH2:39])=[O:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCC#Cc3cccc(S(=O)(=O)N(COCC[Si](C)(C)C)CC(N)=O)c3)ccc2O1
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)(=O)N(COCC[Si](C)(C)C)CC(N)=O)c3)ccc2O1
Yield: 100.5 %

Procedure:
N2-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N2-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide (0.09 g) was stirred with platinum oxide (0.023 g) in ethanol (20 ml) under hydrogen for 3.5 h. The catalyst was filtered off with the aid of celite and the filter cake was leached with ethanol. The combined filtrates were evaporated to give the title compound (0.091 g) LCMS RT=3.10 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ncccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To a 100-mL round-bottomed flask was added (2-methoxy-3-pyridinyl)methanol (1.12 g, 8.05 mmol), triphenylphosphine (2.32 g, 8.85 mmol, Aldrich, St. Louis, Mo.) and carbon tetrabromide (0.86 mL, 8.85 mmol, Aldrich, St. Louis, Mo.) in DCM (20 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 3-(bromomethyl)-2-methoxypyridine (1.10 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][NH:18]2)=[C:14]([NH:1][C@@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[N:13]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(N[C@H]2CCc3ccccc32)c2nc[nH]c2n1
Yield: 79.6 %

Procedure:
(S)-(+)-1-Aminoindane (266.0 mg, 2.0 mmol), 2,6-dichloropurine (380 mg, 2.0 mmol) and N,N-diisopropylethylamine (380 μL, 2.2 mmol), were dissolved in Ethanol (4.0 mL) and reacted in a microwave at 120° C. for 600 s. A yellow solid formed which was filtered, washed with ethanol (20 mL) and dried to give the title compound 0.455 g, 80% yield.
Reaction SMILES: C([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)CC=C)C=C.CN1C(=O)CC(=O)N(C)C1=O.CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=1>C(Cl)Cl.C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([CH:20]1[CH2:19][CH2:18][N:17]([S:14]([C:12]2[S:13][C:9]([CH2:8][NH:4][C:51](=[O:60])[C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=3)=[CH:10][CH:11]=2)(=[O:16])=[O:15])[CH2:22][CH2:21]1)(=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)CCCCCC)CC2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCC(=O)C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3cccc(OC)c3)s2)CC1
Reaction time: 3 h
Yield: 26.9 %

Procedure:
A solution of 327c (100 mg, 0.22 mmol), 1,3-Dimethylbarbituric acid (69 mg, 0.44 mmol) and Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) were stirred in 3 mL CH2Cl2 overnight. The deprotection was followed by TLC. After complete cleavage of the protecting groups, the solvent was evaporated to dryness. The crude was taken up in THF, DIEA (76 ul, 0.33 mmol) was added, followed by the slow addition of 3-anisoylchloride (38 mg, 0.22 mmol) in THF. The reaction was stirred for 3 h, diluted with EtOAc and extracted with NaHCO3 and brine. The organic layers were dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel using cyclohexane/EtOAc 1:1 as eluent to obtain 30 mg (50%) of 327 as a colorless oil: H1 NMR (CDCl3) δ 7.40-7.10 (m, 3H), 6.95 (m, 2H), 6.45 (m, 1H), 4.70 (d, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.58 (m, 2H), 2.40 (m, 2H), 2.27 (t, J=7.5 Hz, 2H), 2.19 (m, 1H), 1.77 (m, 2H), 1.64 (m, 2H), 1.13 (m, 8H), 0.74 (t, J=6.8 Hz, 3H), M/Z APCI: 506.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([NH:11]C(C)=O)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Cl.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(=O)Nc1c(C)cc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(F)cc([N+](=O)[O-])c1N
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A stirred solution of 22.4 grams (0.106 mole) of 5-fluoro-2-methylcarbonylamino-3-methyinitrobenzene, 100 mL of concentrated hydrochloric acid, and 100 mL of ethanol was heated at reflux for about 17 hours. The reaction mixture was cooled and poured into 500 grams of ice. The mixture was made basic with aqueous 50% sodium hydroxide. The resultant solid was collected by filtration and was thoroughly washed with water. The solid was dried at about 60° C. under vacuum, yielding 17.0 grams of 4-fluoro-2-nitro-6-methylaniline, mp 111°-113°C. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain more product.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=3)=[O:26])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Cc1ccc(C(=O)N2CCN(c3cccc4nc(N)nc(N)c34)CC2)cc1
Yield: 41 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and p-toluoyl chloride (63.4 mg; 0.41 mmol) to obtain 29.5 mg. (41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.37 (m, 2H), 7.26 (m, 3H), 7.14 (br s, 1H), 6.98 (d, J=6.4 Hz, 1H), 6.86 (d, J=5.6 Hz, 1H), 5.92 (br s, 2H), 4.58 (br s, 1H), 4.35 (br s, 1H), 3.66 (br s, 1H), 3.44 (m, 1H), 3.11 (m, 3H), 2.77 (m, 2H), 2.35 (s, 3H). ESIMS+363.8 m/z
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C(#N)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:19]1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6])=[O:33]
Reactant: Nc1cc(C(=O)NC2CC2)ccc1N1CCC(CCN2CCCCC2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: O=C(Nc1cc(C(=O)NC2CC2)ccc1N1CCC(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a stirred solution of compound 0.20 g (0.53 mmol) of 3-amino-N-cyclopropyl-4-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-benzamide in acetonitrile (5 mL) is added 0.04 mL (0.31 mmol) 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 30 minutes then volatiles are removed under reduced pressure. The residue is dissolved in dichloromethane and the mixture is washed with 5% aqueous NaOH solution followed by water and then dried over anhydrous magnesium sulfate. The mixture is concentrated under reduced pressure and the crude mass purified by flash silica gel chromatography to yield 0.040 g (15%) of 3-(3-Chloro-benzoylamino)-N-cyclopropyl-4-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-benzamide (112). [M+H]+=479.4
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C([NH:9][C@H:10]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:11][S:12][CH2:13][NH:14][C:15]([CH3:17])=[O:16])=O)CC(=O)N.N(C(OC(C)(C)C)=O)[C@H](C(N1CCC[C@H]1C(O)=O)=O)CSCNC(C)=O.[ClH:61].CC(O)=O>CN(C=O)C>[NH2:9][C@H:10]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:11][S:12][CH2:13][NH:14][C:15]([CH3:17])=[O:16].[ClH:61]
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)NCSC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Boc-Asn-Cys(Acm)-Pro-OH (XIII) is obtained by deblocking XII in HCl/HOAc att room temperature, dissolving the thus obtained raw H-Cys(Acm)-Pro-OH.HCl in DMF and neutralizing it with Et3N, and adding Boc-Asn-ONp (Novabiochem, Laufelingen, CH) at -5° C. while keeping pH neutral. XIII is isolated in 81% yield. [α]D20 =-77.1° (1 g/100 ml DMF). The tetrapeptide derivative X is prepared from XIII and Boc-Gln-ONp (Novabiochem, Laufelingen, CH) in a way corresponding to the preparation of XIII from XII and Boc-Asn-ONp. Yield 78.5%; [α]D20 =-89.7° (1 g/100 ml H2O).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:8].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:20]=[C:2]([CH:22]=[CH2:23])[CH:3]=[CH:4][C:5]=2[F:21])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cc(CNC(=O)c2cc(Br)ccc2F)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(F)c(C(=O)NCc2ccc(Cl)c(OC)c2)c1
Yield: 88 %

Procedure:
To a solution of 5-bromo-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (2.00 g) in toluene (40 mL) were added tetrakis(triphenylphosphine)palladium (217 mg) and tributylvinyltin (1.87 g), and the mixture was heated for 4 hours under reflux. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated potassium fluoride solution. The remaining precipitates were removed by filtration. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1) to give N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide as pale yellow powders (1.51 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[NH:8][C:7](=[O:19])[CH2:6][CH2:5]2.[OH-].[Na+].Cl.O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[NH:8][C:7](=[O:19])[CH2:6][CH2:5]2
Reactant: CCOC(=O)CCc1cc2c(cc1I)CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1cc2c(cc1I)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution of 16.23 g of ethyl 3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoate in 200 ml of ethanol was added 150 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 hours. The reaction mixture was made weakly acidic by the addition dropwise of concentrated hydrochloric acid and diluted by the addition of water. The precipitated solid was collected by filtration and dried to obtain 8.88 g of 3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoic acid as a pale brown solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1>O.CO>[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12](=[N:2][OH:3])[CH2:11]1
Reactant: NO
Reactant: CC1(C)CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCCC(=NO)C1

Procedure:
Hydroxylamine hydrochloride (8.76 g) was dissolved in water (100 mL). To the solution, a solution of sodium acetate (17.8 g) and 3,3-dimethylcyclohexanone (4.55 g) in methanol (20 mL) was added at room temperature, and the mixture was heated to reflux for 1.5 hours. Organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure to obtain a crude product of 3,3-dimethylcyclohexanone oxime.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([O:20][CH:21](OCC)[CH2:22][C:23](Cl)=[O:24])[CH3:19]>ClCCl>[CH2:18]([O:20]/[CH:21]=[CH:22]/[C:23]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:24])[CH3:19]
Reactant: CCOC(CC(=O)Cl)OCC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 97 %

Procedure:
To a solution of 4-(trifluoromethyl)aniline (2.56 g, 15.9 mmol) in dichloromethane (40 ml) was added pyridine (3.77 g, 47.7 mmol). The solution was cooled to 0° C. before a solution of 3,3-diethoxypropanoyl chloride (4 g, crude) in dichloromethane (10 ml) was added dropwise with stirring. The resulting solution was stirred for 4 hours at 20° C. and then washed with water (200 ml). The resulting mixture was extracted with dichloromethane (3×80 ml) and the organic layers were combined and concentrated under vacuum. The crude residue was purified by Pre-TLC with 1-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford (2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide as a yellow solid (4.0 g). (ES, m/z): [M+H]+ 260; 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.72 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.50-7.56 (m, 1H), 5.52 (d, J=12.4 Hz, 1H), 3.90-4.01 (m, 2H), 1.15-1.30 (m, 3H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:25]([O:29][C:30](=[O:33])[CH2:31][NH:32][CH2:16][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])=[N:15][CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OC(=O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 68.8 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol), glycine tert-butyl ester hydrochloride (50 mg, 0.30 mmol) and sodium triacetoxyborohydride (59 mg, 0.28 mmol) to afford 62 mg (68%) of the desired product after purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([OH:22])[C:13]([C:19]([OH:21])=O)=[CH:14]2.ON1C(=O)CCC1=O.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([O:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][CH2:35]1>ClCCl>[CH:41]([O:40][CH:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][NH:31][C:19]([C:13]2[C:12]([OH:22])=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:14]=2)=[O:21])[CH2:35][CH2:36]1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1cc2cccc(OCc3ccccn3)c2cc1O
Reactant: NCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)c1cc2cccc(OCc3ccccn3)c2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
591 mg (2.0 mM) of 5-(2-pyridylmethoxy)3-hydroxy-2-naphthoic acid was dissolved in 20 ml of dichloromethane. Thereto were added 235 mg (2.0 mM) of N-hydroxysuccinimide and 422 mg (2.0 mM) of dicyclocarbodiimide. The resulting mixture was stirred at room temperature for 1 hour. Thereto was dropwise added a solution of 620 mg (2.0 mM) of 1-(2-aminoethyl)-4-(benzhydryloxy)-piperidine in 20 ml of dichloromethane. Stirring was conducted at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, extraction with dichloromethane was conducted. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution two times, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was mixed with 20 ml of acetonitrile. The mixture was filtered, and the filtrate was subjected to distillation to remove the solvent. The residue was purified by silica gel chromatography to obtain 632 mg of the title compound at a yield of 67%.