Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)O)=[C:29]([F:42])[CH:28]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[C:29]([F:42])[CH:28]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1F
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Reaction time: 3 h

Procedure:
The title compound was prepared starting from 1.50 g (8.46 mmol) of the compound from Example 8 and 2.15 g (8.46 mmol) of the compound from Example 85A in analogy to the synthesis of the compound from Example 101. A difference was, however, that stirring was at 80° C. for 3 h. 0.66 g (19% of theory) of the target compound was obtained.
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].Br[C:37]1[C:38]([CH3:44])=[N:39][CH:40]=[N:41][C:42]=1[CH3:43].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O.CO>[C:32]([O:31][C:29](=[O:30])[N:2]([CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[C:38]([CH3:44])=[N:39][CH:40]=[N:41][C:42]=2[CH3:43])=[C:11]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[N:12]=1)=[O:5])[CH3:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#Cc2ccc3ccccc3c2)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ncnc(C)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Cc1ncnc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-(2-naphthalen-2-ylethynyl)pyridin-3-yl]boronic acid D2b (50 mg, 0.11 mmol), 5-bromo-4,6-dimethylpyrimidine (26 mg, 0.14 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (8 mg, 0.01 mmol), Na2CO3 (34 mg, 0.32 mmol), dioxane (0.9 ml), MeOH (0.3 ml) and water (0.1 ml) is stirred under argon atmosphere for 2 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 12 mg (21%). HPLC-MS: M+H=536; tR=2.22 min (*Method—6).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][N:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:20]([C:31](=[O:33])[NH2:32])[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[NH:3])[NH2:2].C(O[C:37]1[O:38][CH2:39][CH2:40][N:41]=1)C.O1CC(=O)N=[C-]1.C(N(CC)CC)C.[ClH:55]>CO>[ClH:55].[ClH:55].[C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][N:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:37]4[O:38][CH2:39][CH2:40][N:41]=4)[CH2:27][CH2:26]3)=[C:20]([C:31](=[O:33])[NH2:32])[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC1=NCCO1
Reactant: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)c(C(N)=O)c1
Agent: Cl
Agent: O=C1CO[C-]=N1
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C3=NCCO3)CC2)c(C(N)=O)c1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-(piperidin-4-yloxy)phenyl]methanesulfonamide (0.32 g) obtained in example 99(a) in methanol (15 ml) were added successively 2-ethoxy-4,5-dihydrooxazole (0.21 g), which was prepared from 2-oxazolidone according to the method described in Eur. J. Org. Chem., 10, 2645 (1999), and triethylamine (0.56 ml) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours and allowed to stand at room temperature overnight and then evaporated in vacuo. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 12% acetonitrile/water). The amorphous solid obtained was dissolved in 1N hydrochloric acid (1.2 ml) and evaporated to dryness in vacuo to afford the title compound (0.15 g, yield: 59%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:24])[CH2:14][CH:15]([NH2:23])[C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:11].C(N(CC)C(C)C)(C)C>C1COCC1.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH:15]([C:16]2([CH3:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:24])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CC(N)C1(C)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCCCC1
Temperature: 95 °C

Procedure:
A mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.83 g, 85.33 mmol), racemic ethyl-3-amino-3-(1-methylcyclohexyl)propanoate, 205a, (2.34 g, 11.0 mmol) and N,N-diisopropylethylamine (4.79 g, 27.50 mmol) in THF (40 mL) and methanol (10 mL) was heated at 95° C. for 3 hours. The solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 620 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=2.6 Hz, 1H), 5.37 (m, 1H), 4.59 (m, 1H), 4.00 (q, 7.2 Hz, 2H), 2.62 (dd, J=14.7, 3.8 Hz, 1H), 1.67 (m, 1H), 1.17 (m, 10H), 1.10 (t, J=7.1 Hz, 3H), 0.85 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.69 minutes (M+H) 344.39.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.C([Sn](Cl)(CCCC)CCCC)CCC.[CH3:37][Si:38]([CH3:54])([CH3:53])[CH2:39][CH2:40][O:41][C:42](=[O:52])[NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Cl)=[CH:46][CH:45]=1>O1CCCC1.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.CN(C)P(N(C)C)(N(C)C)=O>[CH3:53][Si:38]([CH3:37])([CH3:54])[CH2:39][CH2:40][O:41][C:42](=[O:52])[NH:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:48][CH:49]=1
Reactant: C[Si](C)(C)CCOC(=O)Nc1ccc(CCl)cc1
Reactant: CC(C)OCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)OCc1ccc(Cc2ccc(NC(=O)OCC[Si](C)(C)C)cc2)cc1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 3.9 %

Procedure:
To a stirred solution of 1-bromo-4-isopropoxymethyl-benzene (300 mg, 13.1 mmol) (prepared as described in Preparation 1) in dry tetrahydrofuran (1.4 mL) at −78° C. under argon atmosphere was added dropwise 1.7M tert-butyllithium in pentane (1.62 mL, 2.75 mmol). After the mixture was stirred for about 20 minutes, tri-n-butyltin chloride (0.35 mL, 1.31 mmol) was added. The mixture was allowed to reach 0° to 5° C. and stirred for about 1 hour. A mixture of (4-chloromethylphenyl) carbamic acid 2-trimethylsilanyl-ethyl ester (374 mg, 13.1 mmol) (prepared as described in Preparation 2), hexamethylphosphoramide (4.4 mL), tetrakis(triphenylphosphine)palladium(0) (29.3 mg, 0.025 mmol) was added at 0° to 5° C., and then heated to about 65° C. for 20 hours. The solution was partitioned between water (15 mL) and diethyl ether (15 mL). The aqueous phase was extracted with diethyl ether, and the combined organic layers were washed with water and brine, dried (Na2SO4), and evaporated in vacuo. The residue was dissolved in acetonitrile, washed with hexane (2×20 mL), dried (Na2SO4), concentrated in vacuo, and purified by flash chromatography to give pure 4-(4-isopropoxymethylbenzyl)phenyl carbamic acid 2-trimethylsilanyl-ethyl ester (204 mg, 26%) as clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1.C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)C>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[CH:20][NH:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:16])[CH:8]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1-c1c(C)noc1C
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)c(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C
Yield: 86 %

Procedure:
[3-(3,5-Dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine (for a preparation see Intermediate 2) (39 g, 179 mmol) was dissolved in diethyl [(ethyloxy)methylidene]propanedioate (38.6 g, 179 mmol) and heated to 130° C., giving a steady effervescence as ethanol boiled off. The solution was heated for 1 h, then cooled to room temperature and evaporated in vacuo to give a brown oil. The product was dissolved in DCM (100 ml) and loaded onto a 750 g silica column, then eluted with 0-100% EtOAc/cyclohexane to give diethyl({[3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amino}methylidene)propanedioate (59.5 g, 153 mmol, 86% yield) as pale yellow crystalline solid. LCMS (formate) Rt 1.15 min, MH+ 389.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=1)(=O)C.CO.[OH-].[Na+]>C1COCC1.O>[I:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:28][CH:27]=1
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18-(p-Iodophenyl)octadecyl acetate 42 (1.55 g, 3.01 mmol) was dissolved in THF (10 ml), MeOH (5 ml) and solution of NaOH (240 mg, 6.03 mmol) in H2O (1 ml) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with aqueous NaHCO3 solution and extracted with EtOAc. Extract was dried over Na2SO4 and evaporated. Silica gel chromatography in hexane-EtOAc (95:5, 90:10) gave the product, 1.36 g (95%).
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1OCCC1.[CH2:35]([O:37][C:38](=[O:49])[CH:39]=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=[C:44]([CH:46]=O)[CH3:45])[CH3:36]>CO.O>[CH2:35]([O:37][C:38](=[O:49])[CH:39]=[C:40]([CH3:48])/[CH:41]=[CH:42]/[CH:43]=[C:44]([CH3:46])[CH:45]=[CH:10][C:4]1[S:5][C:6]([CH3:9])=[C:7]([CH3:8])[C:3]=1[CH3:2])[CH3:36]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1sc(C)c(C)c1C

Procedure:
3.2 G. of (3,4,5-trimethyl-2-thenyl)triphenyl phosphonium bromide were suspended in 80 ml. of butylene oxide and 1.5 g. of 3-methyl-7-formyl-octa-2,4,6-trienoic acid ethyl ester were added. The resulting mixture was refluxed under argon for one hour after which the solvent was evaporated. The residue which formed was diluted with a mixture of methanol/water (6:4) and extracted four times with hexane. The combined hexane solutions were washed once with methanol/water (6:4) and twice with pure water, dried with sodium sulfate, filtered and evaporated. The resulting crude product was purified by column chromatography on silica gel and elution with hexane/5% ether. Recrystallization of the all trans-3,7-dimethyl-9-(3,4,5-trimethyl-2-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester so obtained from hexane/1% ethyl acetate gave yellow crystals, m.p. 96°-98° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([Zn]CC)[CH3:13]>O1CCOCC1>[CH2:12]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1)[CH3:13]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1cncc(Br)c1
Solvent: C1COCCO1
Product: CCc1cncc(C(=O)OC)c1
Temperature: 70 °C
Yield: 54.9 %

Procedure:
To a solution of methyl 5-bromopyridine-3-carboxylate (10.0 g, 46.29 mmol) in anhydrous dioxane (100 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (677 mg, 0.925 mmol). Then, diethylzinc (5.71 g, 38 mL, 46.29 mmol, 15% solution in toluene) was added dropwise. The reaction mixture was heated at 70° C. for 45 minutes, then cooled to room temperature and quenched with MeOH. The mixture was extracted with ethyl acetate (2×250 mL) and washed with water, 0.1 N HCl, and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate and hexane to provide methyl 5-ethylpyridine-3-carboxylate as a yellow oil (4.20 g, 55% yield); 1H NMR (400 MHz, CDCl3): δ 1. (t, 3H), 1.45 (t, 3H), 2.78 (q, 2H), 3.99 (s, 3H), 8.15 (s, 1H), 8.65 (s, 1H), 8.89 (s, 1H); M+ 165.1.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[Br:17][C:14]1[CH:15]=[CH:16][C:7]2[N:6]3[CH2:1][CH2:2][NH:3][CH2:4][CH:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CNCCN2c2ccc(Br)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1D (1.54 g, 6.07 mmol) in acetic acid/water (1:1, 20 mL) was added N-bromosuccinimide (1.08 g, 6.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. Product precipitated. The precipitate was collected to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.36 (d, J=8.54 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.85 Hz, 1H), 3.54-3.63 (m, 1H), 3.22-3.40 (m, 4H), 2.93-3.07 (m, 2H), 2.65-2.72 (m, 1H), 2.08 (d, J=13.73 Hz, 1H); MS (ESI) m/z 297.8 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][CH2:16][CH3:17].[Na+].C(Br)C=C>C(O)C.C(=O)(O)[O-].[Na+]>[C:2]1([C:1](=[O:8])[CH2:9][CH2:10][CH:16]=[CH2:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C=CCBr
Solvent: CCO
Product: C=CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl benzoylacetate (38.4 g, 0.2 mole, Aldrich) was added to a mixture of sodium ethoxide (13.6 g, 0.2 moles) in 200 mL ethanol. The mixture was stirred magnetically and slowly brought to reflux. After 30 minutes, the reaction mixture was cooled and allyl bromide (26.6 g, 0.22 moles, Aldrich) was added via a syringe with care (10 minutes), and the mixture was refluxed for another 2 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel and diluted with 300 mL saturated sodium bicarbonate and extracted with ether (200 mL×3). The combined ether layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation resulting in a brownish oil. Without further purification, the crude product was suspended in 250 mL 1 normal sodium hydroxide solution and brought to gentle reflux overnight. After cooling, the oil that floated on top was separated and was combine with the organic layer from the extractions that followed. The aqueous layer was acidified with 50% sulfuric acid to pH 1 and heated to reflux for 5 hours. The mixture was extracted with ethyl acetate (200 mL×3). The organic layer was dried over sodium sulfate and the solvent removed by rotary evaporation to yield a yellow oil. Yield: 19.7 g (61.5%) with boiling point 70-80° C. at 0.8 mmHg. 1H-NMR (CDCl3, δ): phenyl ring (7.97, d, 2H, 7.55, m, 1H, 7.4, m, 2H); vinyl group (5.8, m 2H, 5.1 q, 1H); 3.08 (t, 2H); 2.5 (m, 2H). See also, Vogel et al., Vogel's Textbook of Practical Organic Chemistry. Fifth Edition, revised by Furniss et al., 1989, Pearson Prentice Hall).
Reaction SMILES: [BrH:1].[CH3:2][C:3]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34]CC2C=CC=CC=2)[CH:21]=1)=[O:19])([CH3:15])[CH2:4][NH:5][C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H]>C(O)C.[Pd]>[BrH:1].[CH3:15][C:3]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:34])[CH:21]=1)=[O:19])([CH3:2])[CH2:4][NH:5][C:6](=[O:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(CNC(=O)Cc1ccccc1)NCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CC(C)(CNC(=O)Cc1ccccc1)NCC(=O)c1ccc(O)c(O)c1

Procedure:
A solution of 2-bromo-3',4'-bis(benzyloxy)acetophenone (5.24 g.) and N-(2-amino-2-methylpropyl)-2-phenylacetamide (5.5 g.) in dioxan (25 ml.) was stirred for 2 hours at room temperature. The reaction mixture was diluted with dry ether (200 ml.) and the precipitate of N-(2-amino-2-methylpropyl)-2-phenylacetamide hydrobromide was separated by filtration. The ethereal filtrate was washed with water (3×50 ml.), brine (100 ml.) dried (MgSO4) and then a fresh solution of saturated ethereal hydrogen bromide was added until the solution was just acid. After 18 hours at 0°-5° C. the precipitate which had formed was collected to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-bis(benzyloxy)acetophenone hydrobromide as a solid (6.85 g.) m.p. 155°-160° C. This hydrobromide (5.0 g.) was dissolved in absolute ethanol (300 ml.) and the solution was hydrognated at atmospheric pressure using 10% w/w palladium-on-carbon (3.0 g.) as catalyst. When the uptake of hydrogen was complete (about 3 hours), the catalyst was removed by filtration and the ethanolic filtrate was evaporated at a temperature below 30° C. to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-dihydroxyacetophenone hydrobromide as a foam (3.7 g.) which was used directly for further acylation.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:14][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Trifluoromethylbenzoyl chloride (30 mg, 0.14 mmol, CAS RN 2251-65-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol, example 1, intermediate a) and DIPEA (30 μL, 0.17 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (17 mg, 46%). MS (ESI): m/z=371.0 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)O1.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36]2[N:41]=[C:40](Cl)[N:39]=[C:38]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:37]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>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(COC)OC>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36]2[N:41]=[C:40]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[N:39]=[C:38]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:37]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)nc(N3CCOCC3)n2)C1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: COCCOC
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Temperature: 140 °C
Yield: 53.2 %

Procedure:
To a microwave processing tube was added dimethoxyethane (15 mL), aqueous Na2CO3 (2 molar) (4 mL, 8 mmol, 2 eq), (Ph3P)4Pd (317 mg, 0.55 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.81 g, 8.30 mmol, 1.5 eq) and 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 5.53 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were removed and the crude compound was purified by silica gel chromatography using CH2Cl2/Ethyl acetate (10:1) and later CH2Cl2/MeOH/NH3 (15:1:0.1) to give the product as a off-white solid (1.3 g, 53% yield). MS (ESI) m/z=442
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[C:22]([CH:35]=[O:36])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:36][CH2:35][C:22]1[CH:21]=[C:20]([O:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37])=[CH:9][CH:10]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:25]=[CH:24][C:23]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(CO)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 2 h
Yield: 263.8 %

Procedure:
To the solution of 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (36 mg, 0.07 mmol) in methanol (5 ml) is added NaBH4 (3 mg, 0.07 mmol). After 2 h, the mixture is diluted with ethyl acetate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The residue is taken into methanol (20 mL), followed by the addition of sodium hydroxide (5 N aqueous, 1 mL), stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N HCl (1 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (93 mg) as a white solid. MS (ES): 502.2 [M−H]−.