Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:17])[C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>[Pd].CO>[CH3:1][CH:2]([OH:17])[C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(-c2ccc(N)cc2)o1
Yield: 70.9 %

Procedure:
A mixture of 79 g (0.34 mole) of the compound of Example I, 1 tsp. of 5% Pd/C, 50% H2O, and 500 ml of methanol was shaken under hydrogen pressure with the theoretical amount of H2 being absorbed. The catalyst was removed by filtration, and the filtrate was taken to near dryness on a Calab evaporator. The resulting solid was filtered and air-dried to yield 49 g (71%) of title compound. An analytical sample was prepared by recrystallizing a sample twice from ethanol/charcoal, m.p. 100°-104°.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]1([CH2:19][C:20]([O-:22])=[O:21])([CH2:14]C(OC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[NH2:3][CH2:14][C:8]1([CH2:19][C:20]([OH:22])=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CC1(CC(=O)[O-])CCCCC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C

Procedure:
5.6 ml. Triethylamine in 16 ml. anhydrous acetone are added dropwise, with stirring and cooling to 0° C., to a solution of 7.28 g. monomethyl 1,1-cyclohexane-diacetate, whereafter a solution of 3.6 ml. ethyl chloroformate in 16 ml. anhydrous acetone is added thereto. The reaction mixture is further stirred for 30 minutes at 0° C. and and then a solution of 3.4 g. sodium azide in 12 ml. water added dropwise thereto. The reaction mixture is stirred for 1 hour at 0° C., then poured into ice water and extracted three times with 50 ml. amounts of ice-cold toluene. The combined extracts are dried over anhydrous sodium sulphate at 0° C. and subsequently introduced drop-wise into a flask pre-heated to 100° C. The mixture is then heated for a further hour under reflux and thereafter evaporated in a vacuum. The crude methyl 1-isocyanatomethyl-1-cyclohexane-acetate which remains behind is heated under reflux for 3 hours with 50 ml. 20% hydrochloric acid. After cooling the solution, it is extracted three times with 100 ml. amounts of chloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactam formed as a by-product product and the aqueous hydrochloric acid solution evaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acid crystallises as the hydrochloride; m.p. 117°-118° C., after recrystallisation from acetone/methanol/ether. After recrystallization from methanol/ether the melting point of the product is 129°-133° C.
Reaction SMILES: [C:1]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:28][C:22]1([C:20]([NH:19][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=3)=[CH:7][CH:6]=2)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C#N)cc3)cc2)CCOCC1
Solvent: O=CO
Product: N#Cc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)cc1
Temperature: 50 °C
Yield: 33.2 %

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4′-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 3, step (v), 420 mg) was added formic acid (2 mL) and the mixture heated to 50° C. for 10 min. The mixture was evaporated to dryness, dissolved in methanol (4 mL) and purified on reverse phase HPLC (Water's sunfire column) eluting with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid. Fractions containing product were evaporated to remove acetonitrile, neutralised with saturated sodium bicarbonate and extracted with dichloromethane which was dried over magnesium sulfate and evaporated to afford the titled compound (110 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.NC1C=CC=CC=1>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1cc(F)cc(F)c1
Solvent: CCO
Solvent: Nc1ccccc1
Product: CCOC(=O)c1cc(N)ccc1Oc1cc(F)cc(F)c1
Yield: 100.9 %

Procedure:
Using the method of Example 17.3, ethyl 5-nitro-2-(3,5-difluorophenoxy)benzoate (0.76 g) in ethanol (7 mL) and TBF (3 mL) was converted to the corresponding aniline derivative which was obtained as an oil (0.696 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:22]=[CH:21][C:10]2[S:11][C:12]3[S:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[C:13]=3[C:9]=2[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[CH:56]=[CH:55][C:54]4[C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[C:41]=4[CH:40]=3)[CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH:40]1[C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:54]=2[CH:55]=[CH:56][C:39]=1[C:35]1[CH:34]=[C:33]([C:7]2[CH:8]=[CH:9][C:10]3[S:11][C:12]4[S:16][C:15]5[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=5[C:13]=4[C:21]=3[CH:22]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Oc1ccc2sc3sc4ccccc4c3c2c1)C(F)(F)F
Reactant: CC1(C)OB(c2cccc(-c3ccc4c5ccccc5c5ccccc5c4c3)c2)OC1(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc(-c2ccc3sc4sc5ccccc5c4c3c2)c1
Yield: 81.2 %

Procedure:
Benzo[b]benzo[4,5]thieno[3,2-d]thiophen-2-yl trifluoromethanesulfonate (1.5 g, 3.86 mmol), Pd2(dba)3 (0.071 g, 0.077 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.127 g, 0.309 mmol), 4,4,5,5-tetramethyl-2-(3-(triphenylen-2-yl)phenyl)-1,3,2-dioxaborolane (1.82 g, 4.25 mmol), K3PO4 (2.46 g, 11.59 mmol), toluene (90 mL) and water (10 mL) were charged in a 250 mL flask. This mixture was bubbling with nitrogen for 30 minutes then heated up to reflux for overnight. After purification, 1.7 g (81%) of a white solid was obtained. The compound was confirmed by NMR.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (77 mg, 60%), MS (ISP) m/z=447.4 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: [Cl:1][CH:2]([Cl:35])[C:3]([NH:5][C@H:6]([CH2:33][F:34])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][CH:2]([Cl:1])[C:3]([NH:5][C@H:6]([CH2:33][F:34])[C@H:7]([OH:8])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3CCCN3)cc2)cc1)C(Cl)Cl
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of the product of step 1 (210 mg, 0.4 mmol) in DCM (3 mL) is added TFA (1 mL). The mixture is stirred for 1 hour. The reaction is then diluted with DCM, washed with sat.NaHCO3 (aq.) and evaporated to give the title compound (144 mg). 1H-NMR (400 MHz, DMSO) δ(ppm) 1.5-1.65 (1H), 1.7-1.9 (2H), 2.1-2.25 (1H), 2.8-3.0 (1H), 3.0-3.2 (1H), 4.05-4.15 (1H), 4.15-4.35 (1.5H), 4.35-4.45 (0.5H), 4.5-4.6 (0.5H), 4.65-4.75 (0.5H), 4.8-4.9 (1H), 5.9-6.0 (1H), 6.5 (1H), 7.4-7.5 (4H), 7.5-7.65 (4H), 8.6 (1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:15][CH:16]([C:18]([OH:20])=[O:19])[CH3:17])[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].OS(O)(=O)=O.CCO>[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:15][CH:16]([C:18]([OH:20])=[O:19])[CH3:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)NC(C)C(=O)O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC(C)C(=O)O
Yield: 79.8 %

Procedure:
There was dissolved 0.20 g of ethyl-α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate prepared in Example 10 into 11.0 ml of 1% (v/v) H2SO4 -EtOH, to which 0.05 g of 10% Pd/C was added and the hydrogenation reaction was carried out at room temperature under atmospheric pressure. After completion of the reaction, the catalyst was filtered off with suction and the ethanol solution was neutralized with sodium hydroxide, followed by distillation of the solvent under reduced pressure. The residue was dissolved in water and extracted with dichloromethane, the organic layer being concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 0.152 g of ethyl-α-(1-carboxyethyl)amino-γ-phenylbutyrate ((αS,1S)-form/(αR,1S)-form=99/1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 55.2 %

Procedure:
The procedure described in Example 1 is repeated, except that 9.28 g (0.05 mol) of 4-nitrobenzoyl chloride, 6.25 g (0.0625 mol) of ethyl acrylate, 8.65 g (0.05 mol) of tri-n-butylamine and 0.1122 g (0.0005 mol) of palladium acetate are used. After a reaction time of 1 hour at 120° C. in 100 ml of p-xylene as the solvent, 6.1 g (0.0276 mol) of ethyl 4-nitrocinnamate are obtained, corresponding to a yield of 55.2% of theory; melting point 137.5° C. Analysis for C11H11NO4 (molecular weight 221: calculated C 59.73%, H 5.01%, N 6.33%; found C 59.47%, H 4.96%, N 6.27%.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].CCN(CC)CC.S([N:25]=[N+:26]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[N+:25](=[C:1]1[C:2](=[O:3])[CH2:4][O:5][C:6]1=[O:7])=[N-:26]
Reactant: O=C1COC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=C1C(=O)COC1=O
Reaction time: 2 h
Yield: 29.7 %

Procedure:
To tetronic acid (5.00 g, 49.9 mmol) in CH2Cl2 (250 mL) at 0° C. were added Et3N (8.3 mL, 59.6 mmol) and tosyl azide (7.37 g, 37.4 mmol). After a period of 2 h at r.t., the reaction mixture was partitioned between NH4OAc (25%) and CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (20% to 35% EtOAc in Hexane) to provide 1.4 g of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([OH:25])=O)=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([NH:40][C:39]5[CH:41]=[CH:42][C:36]([CH2:35][N:28]([CH:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)[CH3:27])=[CH:37][CH:38]=5)=[O:25])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc2CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3CCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To a solution of 2-(4-piperidinophenyl)-6,7-dihydro-5 H-benzocycloheptene-8-carboxylic acid (0.45 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.31 g) and 1-hydroxybenzotriazole (0.18 g) in dimethylformamide (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (0.37 g) under ice-cooling. Under nitrogen atmosphere, the mixture was warmed to room temperature. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.54 ml), and the mixture was stirred over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 2-(4-piperidinophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-6,7-dihydro-5 H-benzocyclohepten-8-carboxamide (Compound 224) (0.44 g) as pale orange crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH3:14]>C(O)CO.CO.[Cu-]=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH2:14])=[N:3][CH:4]=[CH:5]2
Reactant: COc1ccc2c(Cl)nccc2c1
Reactant: N
Agent: O=[Cu-]
Solvent: CO
Solvent: OCCO
Product: COc1ccc2c(N)nccc2c1
Temperature: 120 °C
Yield: 72 %

Procedure:
A sealable tube was charged with 83E (770 mg, 3.98 mmol), copper (I) oxide (30 mg) and 12M NH3 in ethylene glycol (5 mL). The tube was sealed and the reaction was heated to 120° C. for 72 h. After cooling to rt, the reaction was diluted with methanol and was purified via preparative HPLC (MeOH/water/TFA) to provide 83F (832 mg, 72%). LC-MS: 175.23 (M+H)+.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C@H:62]([CH2:64][C:65]([NH2:67])=[O:66])[OH:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C@H:62]([CH2:64][C:65]([NH2:67])=[O:66])[OH:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)N[C@@H](CC(C)C)[C@@H](O)CC(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](CC(C)C)[C@@H](O)CC(N)=O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 125 mg of Z-Phe-His-OH, 110 mg of H-Leu-Val-Ile-Sta-NH2, 44 mg of HOBt and 68 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.20, Rf (B11)=0.64.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[H-].[Na+].BrC[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:2][S:1][CH2:6][CH2:5][CH2:4][SH:3]
Reactant: COC(=O)CBr
Reactant: C1CSCSC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSCCCS
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
An ice-cold solution of 1,3-dithiane (2.0 mL, 19.9 mmol) in THF (40 mL) was treated with NaH (819 mg, 20.5 mmol). After 30 min., methyl bromoacetate (1.9 mL, 20.0 mmol) was added and the mixture stirred for 3.5 h at room temperature. The reaction was quenched by addition of MeOH and then 50 mL 1 M HCl. The mixture was extracted with ether (2×50 mL) and the combined ether solution washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL) and then was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (10-15% ethyl acetate/hexanes) gave 971 mg (5.38 mmol, 27%) of the thiol.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[CH2:8]([NH:15][C:16](=[O:38])[N:17]([C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:26]=2[OH:37])[CH:22]=[CH:23][CH:24]=1)[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:8]([NH:15][C:16](=[O:38])[N:17]([C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:26]=2[O:37][CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:22]=[CH:23][CH:24]=1)[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: FC(F)(F)CCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC(F)(F)F)c1
Yield: 8.2 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 1.0 mL (8.52 mmol, 7.3 eq) 1-iodo-3,3,3-trifluoropropane and 500 mg (1.17 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3 eq) of potassium carbonate at 80° C. for 7 days, 50 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3,3,3-trifluoropropoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=8%
Reaction SMILES: [Si]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35]3[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH:31]=[CH:32][CH:33]=2)=[CH:26][N:27]=1)([CH3:22])[CH3:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:22][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]3[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=3)[CH:29]=2)=[CH:26][N:27]=1)([CH3:21])[CH2:19][OH:18]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a solution of the product of Step 4 (327 mg, 0.517 mmol) in THF (3 mL) was added TBAF (1.0 M, 1.55 mL, 1.55 mmol), and the mixture stirred at room temperature for 2 weeks at which point LCMS showed complete conversion. The mixture was concentrated in vacuo, then the residue purified by chromatography on silica gel (60:40 to 0:100, hexanes:ethyl acetate) to provide 162 mg (0.411 mmol, 79%) of 2-methyl-2-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-1-ol as a white solid. MS APCI: [M+H]+ m/z 395.0. 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J=4.9 Hz, 1H); 8.07 (s, 1H); 7.85 (s, 1H); 7.63 (s, 1H); 7.49 (d, J=8.2 Hz, 1H); 7.37 (t, J=7.9 Hz, 1H); 7.26 (d, J=7.7 Hz, 1H); 7.07 (d, J=4.9 Hz, 1H); 3.79 (s, 2H); 1.48 (s, 6H). rhSYK activity=+++
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][N+]([O-])=O>C(O)C.C(O)=O.[OH-].[OH-].[Pd+2]>[CH3:16][O:15][C:12]1[CH:11]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:13]=1[OH:14])[NH:17][CH:7]=[CH:6]2
Reactant: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: COc1cc2cc[nH]c2c(OC)c1O
Yield: 14 %

Procedure:
A mixture of 10 g (0. 037 mole) of 3,5-dimethoxy-4-hydroxy-2,β-dinitrostyrene and 10 g of palladium hydroxide on charcoal in 400 cm3 of ethanol and 7 cm3 of formic acid is heated under reflux for 3 hours. After cooling, the reaction mixture is filtered through Celite. The filtrate is evaporated to dryness. The residue is redissolved in dichloromethane and the solution is filtered on silica gel. After distillation of the solvent under reduced pressure and recrystallization from diisopropyl ether, 1 g of the desired product is obtained in the form of a whitish solid (yield =14%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([F:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([Zn]I)[CH:27]=[CH:28][CH:29]=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>[F:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(F)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: Fc1cccc([Zn]I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Temperature: 65 °C
Yield: 11 %

Procedure:
A mixture of 7-acetyl-5-fluoroquinolin-8-yl trifluoromethanesulfonate (3.4 g, 10. mmol, from Example 53, Step 2) in tetrahydrofuran (10 mL) was degassed for 10 minutes, to which was added tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) and 0.5 M (3-fluorophenyl)(iodo)zinc in tetrahydrofuran (50 mL). The reaction mixture was heated at 65° C. overnight, and then cooled to room temperature. The reaction was quenched with sat. NaHCO3 solution. The mixture was filtered through a Celite pad. The filtrate was extracted with dichloromethane. The combined organic layers were wash with brine, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 30% ethyl acetate in hexane) to give the desired product (0.32 g, 11%). LCMS calculated for C17H12F2NO (M+H)+: m/z=284.1; Found: 284.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH2:62])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([NH:62][C:59]1[S:60][C:61]2[C:53]([CH:48]3[CH2:49][O:50][CH2:51][CH2:52][O:47]3)=[CH:54][CH:55]=[C:56]([O:63][CH3:64])[C:57]=2[N:58]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: CC(C)(C)c1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C(C)(C)C)c3)nc12

Procedure:
From 2-tert-butyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 428 (M+H+, 100).