Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:19]([O:18][C:17]([NH:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCCNC(=O)OCc2ccccc2)c1
Yield: 38.9 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (609 mg, 4 mmol), benzyl N-(3-hydroxypropyl)carbamate (754 mg, 3.6 mmol) and polymer supported triphenylphosphine (PS—PPh3) (4 g, 12 mmol) in THF (40 mL) was stirred and diethyl azodicarboxylate (948 mg, 5.44 mmol) was added as a solution in THF (4 mL). The mixture was stirred for 16 h then was filtered and washed with DCM and concentrated by evaporation. The residue was purified by chromatography eluting with DCM to give the title compound (481 mg, 35%) as an oil; 1H NMR δ 1.85-1.92 (2H, m), 3.19 (2H, q), 3.86 (3H, s), 4.05 (2H, t), 5.02 (2H, s), 7.20-7.22 (1H, m), 7.29-7.38 (5H, m), 7.42-7.45 (2H, m), 7.53-7.56 (1H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=O)C>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH2:31][CH2:32][N:28]([CH3:25])[C:29]4=[O:33])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)c(F)c3)CC2)c(C)c1
Yield: 72.5 %

Procedure:
Using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (839 mg) described in Preparation Example 125 and 1-acetylimidazolidin-2-one (329 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (638 mg) was obtained.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[Cl-].[NH4+]>CC1C=CC=CC=1.O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[OH:18])=[CH:15][CH:16]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=C(c1ccc(F)cc1)c1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCC(C(O)(c2ccc(F)cc2)c2cccnc2)CC1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred and cooled Grignard-complex previously prepared starting from a mixture of 134 parts of 4-chloro-1-methylpiperidine, 25 parts of magnesium and 652.5 parts of tetrahydrofuran was added dropwise a solution of 170 parts of (4-fluorophenyl)(3-pyridinyl)methanone in 405 parts of tetrahydrofuran at a temperature between 10°-20° C. Upon completion, stirring was continued for 1 hour at room temperature and for 30 minutes at minutes at reflux. After cooling, the whole was decomposed by pouring onto a mixture of crushed ice and ammonium chloride. 270 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated. The residue was boiled in acetonitrile with activated charcoal. The latter was filtered off over Hyflo and the filtrate was evaporated, yielding 240 parts (95%) of α-(4-fluorophenyl)-α-(1-methyl-4-piperidinyl)-3-pyridinemethanol as a residue (intermediate 18).
Reaction SMILES: C([C:5]1[C:10]2[CH2:11][C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:13][C:9]=2[CH:8]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[OH:28])(C)(C)C.O>ClCCl.CS(O)(=O)=O>[C:24]([C:7]1[C:6]([OH:28])=[CH:5][C:10]2[CH2:11][C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:13][C:9]=2[CH:8]=1)([CH3:25])([CH3:27])[CH3:26]
Reactant: CCCCCC1(CCCCC)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCC1(CCCCC)Cc2cc(O)c(C(C)(C)C)cc2O1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To 1.03 g of 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran synthesized according to JP No. 6-206842A/94 dissolved in 15 ml of dichloromethane was added 7 drops of methanesulfonic acid and the mixture was stirred at room temperature for a whole day and night. Then, the reaction mixture was combined with water and extracted with dichloromethane. The extracted layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.19 g of 6-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran as a colorless oil (yield 22%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[C:13]([N+:15]([O-])=O)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[C:19](=[O:28])[C:20]3=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]3[C:22]2=[O:23])=[C:13]([CH:14]=1)[NH2:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(N)c1
Yield: 89 %

Procedure:
A suspension of 5-(tert-butyldimethylsilyloxy)-2-phthalimido-1-nitrobenzene (5.00 g, 12.5 mmol) and 10% palladium-on-carbon (2.5 g) in ethyl acetate (60 mL) was stirred under 1 atm of hydrogen for 16 h. The mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo to yield 4.1 g (89%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=O)=[CH:6][CH:5]=1.CC(O)=O.[BH4-].[Na+]>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]2=[O:18])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)C2C(=O)OC(C)(C)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
The mixture of crude 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-benzoic acid methyl ester from step A was dissolved in DCM (50 mL) and AcOH (5 mL) and chilled to ice-bath temperature. To the solution was added portion-wise, over 30 min, NaBH4 (722 mg, 19.1 mmol). The reaction mixture was allowed to warm to RT overnight. The mixture was quenched with water, stirred for 10 min then extracted with DCM. The organic solution was dried over Na2SO4 and concentrated to afford an off-white solid that was suspended in Et2O to give pure 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-benzoic acid methyl ester as a white solid (2.24 g, 60%). 1H NMR (500 MHz, DMSO-d6): δ 7.87 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H), 4.86 (t, 7.87 (d, J=5 Hz, 1H), 2H), 3.84 (s, 3H), 3.35 (d, J=5 Hz, 2H), 1.83 (s, 3H), 1.64 (s, 3H)
Reaction SMILES: [C:1]([C:4]([NH:9][CH2:10][C:11]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[Na].BrBr>C(O)(=O)C>[CH2:20]([C:17]1[CH:18]=[N:19][C:11]([C:10]2[NH:2][C:1](=[O:3])[C:4]([CH:5]([CH3:7])[CH3:6])([CH3:8])[N:9]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[CH3:21]
Reactant: CCc1cnc(CNC(C)(C(N)=O)C(C)C)c(C(=O)O)c1
Agent: BrBr
Agent: [Na]
Solvent: CC(=O)O
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
A mixture of 0.8 g of 2-{[(1-carbamoyl-1,2-dimethylpropyl)amino]methyl}-5-ethylnicotinic acid (2.7 mmol) and 0.56 g sodium acerate (6.8 mmol) in 10 mL acetic acid is warmed until homogeneous and cooled to room temperature. The solution is treated with 0.88 g bromine (5.45 mmol), and the reaction is stirred at 25° C. for 16 hours, then at 75° C. for three days. The reaction mixture is partitioned between CH2Cl2 and water, and the organic phase is dried and concentrated in vacuo. The residue is recrystallized from ethyl acetate-hexanes to afford 0.4 g of the title product having mp 172°-175° C.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH3:19][Mg]Br.[NH4+].[Cl-]>C1COCC1>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([CH:17]([OH:18])[CH3:19])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-carbaldehyde (3.79 g, 17.14 mmol) in THF (173.0 mL) was treated at −78° C. with methylmagnesium bromide (17.1 mL of a 1M solution in THF, 17.14 mmol). The reaction mixture was stirred at −78° C. for 4 h then poured on sat. aq. NH4Cl (150 mL) and extracted with EA (2×300 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.24. LC-MS-conditions 02: tR=0.79 min. 1H NMR (400 MHz, CDCl3) δ 1.55 (d, J=6.5 Hz, 3H), 2.09 (d, J=5.0 Hz, 1H), 4.83-4.95 (m, 1H), 5.31 (s, 2H), 6.28 (d, J=3.0 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 8.09 (s, 1H), 8.13 (s, 1H).
Reaction SMILES: [OH:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([OH:11])([CH2:10][C:4]([C:13]([OH:15])=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:16](O)[CH2:17][CH2:18][CH3:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([OH:1])([CH2:3][C:4]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C12CC3CC(O)(CC(O)(C3)C1)C2

Procedure:
A mixture of 300 mmole of the above-prepared 3,5-dihydroxy-1-adamantanecarboxylic acid, 450 mmole of n-butanol, 15 mmole of sulfuric acid, and 900 ml of toluene was stirred under reflux of toluene for 5 hours. The reaction mixture was concentrated and was then subjected to column chromatography on a silica gel to yield n-butyl 3,5-dihydroxy-adamantanecarboxylate.
Reaction SMILES: [N:1]([CH2:4][C:5]1([O:34][CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[O:33][CH:32]=[CH:31][C:13]=3[N:14]=[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]4[O:22][C:23]([CH3:28])([CH3:27])[C:24](=[O:26])[NH:25][C:20]=4[CH:19]=3)[N:16]=2)[CH2:7][CH2:6]1)=[N+]=[N-].N(CC1(OC)CCN(C(OC(C)(C)C)=O)CC1)=[N+]=[N-].ClC1N=C(Cl)C2OC=CC=2N=1.NC1C=CC2OC(C)(C)C(=O)NC=2C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1([O:34][CH3:35])[CH2:6][CH2:7][N:8]([C:11]2[C:12]3[O:33][CH:32]=[CH:31][C:13]=3[N:14]=[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]4[O:22][C:23]([CH3:27])([CH3:28])[C:24](=[O:26])[NH:25][C:20]=4[CH:19]=3)[N:16]=2)[CH2:9][CH2:10]1
Reactant: COC1(CN=[N+]=[N-])CCN(c2nc(Nc3ccc4c(c3)NC(=O)C(C)(C)O4)nc3ccoc23)CC1
Agent: CC1(C)Oc2ccc(N)cc2NC1=O
Agent: COC1(CN=[N+]=[N-])CCN(C(=O)OC(C)(C)C)CC1
Agent: Clc1nc(Cl)c2occc2n1
Solvent: C1CCOC1
Solvent: O
Product: COC1(CN)CCN(c2nc(Nc3ccc4c(c3)NC(=O)C(C)(C)O4)nc3ccoc23)CC1
Yield: 76 %

Procedure:
A mixture of 6-(4-(4-(azidomethyl)-4-methoxypiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.030 g, 0.063 mmol, prepared using C from tert-butyl 4-(azidomethyl)-4-methoxypiperidine-1-carboxylate [WO 2010/080864, Example 257], A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ArkPharm]) and triphenylphosphine (0.025 g, 0.094 mmol) in THF (16 mL) and water (2 mL) was stirred at about 100° C. overnight. The organic phase was removed and diluted with water. The aqueous phase was neutralized with aqueous 2 N NaOH and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4, filtered, concentrated under vacuum and purified by HPLC (Table 2, Method v) to afford 6-(4-(4-(aminomethyl)-4-methoxypiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.022 g, 76%). LC/MS (Table 2, method h) Rt=1.77 min.; MS m/z: 453 (M+H)+. Syk IC50=A
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([N:8]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[C:24](O)[CH:23]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.OC1C=C(N(C2C=CC=C(O)C=2)C2C=CC=C(C)C=2)C=CC=1.OC1C=C(N(C2C=CC=CC=2)C2C=CC(CC3C=CC(N(C4C=CC=CC=4)C4C=CC=C(O)C=4)=CC=3)=CC=2)C=CC=1.C1(N(C2C=CC=C(O)C=2)C2C=CC(C3C=CC(C4C=CC(N(C5C=CC=CC=5)C5C=CC=C(O)C=5)=CC=4)=CC=3)=CC=2)C=CC=CC=1.OC1C=C(N(C2C=CC3C4C(=CC(N(C5C=CC=C(O)C=5)C5C=CC=C(O)C=5)=CC=4)CC=3C=2)C2C=CC=C(O)C=2)C=CC=1.OC1C=C(N(C2C3C4=C5C(=CC=3)C=CC(N(C3C=CC=C(O)C=3)C3C=CC=C(O)C=3)=C5C=CC4=CC=2)C2C=CC=C(O)C=2)C=CC=1.OC1C=CC(N(C2C=CC(O)=CC=2)C2C=CC=C(C)C=2)=CC=1.OC1C=CC(N(C2C=CC=CC=2)C2C=CC(CC3C=CC(N(C4C=CC=CC=4)C4C=CC(O)=CC=4)=CC=3)=CC=2)=CC=1>>[C:4]1([N:8]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Oc1cccc(N(c2ccc(-c3ccc(N(c4cccc(O)c4)c4cccc(O)c4)cc3)cc2)c2cccc(O)c2)c1
Agent: Cc1cccc(N(c2ccc(O)cc2)c2ccc(O)cc2)c1
Agent: Cc1cccc(N(c2cccc(O)c2)c2cccc(O)c2)c1
Agent: Oc1ccc(N(c2ccccc2)c2ccc(Cc3ccc(N(c4ccccc4)c4ccc(O)cc4)cc3)cc2)cc1
Product: Oc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4cccc(O)c4)cc3)cc2)c1

Procedure:
N,N,N',N',-tetra(3-hydroxyphenyl)-[1,1'-biphenyl]-4,4'-diamine; N,N-di(3-hydroxyphenyl)-m-toluidine; 1,1-bis-[4-(di-N,N-m-hydroxpyphenyl)-aminophenyl]-cyclohexane; 1,1-bis[4-(N-m-hydroxyphenyl)-4-(N-phenyl)-aminophenyl]-cyclohexane; Bis-(N-(3-hydroxyphenyl)-N-phenyl-4-aminophenyl)-methane; Bis[(N-(3-hydroxyphenyl)-N-phenyl)-4-aminophenyl]-isopropylidene; N,N'-diphenyl-N,N'-bis(3-hydroxyphenyl)-[1,1':4', 1"-terphenyl]-4,4"-diamine; 9-ethyl-3.6-bis[N-phenyl-N-3(3-hydroxyphenyl)-amino]-carbazole; 2,7-bis[N,N-di(3-hydroxyphenyl)-amino]-fluorene; 1,6-bis[N,N-di(3-hydroxyphenyl)-amino]-pyrene; 1,4-bis[N-phenyl-N-(3-hydroxyphenyl)]-phenylenediamine. N,N'-diphenyl-N-N'-bis(4-hydroxy phenyl)[1,1'-biphenyl]-4,4'-diamine N,N,N',N',-tetra(4-hydroxyphenyl)-[1,1'-biphenyl]-4,4'-diamine; N,N-di(4-hydroxyphenyl)-m-toluidine; 1,1-bis-[4-(di-N,N-p-hydroxpyphenyl)-aminophenyl]-cyclohexane; 1,1-bis[4-(N-o-hydroxyphenyl)-4-(N-phenyl)-aminophenyl]-cyclohexane; Bis-(N-(4-hydroxyphenyl)-N-phenyl-4-aminophenyl)-methane; Bis[(N-(4-hydroxyphenyl)-N-phenyl)-4-aminophenyl]-isopropylidene; Bis-N,N-[(4'-hydroxy-4-(1,1'-biphenyl)]-aniline Bis-N,N-[(2'-hydroxy-4-(1,1'-biphenyl)]-aniline
Reaction SMILES: [NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@@H:10]([C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>CO.O.[Pd]>[NH:1]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C@H:2]([C:7]([NH:9][C@@H:10]([C:22]([OH:24])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)O
Yield: 98.2 %

Procedure:
Boc-L-Leu-D-Trp(CH3)-OBzl (2.40 g) in MeOH (50 ml) and water (1 ml) was hydrogenated over 10% palladium on carbon in a similar manner to that of Preparation 1-4) to give Boc-L-Leu-D-Trp(CH3)-OH (1.95 g).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](O)=[O:19])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:1]1([CH2:6][C@H:7]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](=[O:19])[N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)cc1

Procedure:
The title compound was prepared from (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and piperidine as described in Example 12. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.66 (d, 2H), 7.46 (s, 1H), 3.96 (t, 1H), 3.63 (s, 2H), 3.48 (broad t, 2H), 3.43 (broad t, 2H), 3.09 (s, 3H), 2.25-2.18 (m, 1H), 1.88-1.48 (m, 14H), 1.17 (m, 2H); HPLC-MS: m/z: 536 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[F:19])=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:35]([N:36]=[C:37]=[S:38])=[C:34]([Cl:39])[CH:33]=[CH:32][C:23]=1[CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH:16][C:37]([NH:36][C:35]3[C:34]([Cl:39])=[CH:33][CH:32]=[C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[C:22]=3[Cl:21])=[S:38])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[F:19])=[CH:6][CH:7]=1
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1NC(=S)Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl
Reaction time: 72 h

Procedure:
A mixture of N-(4-bromophenyl)-2-fluoro-4-methylamino-5-amino-benzamide (220 mg, 0.543 mmol), N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (0.172 mg, 0.543 mmol) and DMF (5 mL) is stirred for 3 d, diluted with water, and extracted with EtOAc. The organic phase is washed with water, dried with Na2SO4 and concentrated to give the crude product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=C)[CH3:15])=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2].ClC1C=C(C=C(Cl)C=1)C(N(C[C@H](C1C=CC(F)=CC=1)CC=C)C)=[O:33]>>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[O:33])[CH3:15])=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCC2)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2c1CCC2

Procedure:
The compound was synthesized in an analogous way to that of Method 21b but using 6-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylindane-4-carboxamide rather than 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (yield, 89%). 1H NMR (300 MHz, CDCl3): 0.9-4.2 (cm, 14H), 5.9 (s, <1H), 6.6-8.2 (cm, 6H), 8.0 (s, <1H), 9.8 (s, 1H).
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([Cl:16])[C:10](Cl)=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.Cl>C1(C)C(C)=CC=CC=1.[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O>[CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([Cl:16])[C:10]([S:31][C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(S)cc1
Reactant: CN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CN=C(O)c1c(Cl)c(Cl)c(Sc2ccc(C)cc2)c(Cl)c1C(=O)O
Reaction time: 0.5 h

Procedure:
2 g (6.69 millimols) of tetrachlorophthalic acid N-methylimide are dissolved in 20 ml of xylene at 100° C.; 0.86 ml of water, 0.95 g of potassium carbonate and 120 mg of hexadecyltrimethylammonium bromide are added and a solution of 0.86 g (6.89 millimols) of p-thiocresol in 1 ml of xylene is added dropwise at 100° C. After 30 minutes, the mixture is cooled, acidified with 2N HCl solution and extracted with methylene chloride. The solution is dried with sodium sulfate and evaporated and the residue is recrystallised from toluene/cyclohexane. This yields 0.69 g (27%) of the title compound; melting point 212°-216°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[F:21][C:22]1[C:23]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[C:23]=4[C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)=[O:26])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Product: O=C(c1cccc(F)c1-c1ncccn1)N1CC2CN(c3cnc4cc(F)c(F)cc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and Intermediate 50 in the last step MS (ESI): mass calculated for C25H19F3N6O, 476.16; m/z found 477.2 [M+H]+. 1H NMR (500 MHz, CDCl3) 8.74 (t, J=12.5, 2H), 8.25 (d, J=20.5, 1H), 7.65 (dd, J=10.5, 8.4, 1H), 7.52-7.40 (m, 2H), 7.26-7.12 (m, 3H), 3.97-3.74 (m, 3H), 3.73-3.52 (m, 4H), 3.38 (dd, J=11.1, 4.6, 1H), 3.22-3.02 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.FC1C=CC(O)=C(C(C2C=C(F)C=CC=2OC)(C)C)C=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:12][CH3:13])([CH3:10])[CH3:9])[CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc(F)cc1C(C)(C)O
Agent: COc1ccc(F)cc1C(C)(C)c1cc(F)ccc1O
Product: COc1ccc(F)cc1C(C)(C)c1cc(Cl)ccc1O

Procedure:
2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane (m.p. 97° C.) was prepared from 2-(5-fluoro-2-methoxyphenyl)propan-2-ol and 4-chlorophenol following the method described in Example 3 for the preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane.