Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH2:43][CH3:44])[CH2:30][CH3:31])=[CH:42][CH:41]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 6.4 %

Procedure:
A mixture of 120 mg (0.27 mmol) of 3-(2,6-dichlorophenyl)-7-methane-sulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 370 mg (1.8 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 40 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residual solid was purified by crystallisation from cyclohexane/ethyl acetate to give 10 mg (6%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino) ethoxy]anilino]-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 162-163° C.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH:22]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCCl>[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]([C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH2:23][CH:22]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc2NC1=O
Yield: 99.7 %

Procedure:
1-Adamantylcarbonyl chloride (795 mg) and pyridine (0.33 ml) were added to 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) in anhydrous 1,2-dichloroethane (20 ml). The mixture was refluxed with heat for one hour. After the reaction mixture was allowed to cool, crystals so precipitated were collected by filtration, to thereby obtain 1.58 g of the titled compound as a white solid (yield: 99.8%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]3[C:46]([Cl:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=3[Cl:49])=[CH:33][CH:32]=2)[CH2:21][NH:22]C(=O)OC(C)(C)C)=[C:16]([CH3:50])[CH:15]=1)(=[O:3])[CH3:2].Cl>CCOCC.CCOC(C)=O>[ClH:47].[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]3[C:42]([Cl:49])=[CH:43][C:44]([CH3:48])=[CH:45][C:46]=3[Cl:47])=[CH:33][CH:32]=2)[CH2:21][NH2:22])=[C:16]([CH3:50])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)NCCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 2, step 5 using tert-butyl (2-{2′-[(acetylamino)propyl]-3-methylbiphenyl-4-yl}-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 1 as starting materials. Following flash chromatography the desired material (colorless oil) was dissolved in CH2Cl2/Et2O (1/1). HCl (4M in dioxane) was added in excess and the resulting suspension was triturated with Et2O to afford after filtration the title compounds as an off white salt. 1H NMR (500 MHz, CD3OD): δ 7.45 (d, 1H), 7.31-7.11 (m, 7H), 7.06 (s, 1H), 6.98 (d, 2H), 6.83 (d, 2H), 4.33 (brd, 4H), 3.55-3.49 (m, 1H), 3.44-3.34 (m, 2H), 3.07-3.01 (m, 3H), 2.86 (dd, 1H), 2.66-2.63 (m, 2H), 2.31 (s, 3H), 2.14 (s, 3H), 1.90 (s, 3H), 1.65-1.61 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1.S(=O)(=O)(O)O>CO>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(OCCBr)c(-c2ccnn2C)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cn1nccc1-c1cc(N)ccc1OCCBr
Temperature: 90 °C
Yield: 98.6 %

Procedure:
To a solution of N-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (3 g, 8.9 mmole) in methanol (6 mL) was added Sulfuric acid (2.2 mL, 42 mmole, 4.78 eq) at 0° C. while stirring. The reaction mixture was refluxed at 90° C. for 1 hour 20 minutes. Crude was quenched with water, neutralized with saturated sodium hydroxide solution until pH 8, extracted with ethyl acetate, and then concentrated in vacuo to give title compound as a solid (2.6 g, 99%). Exact mass calculated for C12H14BrN3O 295.0. found 296.1 (M+H 79Br, 100), 298.2 (M+H 81Br, 98).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.[CH3:24]C1C=CC(S(OC[C@H](NC(OC(C)(C)C)=O)C)(=O)=O)=CC=1>>[NH2:1][C@H:2]([CH3:24])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)NC(=O)OC(C)(C)C)cc1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(C[C@@H](C)N)c2)c1

Procedure:
The title compound was synthesized according to procedure described for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide starting with (R)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate was performed according to Bioorg. Med. Chem. 16 (2008) 1966-1982. LC-MS conditions B: tR=0.55 min, [M+H]+=326.11.
Reaction SMILES: [O:1]([C:8]1[CH:21]=[CH:20][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([OH:25])(=[S:24])[CH3:23]>C(OCC)C>[C:22]([S:24][CH:15]([CH2:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:25])[CH3:23]
Reactant: CC(O)=S
Reactant: COC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)C(CC(=O)c1ccc(Oc2ccccc2)cc1)SC(C)=O
Reaction time: 3 h

Procedure:
2.82 g of methyl 3-(4-phenoxybenzoyl)acrylate were dissolved in 30 ml of diethyl ether, then 1.5 ml of thioacetic acid were added. The mixture was stirred for 3 hours. The reaction mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water and then dried over magnesium sulfate. The diethyl ether was removed by distillation under reduced pressure. The residue was purified first by silica gel column chromatography, eluted with a mixture of hexane and diethyl ether, then by recrystallization from a mixture of hexane and diethyl ether to give 2.91 g of methyl 2-acetylthio-3-(4-phenoxybenzoyl)-propionate.
Reaction SMILES: C([O:4][C:5]1([C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH:27][C:28]([C:30]5[N:34]([CH3:35])[N:33]=[C:32]([CH3:36])[CH:31]=5)=[O:29])[CH:21]=4)=[N:15][N:14]3[CH:37]=2)=[O:9])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[OH:4][C:5]1([C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH:27][C:28]([C:30]5[N:34]([CH3:35])[N:33]=[C:32]([CH3:36])[CH:31]=5)=[O:29])[CH:21]=4)=[N:15][N:14]3[CH:37]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(=O)OC1(C(=O)Nc2cn3nc(Oc4ccc(C)c(NC(=O)c5cc(C)nn5C)c4)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5(O)CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 1-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropyl acetate (130 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid (2.5 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (99 mg, 86%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[CH3:27][O:28][N:29]1[C:34]([CH3:36])([CH3:35])[CH2:33][CH:32](O)[CH2:31][C:30]1([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O:16][CH:32]3[CH2:33][C:34]([CH3:35])([CH3:36])[N:29]([O:28][CH3:27])[C:30]([CH3:39])([CH3:38])[CH2:31]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Product: CON1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccc(Cl)cc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C

Procedure:
3-(5-Chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid (12.0 g, 0.032 mol) and 1-methoxy-2,2,6,6-tetramethyl-4-hydroxypiperidine (6.66 g, 0.036 mol) are reacted together according to the procedure given in Example 3. The title compound is obtained in a yield of 8.79 g (50.5%) as a light yellow solid, melting at 132-137° C., whose structure is consistent with 1Hnmr and mass spectrometry. The compound has a molar absorptivity of 17,210 l/mole cm.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([O:30][C:31]([NH:1][C@@H:2]([CH2:7][C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1

Procedure:
Methyl (2S)-2-amino-3-(3,5-difluorophenyl)propanoate (XV, EXAMPLE 11, 0.300 g, 1.40 mmol, 1 equivalent) and water (10 mL) are mixed. Sodium carbonate (0.15 g, 1.40 mmol, 1 equivalent) of is added followed by benzylchloroformate (0.2 mL, 0.24 g 1.4 mmol, 1 equivalent) and the mixture stirred at 20-25° until complete as measured by HPLC. Once the reaction is complete, ethyl acetate (20 mL) is added and the phases separated. The aqueous phase is extracted with ethyl acetate (2×20 mL), and the combined organic phases are dried over sodium sulfate, filtered, and concentrated. The concentrate is crystallized from hexanes/ethyl acetate to give the title compound, mp=54°; NMR (DMSO-d6) δ 7.84, 7.28, 7.06, 4.98, 4.35, 3.68, 3.12 and 2.88.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[F:13]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Under an argon atmosphere, to a solution of methyl 5-bromo-6-chloropicolinate (12.0 g) in toluene (300 mL) was added a solution of 2-fluoro-5-methoxyphenylboronic acid (9.83 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.00 g) and sodium carbonate (14.8 g) in water (60 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude crystals were recrystallized from ethyl acetate to give the title compound (13.1 g) as pale-yellow crystals.
Reaction SMILES: [C:1](O)(=[O:4])[CH:2]=[CH2:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:55]=[CH:56][CH:57]=1)[O:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=1[C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:44][CH:43]=1>O1CCOCC1>[NH2:41][C:37]1[N:38]=[CH:39][N:40]=[C:35]([O:34][C:33]2[CH:32]=[C:31]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:57]=[CH:56][CH:55]=2)[C:36]=1[C:42]1[CH:43]=[CH:44][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:46][CH:47]=1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Reactant: C=CC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Into a 20 mL reaction vial was added acrylic acid (0.01 ml; 0.12 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42.04 mg; 0.17 mmol), and N,N-diisopropylethylamine (0.07 ml; 0.41 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at rt for 1 h. 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (40.00 mg; 0.08 mmol) was then added. The reaction mixture was stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes, then 0-40% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was then purified using preparative HPLC eluting from 35-45% CH3CN in 0.1% TFA in H2O. fractions containing the desired product were combined and lyophilized overnight to afford N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide as a white solid (29.00 mg, 25% yield). HPLC purity: 97%, RT=4.264 min. MS: m/z=425 [M+H]+, RT=2.14 min. 1H-NMR (DMSO-d6) δ 10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:36]2[CH:35]=[C:34]([F:37])[CH:33]=[CH:32][C:31]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: Cc1ccc(F)cc1B(O)O
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: C1COCCO1
Product: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N ,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-methyl-5-fluorobenzene boronic acid (73 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc ×3. The combined extracts were dried and evaporated. The residue was purified on a 12+M column eluting with Pet Et2O to 60% EtOAc/Pet Et2O to afford the title compound in a 27% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:12]=2[N:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:12]=2[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccc(N)cc1)Cc1nc2cc(N)ccc2o1
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1nc2cc(NS(C)(=O)=O)ccc2o1

Procedure:
Methanesulphonyl chloride (0.38 g, 3.3 mmole) and N-methyl-N-(5-aminobenzoxazol-2-ylmethyl)-4-aminophenethylamine (see Preparation 1C - 0.45 g, 1.5 mmole) in pyridine (20 ml) when reacted together under conditions similar to those of Example 2 gave the title compound, yield from ethanol 0.25 g, m.p. 174°-176°.
Reaction SMILES: [C:1]([CH2:3][C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH2:6][CH2:5]1)#[N:2].CCN(S(F)(F)[F:35])CC>ClCCl>[F:35][C:4]1([CH2:3][C:1]#[N:2])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH2:6][CH2:5]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CC#N)CC3)c(F)c2)C(=O)O1
Yield: 47 %

Procedure:
The title compound was prepared by stirring (S)-N-{3-[4-(4-cyanomethyl-4-hydroxypiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.45 mmol) with DAST (3.06 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 47% yield.
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)=O.[C:25]([O:29][C:30](=[O:41])[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[NH:40])[NH2:39])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:25]([O:29][C:30](=[O:41])[NH:31][CH:32]1[CH2:33][CH2:34][N:35]([C:38]2[NH:40][C:3](=[O:24])[C:4]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=3)[N:39]=2)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=N)N)CC1
Reactant: COC(=O)C(C(=O)c1ccc(C#N)c(F)c1)c1ccc(OC)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)[nH]c2=O)cc1
Yield: 3.5 %

Procedure:
A mixture of 3-(4-cyano-3-fluoro-phenyl)-2-(4-methoxy-phenyl)-3-oxo-propionic acid methyl ester (1.8 g, 5.5 mmol), (1-carbamimidoyl-piperidin-4-yl)-carbamic acid tert-butyl ester (2.6 g, 9.2 mmol), DIEA (2.4 g, 18.3 mmol) in toluene (50 mL) was refluxed overnight. The solvent was concentrated in vacuo. The residue was suspended in MeOH and the solids were filtered to give 100 mg (4%) of the title compound. [M+H] Calc'd for C28H30FN5O4, 520. Found, 520.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:39]6[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(-c3ccc4c(n3)-c3sc(-c5ncnn5-c5ccc(F)cc5F)cc3CCO4)cn2)CC1
Temperature: 150 °C
Yield: 56.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), 1-Methyl-piperazine (120 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 249 (315 mg, yield: 57%). 1HNMR (DMSO-d6, 400 MHz): δ8.71 (s, 1H), 8.27 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.42 (t, J=2 Hz, 1H), 7.90-7.88 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.14 (m, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.26 (s, 2H), 3.50 (s, 3H), 3.10 (s, 2H), 2.38 (s, 4H), 2.18 (s, 3H). ESI-MS: m/z=558 [M+H+]
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: CCNc1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1ccc([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 94 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (59 mg) and (4-formylphenyl)acetic acid (126 mg) according to an analogous synthetic method to Example 212, the title compound (77 mg) was obtained.