Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Reaction time: 48 h
Yield: 44.8 %

Procedure:
A solution of 4-bromo-2-methoxyaniline (8.096 g, 40.04 mmol) in dichloromethane (100 mL) was treated with triethylamine (6.06 g, 60.06 mmol), then hydrocinnamoyl chloride (7.08 g, 42.04 mmol). The reaction mixture was stirred for 48 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added. The precipitate was filtered, and the filtrate was evaporated to a solid under reduced pressure. The solid was dissolved in ethyl acetate, and washed with 5 N hydrochloric acid solution, 5 N sodium hydroxide solution, water and brine. The crude material (two spots by thin layer chromatography) was triturated with methanol. The un-dissolved solid was filtered to give 6 g (50%) of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 7.92-7.90 (m, 1H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 7.09-7.07 (m, 1H), 3.83 (s, 3H), 2.90-2.86 (m, 2H), 2.72-2.69 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.491 min (97%).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:2]([O-:5])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Methanesulfonic acid (0.65 ml, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered immediately and dried at 55° C. under vacuum to give the title compound. Melting point: 180.1° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:48]=[N+:49]=[N-:50])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.O1CCCC1.CN1CCCN(C)C1=O>[N:48]([C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12)=[N+:49]=[N-:50]
Reactant: CC1CCCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(N=[N+]=[N-])CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10.0 g (39.0 mmol) (+/−)10-methyl-2-pyrimidin -4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one in a mixture of dry tetrahydrofuran/dimethyltetrahydropyrimidinone (150/20 mL) under argon at −78° C. was added 81.9 mL (81.9 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −78° C. for 5 min. The solution was warmed to 0° C. by changing the cold bath and 13.3 g (42.9 mmol) of 2,4,6-triisopropylbenzene -sulfonyl azide in 30 mL of dry tetrahydrofuran was added. The reaction was stirred at 0° C. for 1 h, at room temperature for 1 h and 10.0 mL (175.6 mmol) of acetic acid was added. The mixture was stirred at room temperature for 1 h and then diluted with ethyl acetate. The organic phase was washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to afford 10-azido-1 0-methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one as an orange oil. The compound was used as such in the next step.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[O:12]([C:13]1[CH:14]=[CH:15][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chlorosulfonic acid (4.3 mL, 64.6 mmol) in dichloromethane (20 mL) is added dropwise to a solution of diphenyl ether (10 g, 58.8 mmol) in dichloromethane (20 mL) at 0° C. under nitrogen atmosphere. The reaction mixture is slowly warmed up to RT and stirred for 2 h. To the mixture are added oxalyl chloride (6.5 ml, 76.4 mmol) and then DMF (1.5 mL) at RT. After being heated at 40° C. for 1 h, the reaction mixture is stirred at RT for 15 h. The mixture is poured to ice-water and extracted with ether. The organic layer is dried over MgSO4 and evaporated in vacuo to give the title compound quantitatively: NMR (CDCl3) 7.10 (t, 4H, J=8.6 Hz), 7.22-7.30 (m, 1 H), 7.46 (t, 2H, J=8.6 Hz), 7.98 (d, 2H, J=9.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C.CN(C=O)C>[F:29][C:11]1[N:12]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[S:9][C:10]=1[N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(-c2cncc(F)c2)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1F
Temperature: 25 °C
Reaction time: 168 h
Yield: 82.2 %

Procedure:
To a degassed solution of di(tert-butyl) 2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-ylimidodicarbonate (1.0 g, 2.53 mmol) in anhydrous acetonitrile (20 mL) and DMF (10 mL) was added F-TEDA (SELECTFLUOR™) (1.8 g, 5.06 mmol). The reaction mixture was stirred at ambient temperature for 7 days. Water was added to the reaction mixture and the target extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, was filtered and was concentrated. The crude mixture was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to afford a beige solid (860 mg, 82%): mp 143-143° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (t, J=1.4 Hz, 1H), 8.54 (d, J=2.7 Hz, 1H), 7.91 (ddd, J=8.9, 2.7, 1.8 Hz, 1H), 1.48 (s, 18H); ESIMS m/z 414 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][CH2:20][CH2:21][C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][O:19][CH3:18])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: COCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: COCCC(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 13.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (37 mg, 1.1 eq, 0.16 mmol) was added to a solution of 3-methoxypropionic acid (15.5 mg, 1.0 eq, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 1.0 eq, 0.16 mmol), 1-hydroxybenzotriazole (20 mg, 1.0 eq, 0.15 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and solvent was removed in vacuo. The resultant solid was washed with water and purified by semi-preparative HPLC to yield the title compound as a white solid (5.8 mg, 0.02 mmol, 12%). LCMS: [M+H]+=313, Rt=1.35 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH2:27][CH2:28][CH2:29][OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12]([NH:27][CH2:28][CH2:29][OH:30])[N:13]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C(C)C
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2C(C)C

Procedure:
The product of Example 56 and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.78 (m, 6H), 2.29 (s, 3H), 3.70 (br s, 2H), 3.89 (br s, 3H), 5.81 (m, 1H), 6.02 (br s, 1H), 6.23 (d, 1H, J=9.7 Hz), 7.00 (m, 2H), 7.11 (d, 1H, J=9.7 Hz), 7.19 (m, 1H), LC MS (m/e)=357.2 (MH+). Rt=1.80 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[CH:12](Cl)(Cl)Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[N+:5]#[C-:12])[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: [C-]#[N+]c1c(CC)cccc1CC

Procedure:
The procedure of Example 1 was again followed, using 75 g (0.5 mole) of 2,6-diethylaniline, 60 ml of chloroform, 100 ml of methylene chloride, 200 ml of 50% aqueous sodium hydroxide, and 700 mg of benzyltriethylammonium chloride. The product was an oil weighing 36 g, with structure confirmed by mass spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
The product from Example 33A (0.1520 g, 0.396 mmoles), methyl-4-bromobenzoate (0.1702 g, 0.792 mmoles), K3PO4 (0.1680 g, 0.792 mmoles), Pd(OAc)2 (0.0070 g, 0.032 mmoles), and 2-(di-tert-butylphosphino)biphenyl (0.0140 g, 0.048 mmoles) was treated with toluene (1.16 mL) under a nitrogen atmosphere. The resulting red solution was degassed, stirred for 10 min, and heated to 100° C. overnight. The black solution was diluted with diethyl ether, extracted with sat. NH4Cl and sat. NaCl, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10:1 hexane:ethyl acetate) on silica gel to provide the title compound (0.1886 g, 92%) as a yellow oil.
Reaction SMILES: C(O)(=O)C(C1C=CC=CC=1)O.Cl.COC(=O)CNC1C=CC=CC=1.Cl.C(OC(=O)CNC1C=CC=CC=1)(C)C.[CH2:40]([O:50][C:51](=[O:60])[CH2:52][NH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:41][CH2:42][CH2:43]CCCCCC>>[CH2:40]([O:50][C:51](=[O:60])[CH2:52][NH:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCOC(=O)CNc1ccccc1
Agent: CC(C)OC(=O)CNc1ccccc1
Agent: COC(=O)CNc1ccccc1
Agent: Cl
Product: CCCCOC(=O)CNc1ccccc1

Procedure:
Using the method of Example 1, racemic mandelic acid was resolved in separate experiments with D(-) phenylglycine methyl ester HCl, D(-) phenylglycine isopropylester HCl, and D(-) phenylglycine decyl ester DCl. The following table gives the results of these experiments (compared with phenylglycine butyl ester):
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:23]=1[F:32].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:4]1[CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=[C:2]([F:1])[C:3]=1[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:23]=1[F:32]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: COCc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 120 °C

Procedure:
A mixture of 2-[2,6-difluoro-4-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.364 g, 1.28 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (0.300 g, 1.28 mmol) and DIPEA (0.67 mL, 3.8 mmol) in 1,4-dioxane (6 mL) and water (0.30 mL) was purged with nitrogen. Bis(tri-tert-butylphosphine)palladium (65.5 mg, 0.128 mmol) was added to the mixture. The resulting reaction mixture was then heated at 120° C. for 40 min. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylate as a white powder.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[Cl:19])[CH2:17][NH:18][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2cc(CN)ccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C(C)(C)C)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 2-tert-butyl-5-(5-(aminomethyl)-2-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-75, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL), and dry THF (5 mL) to afford 0.180 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.08 (s, 9H), 1.49 (s, 9H), 4.24 (d, J=4.5 Hz, 2H), 7.32 (dd, J=4.5 Hz, 3.6 Hz, 2H), 7.43 (s, 1H), 7.50 (s, 1H), 8.14 (d, J=4.5 Hz, 1H); MS (m/z): 365.20 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:23][C@H:22]1[CH3:35])=[O:20])=[O:8].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:23][C@H:22]2[CH3:35])=[O:20])=[C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])[CH:15]=1
Reactant: COC(=O)CCNC(=O)Nc1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ureido]-propionic acid methyl ester (0.057 g, 0.11 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.023 g, 0.55 mmol). The reaction was stirred at ambient temperature overnight, concentrated in vacuo, taken up in methanol, passed through an ion exchange column and then treated with hydrogen chloride gas to give the title compound as its hydrochloride salt (0.035 g, LRMS: 507.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].O.[NH2:23][NH2:24].C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NN
Reactant: CCOC(=O)COc1ccc(C(=O)CCC(=O)O)cc1Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Temperature: 25 °C

Procedure:
1.58 g of 4-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl]-4-oxobutyric acid [prepared as described in step (a) above] was dissolved in 10 ml of ethanol and 0.31 g of 80% v/v aqueous hydrazine hydrate was added thereto, whilst ice-cooling. The mixture was stirred, with ice-cooling, for 5 minutes, and then heated under reflux for 3 hours, after which ethyl acetate was added thereto. The mixture was then cooled to room temperature and the resulting precipitate was recrystallized from a mixture of ethyl acetate and hexane, to give 1.49 g of the title compound, having the same characteristics as the product of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+]>C(#N)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Br)c(F)c(N)c1Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A stream of nitrogen was passed through a colorless mixture of methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate (2.8 g, 10 mmol) and 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (3.2 g, 13 mmol) in acetonitrile (CH3CN; 40 mL) and KF (1.7 g, 30 mmol) in H2O (20 mL) while heating to 50° C. (20-30 min). Dichloro-bis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2; 140 mg, 0.2 mmol) was added, and the mixture was heated to 65° C. The reaction was monitored by HPLC and was complete after 5 h. The reaction mixture was filtered hot through a short pad of Celite then was diluted with H2O (20 mL) and allowed to cool. The product was collected by filtration. The light tan solid was dried under vacuum to give methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (2.6 g, 72%): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:21])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc(N(C)C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)C=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(4-methoxyphenyl)-3-(4-dimethylaminophenyl)-1-oxo-prop-2-ene (14.1 g, 0.05 mol) was dispersed in methanol (100 ml). Sodium borohydride (5.6 g, 0.15 mol) was added slowly at ambient temperature under vigorous stirring. After completion of the addition of sodium borohydride the reaction mixture was kept stirred at ambient temperature for 5 hours. When the reaction was complete, the reaction mixture was poured into water (500 ml), and extracted with toluene. The toluene was removed using a rotary evaporator leaving an oily residue. The crude product was crystallized from methanol to give 1-(4-methoxyphenyl)-3-(4-dimethylaminophenyl)prop-2-en-1-ol as a white coloured solid in a yield of 4.0 g (28.3% of theory) with a melting point of 137-148° C.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1
Reactant: Clc1nccs1
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(Oc2nccs2)cc1
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
A mixture of 2-chlorothiazole (5.0 g), ethyl 2-(4-hydroxyphenyl)propionate (8.1 g), potassium carbonate powder (8.65 g) and dimethylformamide (80 ml) is stirred at 150°-155° C for 2.5 hours. The solvent is distilled out under reduced pressure. To the residue is added water and extracted with ether. The extract is washed with a 10% aqueous solution of sodium hydroxide and water and dried. The ether is evaporated. The residue is subjected to chromatography using silica gel and eluted with 50% benzene-hexane, benzene and 10% ether-benzene to yield ethyl 2-[4-(2-thiazolyloxy)phenyl]propionate (5.8 g.). IR νmaxCCl4 1740, 1240, 700 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:5][CH:4]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].[I-].[K+]>CN(C)C=O.O>[O:36]=[C:34]1[C:33]2[C:32](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31](=[O:41])[N:35]1[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:5][CH:4]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 57 %

Procedure:
4-(Chloromethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]benz amide (1.2 g) was dissolved in N,N-dimethylformamide (15 ml). To the solution, potassium phthalimide (0.95 g) and potassium iodide (0.09 g) were added and the mixture was stirred under heating at 60° C. for 2 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with tert-butyl methyl ether to obtain 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-methyl]-N-[2-ethyl-4-(1,1,1,2,3,3,3-hepta-fluoropropan-2-yl)-6-methylphenyl]-benzamide (0.85 g, yield 56%).