Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[Li]C(C)(C)C.[C:36]1(=[O:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:36]3([OH:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: O=C1CCCCC1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cc(C3(O)CCCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (159 mg, 0.397 mmol, as prepared in Example 1, step (g)) in THF (15 mL) was placed under Ar, cooled to −78° C., and treated with i-PrMgCl (199 μL, 0.397 mmol). The mixture was warmed to RT, allowed to stir at that temperature for 10 min, cooled to −78° C., treated with t-BuLi (701 μL, 1.19 mmol), stirred at that temperature for 10 min, and then treated with cyclohexanone (411 μL, 3.97 mmol). The mixture was warmed to RT, stirred 1.5 h, quenched with satd aq NH4Cl (20 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane on a 20-g Isolute SPE column afforded 75.0 mg (45%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 12.11-11.91 (br s, 1H), 9.63 (s, 1H), 8.31 (d, 1H, J=8.4 Hz), 7.71 (s, 1H), 7.43 (dd, 1H, J=8.4, 2.0 Hz), 7.36 (d, 1H, J=2.0 Hz), 5.82-5.75 (m, 1H), 3.77-3.67 (m, 1H), 2.62-2.53 (m, 1H), 2.42-2.24 (m, 4H), 2.17-2.07 (m, 2H), 1.96-1.55 (m, 10H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H30NO2, 419.2 (M+H), found 419.1.
Reaction SMILES: [CH:1]1([C:4]2[N:22]=[C:7]3[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.CC(O)=O.[NH2:27][NH2:28]>CCO>[CH:1]1([C:4]2[N:22]=[C:7]3[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:12]4[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:27][N:28]=4)[N:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)C(C)CC(=O)O)n2nc(C3CC3)nc12
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)CC2C)n2nc(C3CC3)nc12

Procedure:
Under an argon atmosphere 4-(2-Cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3-methyl-4-oxo-butyric acid (0.1 g, ca. 0.33 mmol) was dissolved in EtOH (1.5 mL). AcOH (0.11 mL, 1.98 mmol) and NH2NH2*H2O (0.048 mL, 0.99 mmol) were added. The solution was heated at reflux for 17 h after which it was concentrated in vacuo and co-concentrated with toluene. Aq. NaHCO3 was added and the aqueous phase was extracted with ÉtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]C=O)=[CH:13][CH:12]=1.C(O)(=O)C>O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:7]2[O:6][C:4](=[O:5])[C:3](=[CH2:8])[CH2:2]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CCC=O)cc1
Reactant: C=C(CBr)C(=O)OC
Solvent: CC(=O)O
Solvent: O
Product: C=C1CC(CCc2ccc(OC)cc2)OC1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 54.6 %

Procedure:
To a suspension formed from metallic tin (730 mg, 6.15 mmoles), diethyl ether (12.5 ml) and water (3.1 ml) were added 1.10 g (6.15 mmoles) of methyl 2-bromomethyl-2-propenoate and 1.11 g (6.77 mmoles) of 3-(4-methoxyphenyl) propanal, with catalytic quantities of acetic acid. The mixture was kept warm at 50° C. with stirring for 9 hours. At the end of this time it was poured into water (200 ml) and an extraction was performed with diethyl ether (3×100 ml). The result was dried over anhydrous sodium sulphate and vacuum concentrated, giving an oil 780 mg (70% yield) of 5-[2-(4-methoxyphenyl)-ethyl]-3-metylene-dihydrofuran-2-one [(I), R═CH3; R1═H].
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]3[C:15]=2[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([NH:16][C:15]1[N:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:5]1[S:6][C:2]([C:28]#[C:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2cnccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 50 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
420 mg (1.2 mmol) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-tert-butyl-amine were dissolved together with 0.33 ml (3.0 mmol) of phenylacetylene, 42 mg (0.06 mmol) of bis(triphenylphosphine)-palladium(II) chloride and 22 mg (0.12 mmol) of copper(I) iodide in DMF (9 ml). After addition of 1.6 ml (12.0 mmol) of triethylamine, the mixture was stirred at 50° C. for 16 h. The reaction solution was then diluted with EA and combined with a sat. aq. sodium carbonate solution. The phases were separated and the aqueous phase extracted with EA. The combined organic phases were washed 2× with a sat. aq. sodium carbonate solution and 2× with a sat. aq. common salt solution and dried over magnesium sulfate. After filtration and removal of the solvents under a vacuum, column chromatography (EA/DCM 1:4) was carried out with the group, after which 326 mg (0.88 mmol, 73% of theoretical) of tert-butyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[CH2:12][C:11](=O)[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[CH:8][CH:9]=2)[O:4]1)[CH3:2].C1(C=CC=C(O)C=1)O.B(F)(F)F.CCOCC.C1C=CC2OCCC(=O)C=2C=1.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([Mg]Br)[CH:49]=[CH:50][CH:51]=1>>[CH2:1]([C:3]1([CH3:15])[CH:12]=[C:11]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([C:45]([F:55])([F:54])[F:44])[CH:51]=2)[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[CH:8][CH:9]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Agent: FB(F)F
Agent: O=C1CCOc2ccccc21
Agent: Oc1cccc(O)c1
Solvent: CCOCC
Product: CCC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1

Procedure:
2-Ethyl-7-hydroxy-2-methyl-4-chromanone, m.p. 109°-110.5° C., was prepared by condensing resorcinol with 3-methyl-2-pentanoic acid in the presence of boron trifluoride diethyl etherate. Reaction of the chromanone with 3-trifluromethylphenyl magnesium bromide as described in Preparation 5 gave the title chromene as a golden yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24]C)=[O:23])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([OH:24])=[O:23])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Yield: 102.3 %

Procedure:
A solution of methyl (E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-3,5-dihydroxy-hept-6-enoate (1.30 g, 3.47 mmoles) and aqueous NaOH (5.2 ml of a 1N solution) in 15 ml methanol was stirred for 30 minutes at 25° C., cooled to 0°-5° C., acidified, diluted with water and extracted with ethyl acetate. The organic layers were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo provided 1.28 g of the solid product which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]S([O-])(=O)=O.[Mg+2].[Na]>C(Cl)Cl.C(O)(=O)C.C1COCC1>[CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1
Reactant: CN(C)c1nncc2cc(C=O)ccc12
Reactant: Nc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)c1nncc2cc(CNc3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A mixture of 1-dimethylamino-phthalazine-6-carbaldehyde (25 mg, 0.13 mmol), aniline (14 μL, 0.15 mmol), THF (1 mL) and MgSO4 (43 mg, 0.357 mmol) were stirred at room temperature. To this mixture was added acetic acid (8 μL) followed by sodium cyanoboroahydride (13 mg, 0.207 mmol) and the reaction stirred for 15 h. The reaction was diluted with CH2Cl2, washed with aq. NaHCO3, dried (Na2SO4) and concentrated. Purification by prep. HPLC yielded the desired compound. m/z 279.22 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:26])[C@H:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:6][C:7](=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])C>CO>[C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][C@H:5]([C:4]([OH:26])=[O:3])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)NCCCCCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC
Solvent: CO
Product: C=CC(=O)NCCCCCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
0.72 g of the N-(6-acryloylaminocaproyl)phenylalanine ethyl ester obtained in Reference Example 13 was added to 50 ml of methanol containing 1 N sodium hydroxide, followed by stirring at room temperature for 4 hours. After the reaction, an H+ cation exchange resin, Dowex 50W (Dow Chemical Co.), was added for neutralization. The ion exchange resin was then filtered off, and the filtrate was evaporated to afford the target compound (0.65 g).
Reaction SMILES: FC(F)(F)C([O-])=O.[OH:8][CH:9]([CH2:37][OH:38])[CH2:10][O:11][C:12]([C:14]1[C:23](=[O:24])[C:22]2[C:17]3=[C:18]([O:33][CH2:34][C@H:35]([CH3:36])[N:16]3[CH:15]=1)[C:19]([N:26]1[CH2:31][CH2:30][NH+:29]([CH3:32])[CH2:28][CH2:27]1)=[C:20]([F:25])[CH:21]=2)=[O:13].[OH-].[Na+]>CO>[F:25][C:20]1[CH:21]=[C:22]2[C:17]3=[C:18]([O:33][CH2:34][CH:35]([CH3:36])[N:16]3[CH:15]=[C:14]([C:12]([O:11][CH2:10][C@@H:9]([OH:8])[CH2:37][OH:38])=[O:13])[C:23]2=[O:24])[C:19]=1[N:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: C[C@H]1COc2c(N3CC[NH+](C)CC3)c(F)cc3c(=O)c(C(=O)OCC(O)CO)cn1c23
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC[C@@H](O)CO)cn1c23
Temperature: 0 °C
Yield: 88.3 %

Procedure:
(S)-4-(6-((2,3-dihydroxypropoxy)carbonyl)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-10-yl)-1-methylpiperazin-1-ium 2,2,2-trifluoroacetate (0.50 g, 0.91 mmol) was dissolved in methanol under argon and cooled to 0° C. (ice/salt bath). 1 equiv. of NaOH dissolved in methanol (25 ml) was added slowly until the solution reached pH 7-pH 8. The reaction mixture was passed through a plug of Al2O3 (10% MeOH in CHCl3). The organic solvent was removed under reduced pressure giving a yellow solid (0.35 g, 88%)
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](N)=[C:4]([O:10][CH3:11])[CH:3]=1.N([O-])=O.[Na+].S(=O)(=O)(O)O.[BrH:21]>C(OCC)(=O)C>[Br:21][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11]
Reactant: COc1cc(F)c(C)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C)cc1Br
Temperature: 110 °C
Yield: 47 %

Procedure:
A suspension of 4-fluoro-2-methoxy-5-methyl-phenylamine (25.75 g, 0.17 mol) in 180 mL of HBr (48%, 0.9 M) in an ice bath was treated dropwise with an aq solution of sodium nitrite (12.6 g, 0.18 mol, 3.6 M). A brown gas was evolved and the temperature of the reaction was monitored so that the internal temperature did not raise above 10° C. In the meantime, a suspension of CuBr (13.1 g, 0.09 mol) in 6.5 mL of HBr (48%, 13.9 M) was heated to 110° C. Next, the solution at 0° C. was slowly poured (over a period of 20 minutes) into the stirring CuBr suspension. The combined reaction mixture was heated for 2.5 h at 110° C. After cooling to room temperature, the solution was diluted with ethyl acetate and treated with aq sulfuric acid ( 50% v/v). The organic layer was separated and was washed successively with water, sulfuric acid, water, 1.25 M NaOH, water, and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified via silica gel flash chromatography (5% ethyl acetate in heptane) to afford 1-bromo-4-fluoro-2-methoxy-5-methyl-benzene (17.1 g, 47%) as a clear liquid: Rf 0.70 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.34 (d, J=8.4 Hz, 1H), 6.61 (d, J=10.8 Hz, 1H), 3.85 (s, 3H), 2.18 (d, J=1.8 Hz, 3H); Anal. calcd for C8H8BrFO: C, 43.86. ; H, 3.68; Br, 36.48. Found C, 44.01; H, 3.68; Br, 36.57.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.[Cl-].[Cl-].C1(P)C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.N>O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]1[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=C(Nc1cn[nH]c1-c1ccc(F)cc1)c1c(F)cccc1F
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: Pc1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)c(-c1c(F)cccc1F)nc1cn[nH]c12
Temperature: 165 °C
Yield: 27.7 %

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 2.6 g of 2,6-difluoro-N-[5′(4-fluorophenyl)-1H-pyrazol-4-yl]benzamide, 60 ml of phenylphosphine dichloride and 17.5 g of phosphorus pentoxide. After 23 h of heating at 165° C., the mixture is cooled to RT and then poured into a mixture of 260 ml of water and 400 g of ice. The temperature rises to 40° C. The mixture is neutralized by slow addition of 120 ml of 28% aqueous ammonia. It is extracted with AcOEt, washed with saturated NaCl solution and dried over MgSO4, then concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (99/1 by vol.), to give 680 mg of 5-(2,6-difluorophenyl)-7-fluoro-1H-pyrazolo[4,3-c]isoquinoline (cream solid). MS (E/I): m/z=299 (M+); 1H NMR: 7.34 (t, J=7.8 Hz, 2 H) 7.38 (broad m, 1 H) 7.70 (m, 1 H) 7.96 (broad t, J=9.1 Hz, 1 H) 8.48 (broad s, 1 H) 8.63 (dd, J=9.1, 5.6 Hz, 1 H) 14.29 (broad s, 1 H).
Reaction SMILES: C([O:8][C:9]([C@H:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:46])[NH:21][CH2:22][C:23]([N:25]2[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:28]([C:36]([OH:38])=[O:37])[S:27][C@H:26]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:24])[CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:10])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[C:42]([O:41][C:39]([C@H:26]1[N:25]([C:23](=[O:24])[CH2:22][NH:21][C:20](=[O:46])[NH:19][C:15]2[CH:14]=[C:13]([CH:11]([CH3:12])[C:9]([OH:10])=[O:8])[CH:18]=[CH:17][CH:16]=2)[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:28]([C:36]([OH:38])=[O:37])[S:27]1)=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: C[C@H](C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@H](C(=O)OC(C)(C)C)S[C@@H](C(=O)O)[C@@H]2c2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(NC(=O)NCC(=O)N2[C@H](C(=O)OC(C)(C)C)S[C@@H](C(=O)O)[C@@H]2c2ccccc2)c1
Yield: 42.1 %

Procedure:
The process is performed as in Example 4, but starting with 0.58 g of (2S,4S,5R)-3-{2-{3-[(S)-3-(1-benzyloxycarbonylethyl)phenyl]ureido}acetyl}-2-tert-butoxycarbonyl-4-phenyl-5-thiazolidinecarboxylic acid, 0.34 g of ammonium formate and 0.6 g of 10% palladium-on-charcoal. 0.21 g of 2-{3-{3-[2-((2S,4S,5R)-2-tert-butoxycarbonyl-5-carboxy-4-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenyl}propionic acid is thus obtained in the form of a white solid melting at 142° C., [α]D25 =+24.5°±0.6° (c=1.01; MeOH); 1H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, δ in ppm): 1.41 (d, J=7 Hz, 3H: CH3); 1.51 (s, 9H: CH3 of the tert-butyl); 3.62 (q, J=7 Hz, 1H: CHCOO); 3.66 and 4.05 (broad d and d respectively, J=17.5 Hz, 1H each: COCH2 N); 4.18 (d, J=4 Hz, 1H: H at C5 of the ring); 5.72 (s, 1H: H at C2 of the ring); 5.77 (d, J=4 Hz, 1H: H at C4 of the ring); 6.86 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH)); 7.17 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH); from 7.20 to 7.50 (mt, 5H: aromatic H); 7.73 (dd, J=7.5 and 1.5 Hz, 2H: H ortho to the phenyl).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[CH:5]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]4)=O)=[CH:23][CH:22]=3)[CH:20]=2)[CH:3]=1.C(N1CCN(CC2C=CC(B(O)O)=CC=2)CC1)(C)C>>[CH:35]([N:32]1[CH2:31][CH2:30][N:29]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[CH:20]=[C:15]([C:4]4[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=5)[CH:5]=4)[CH:16]=[N:17][CH:18]=3)=[CH:26][CH:25]=2)[CH2:34][CH2:33]1)([CH3:37])[CH3:36]
Reactant: Cc1cccc(-c2cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)cc(O)n2)n1
Agent: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Product: Cc1cccc(-c2cc(-c3cncc(-c4ccc(CN5CCN(C(C)C)CC5)cc4)c3)cc(O)n2)n1

Procedure:
is prepared analogously to [4-(6′-Hydroxy-6-methyl-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone (Example 2.109) by replacing (4-isopropyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 4-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B3).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14](=[O:26])[NH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:17][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:29][C:30]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31]>CN(C=O)C>[CH2:3]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14](=[O:26])[N:15]([CH2:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:17][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CI)NCCc1ccccc1
Reactant: O=C(Nc1ccc(-c2ccccc2Cl)[nH]c1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccccc2Cl)ccc(NC(=O)OCc2ccccc2)c1=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a suspension of NaH (60% in mineral oil, 287 mg, 7.17 mmol, 1.2 eq.) in anhydrous DMF (12 mL) is added [6-(2-chloro-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-carbamic acid benzyl ester (15A) (Bernstein, P. R. et. al., J. Med. Chem., vol. 37, p 3313-3326 (1994)) (2.121 g, 5.98 mmol). After being stirred for 30 minutes, the orange solution is cooled to 0° C. and 2-iodo-N-phenethyl-acetamide (1.902 g, 6.58 mmol, 1.1 eq.) is added. The mixture is stirred at room temperature for 3 hours and is quenched with 1 N HCl (8 mL), extracted with ethyl acetate (3×). The organic layer is washed in sequence with 1 N HCl, saturated Na2S2O3, water and brine; is dried over anhydrous Na2SO4 and concentrated. The residue is purified via silica gel chromatography (2-10% ethyl acetate in dichloromethane) to provide compound 15B as a yellow solid (605 mg, 20%):
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCCCOc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
3-(4-Fluorophenoxy)propanol (7.55 g, 44 mmol) was stirred in 50 mL of pyridine under a nitrogen atmosphere at 5° C. p-Toluenesulfonyl chloride (9.2 g, 50 mmol) was added in one portion and the resulting solution was allowed to stir at 5° C. for 1 hour and then was placed in a refrigerator set at 5° C. overnight. The reaction was then poured into about 300 mL of ice water. This mixture was extracted three times with diethyl ether. The combined extracts were washed 2 times with cold 1N hydrochloric acid and once with cold water. The extracts were then dried over sodium sulfate/potassium carbonate, filtered, and concentrated to give 13.24 g of a solid product. Yield: 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: COc1cc(OC)c(C=O)c(-c2cccs2)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)c(-c2cccs2)c1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-6-thiophen-2-yl-benzaldehyde (Ex-39A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 61% yield, mp 231° C. (dec.). 1H-NMR (DMSO-d6) δ 8.02 (d, 2H), 7.93 (d, 2H), 7.73 (m, 3H), 7.15 (t, 1H), 7.07 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H). MS m/z=394 ([M]+, 6%), 245 (100%). HRMS m/z: calc. 395.0953, found 395.0949.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[C:23]4[C:22](=[O:24])[N:21]([CH:25]5[CH2:27][CH2:26]5)[C:20](=[O:28])[N:19]([C:29]5[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=5[F:36])[C:18]=4[N:17]([CH3:37])[C:16](=[O:38])[C:15]=3[CH3:39])[CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:14]4=[C:15]([CH3:39])[C:16](=[O:38])[N:17]([CH3:37])[C:18]([NH:19][C:29]5[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=5[F:36])=[C:23]4[C:22](=[O:24])[N:21]([CH:25]4[CH2:27][CH2:26]4)[C:20]3=[O:28])[CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1c(Nc2cccc(C(=O)N3CCC3)c2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)n(C3CC3)c(=O)n(-c3cccc(C(=O)N4CCC4)c3)c12
Reaction time: 1 h
Yield: 82.5 %

Procedure:
5-((3-(azetidine-1-carbonyl)phenyl)amino)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4b) (0.11 g, 0.17 mmol) was taken in tetrahydrofuran (3 ml) at room temperature, sodium methoxide (25% in MeOH, 371 mg, 1.71 mmol) was added and the reaction mixture was stirred at the same temperature for 1 hr under nitrogen atmosphere. The progress of the reaction was monitored by HPLC. After complete consumption of the substrate, the reaction mixture was diluted with HCl (2 mL, 2 N) and concentrated under vacuum. To the residue DCM (20 ml) was added, the organic layer was dried over sodium sulphate and concentrated under vacuum to give the crude compound which was purified by column chromatography to give the title product (0.09 g).