Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].CN(C)C1C=CC=CC=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:35](=[O:38])[CH:36]=[CH2:37])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(/C=C/c2ccc(OCCCCCCO)cc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Product: C=CC(=O)OCCCCCCOc1ccc(/C=C/c2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Yield: 71.3 %

Procedure:
A mixture of 4.38 g (12.8 mmole) of (E)-4-carboxy-4′-[6-hydroxyhexyloxy]stilbene (16), 1.87 g (15.4 mmole) of N,N-dimethylaniline, 1.38 g (15.4 mmole) of acryloyl chloride, 8 mg of 2,6-di-t-butyl-4-methylphenol and 9 ml of 1,4-dioxane was heated at 60° C. under a nitrogen atmosphere. After 3 hours the mixture was cooled and 10 ml of 1,4-dioxane were added. The product was collected on a filter and washed with 40 ml of ethanol. 3.6 g of product (71%) were obtained after drying over silica in a dessicator.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:17]2[O:16][C:15]([C:18](=[O:34])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH:26]C(OC(C)(C)C)=O)=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCC(O)=O)=CC=2C=1)=O>>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:18]([C:15]1[O:16][C:17]2[C:9]([O:8][CH2:7][C:6]([OH:35])=[O:5])=[CH:10][CH:11]=[CH:12][C:13]=2[CH:14]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)COc1cccc2cc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)oc12
Agent: Nc1ccccc1NC(=O)c1cc2cc(OCC(=O)O)ccc2s1
Product: Nc1ccccc1NC(=O)c1cc2cccc(OCC(=O)O)c2o1

Procedure:
was prepared from [2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-benzofuran-7-yloxy]-acetic acid tert-butyl ester (48) in an analogous manner to that described for the preparation of (45) example 19, step 2; mp.: 208–210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(N3CCOCC3)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C25H25N5O4, 459.2.
Reaction SMILES: CC(C)([O-])C.[K+].O[C@H]1C[C@H](C(OC)=O)[C@@H](C(N2CCN(C3C=CC=CC=3)CC2)=O)CC1.Cl.ClCC1C=NC=CC=1.[OH:41][NH2:42].[C:43]1([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C@H:57]3[CH2:62][CH2:61][C@@H:60]([O:63][CH2:64][C:65]4[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=4)[CH2:59][C@@H:58]3[C:71](OC)=[O:72])=[O:56])[CH2:51][CH2:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CO>O1CCCC1>[OH:41][NH:42][C:71]([C@H:58]1[CH2:59][C@H:60]([O:63][CH2:64][C:65]2[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=2)[CH2:61][CH2:62][C@@H:57]1[C:55]([N:52]1[CH2:53][CH2:54][N:49]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:50][CH2:51]1)=[O:56])=[O:72]
Reactant: COC(=O)[C@H]1C[C@H](OCc2cccnc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: COC(=O)[C@H]1C[C@H](O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)[C@H]1C[C@H](OCc2cccnc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 M of Potassium tert-butoxide in tetrahydrofuran (0.212 mL) was added to a mixture of methyl (1S,2S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate (36.8 mg, 0.000106 mol) and 3-chloromethylpyridine hydrochloride (17.4 mg, 0.106 mmol) in tetrahydrofuran (1.0 mL, 0.012 mol) at 0 Celsius. The mixture was stirred at room temperature for 1 hr then purified by HPLC. 1.5 M of hydroxyamine solution (0.7 ml) was added to a solution of methyl (1S,2S,5R)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-ylmethoxy)cyclohexanecarboxylate (0.075 mmol, 0.000075 mol) made above in methanol (0.5 mL, 0.01 mol). It was stirred at rt for 2 hrs then purified by Prep-HPLC.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][CH3:25])[C:18]3=[N:19][CH:20]=2)[O:12][N:11]=1)=[O:7].[H-].[Na+]>CN(C)C=O.O>[CH2:24]([N:21]1[C:18]2=[N:19][CH:20]=[C:15]([C:13]3[O:12][N:11]=[C:10]([CH2:9][N:8]4[CH2:2][CH2:3][CH2:4][CH2:5][C:6]4=[O:7])[N:14]=3)[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]2[CH:23]=[N:22]1)[CH3:25]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCCl)no3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN4CCCCC4=O)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Intermediate 120 (46 mg, 0.1 mmol) in dry dimethylformamide (2 ml) was added to sodium hydride (60% dispersion in mineral oil, 4.4 mg, 0.11 mmol), and the resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with water (2 ml) and extracted with chloroform (3×5 ml). The combined organic extracts were dried over anhydrous sodium sulphate and evaporated to give the crude product. Purification of the crude product on a SPE cartridge (silica, 2 g) using a gradient of ethyl acetate in petroleum ether afforded Example 174. LCMS showed MH+=426, TRET=2.66 min.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A solution containing the product from Example 46D (0.151 g, 0.403 mmol) in dichloromethane (3 mL) was treated with trifluoracetic acid (3 mL), and the mixture was stirred at 25° C. for 16 hours. The solvent was concentrated and the product was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.141 g, 81% yield) as the trifluoroacetic acid salt.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[F:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cc(F)ccc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cc(F)ccc3F)ccc12
Yield: 5 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (48 mg, 0.185 mmol), 2,5-difluorobenzylamine (0.026 mL, 0.222 mmol), Pd2(dba)3 (6 mg, 0.0066 mmol), rac-BINAP (21 mg, 0.021 mmol) and NaOtBu (45 mg, 0.468 mmol) in DMA (3 mL) was heated in a microwave at 90° C. for 5 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Column chromatography (Hex/EtOAc) afforded 4-chloro-6-(2,5-difluoro-benzylamino)-2H-phthalazin-1-one (3 mg) as an off white solid, 1H (400 MHz, CDCl3) δ: 4.46 (s, 2H), 6.90 (m, 2H), 7.00 (m, 3H), 8.10 (d, 1H), 10.09 (s, 1H) ppm; m/z (M+1) 321.98.
Reaction SMILES: C([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1)(=O)C.FC(F)(F)C(O)=O.[N-:23]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].C(=O)(O)[O-].[Na+].C(NC1C2C(=CC(OC)=CC=2)C=CC=1)(=O)C.CNC(C1C2C(=CC(OC)=CC=2)C=CC=1)=O.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[NH2:23][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Agent: CNC(=O)c1cccc2cc(OC)ccc12
Agent: COc1ccc2c(NC(C)=O)cccc2c1
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(N)ccc2c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A 2-necked 100 mL round bottom flask was charged with commercially available 2-acetyl-6-methoxynapthalene(5.0 g, 25 mmol) and trifluoroacetic acid (500 mmol, 38 mL) and fitted with a reflux condenser and a stopper. The solution was heated to 120° C. and sodium azide (3.25 g, 50 mml) was added over 30 minutes. Each addition resulted in a visible exotherm. Gas evolution ceased 30 minutes after complete addition of the azide. The reaction was cooled and poured into excess saturated aqueous sodium bicarbonate. The resulting mixture was extracted (2x, ethyl acetate). The combined organic extracts were washed (2x, brine), dried (Na2SO4), filtered and concentrated in vacuo to afford a light red solid which was a mixture (~5:1) of the respective N-acetyl-6-methoxynapthylamine and N-methylaminocarbonyl-6-methoxynapthalene. The mixture was carried on without purification. The unpurified solid (4.51 g, 20.9 mmol) was dissolved in hot ethanol (100 mL). Water (15 mL) and concentrated sulfuric acid (2.24 g, 41.9 mmol) were added and the reaction heated at reflux for 24 h during which time a thick precipitate formed. The reaction was cooled to 0° C. and the solid 2-amino-6-methoxynapthalene hydrogen sulfate salt was collected by filtration. The salt was neutralized by partitioning between aqueous sodium hydroxide(15.8 g, 0.396 mmol in 200 mL of water) and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate (2x). The organic layers were combined, washed (brine, 3x), dried (Na2SO4), filtered and concentrated in vacuo to afford a purple solid. Recrystallization from ethyl acetate and acetone gave the title compound in three fractions (2.64 g, 61%) as a light beige solid. mp 133°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O>CO.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(N)c1
Yield: 97 %

Procedure:
Methyl 4-hydroxy-3-nitrophenylacetate (52.2 g, 0.247 mol) was dissolved in methanol (400 ml) and the resultant solution was then hydrogenated at 5 bar over a 5% w/w palladium on carbon catalyst. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. Trituration with hexane gave methyl 3-amino-4-hydroxyphenylacetate (43.4 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:23])C=1.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[CH3:10][C:8]1[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]2[O:14][CH:2]([CH2:3][OH:23])[CH2:1][C:4]=2[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C)cc([N+](=O)[O-])c1O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c([N+](=O)[O-])c1)OC(CO)C2
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 2-allyl-4-methyl-6-nitrophenol (7b) (0.50 g, 2.5 mmol) and m-CPBA (0.64 g, 2.5 mmol) in CHCl3 (9 mL) was stirred for 6 h at 85° C. The mixture was poured into saturated NaHSO3 (20 mL), extracted with DCM (40 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (7c) as a solid. MS-ESI (m/z): 210 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>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.C1(C)C=CC=CC=1>[C:36]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1)(=[O:38])[CH3:37]
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a reaction vessel charged with 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (0.5 g, 1.05 mmol), tributyl-(1-ethoxy-vinyl)-stannane (0.49 g, 1.36 mmol), Pd (PPh3)4 (0.061 g, 0.053 mmol) and toluene (5 mL) is purged with N2 and heated to 100° C. for 2 h. After cooling down to room temperature, the solvent is removed under vacuum and the residue is treated with acetonitrile (10 mL) and 1 N HCl (40 mL) for 1 h. The mixture is then extracted with EtOAc (3×30 mL) and the combined organic layer is washed with saturated aqueous KF solution (20 mL). The resulted precipitate is removed by filtration and washed with EtOAc (2×10 mL). The organic layer is washed with brine and dried (MgSO4). After filtering off the drying agent, the solvent is removed under vacuum and the residue is purified by flash column chromatography (silica gel, 0%˜50% EtOAc/hexane) to provide the titled compound 6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (450 mg, 95%). HPLC-MS calculated for C25H17ClN4O2 (M+1+): 441.1. Found: 441.1.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[N:19]1([C:18]2[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CCNCC2)c(N2CCCC2)c1
Reaction time: 0.33 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-(1-pyrrolidinyl)-2-pyridinyl]piperazine (PREPARATION 16, 0.26 g) is dissolved in 1.3 ml of THF and cooled to 0°. Trifluoroacetic acid (1.3 ml) is added and the reaction is stirred at 0° for 20 min, and then warmed to 20°-25° for 20 min. Then the reaction is poured into 1N aqueous sodium hydroxide and extracted with methanol/chloroform (10/90, 2×50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.64, 6.81, 6.61, 3.05-2.94, 2.86-2.79 and 1.78-1.65 δ.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]=1O.C[Si](OP(=O)=O)(C)C>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:17][C:24]3[CH:23]=[CH:22][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:20][C:19]=3[N:18]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Agent: C[Si](C)(C)OP(=O)=O
Product: Cc1ccc(Cn2nc(-c3nc4cc(-c5ccccc5)ccc4o3)cc2C)cc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
A flask containing 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 5.0 g, 21.7 mmol), 3-aminobiphenyl-4-ol (4.0 g, 21.7 mmol) and trimethylsilyl polyphosphate (40 g) was heated at 180° C. for 30 min, and then the reaction mixture was poured into ice water (1 L). The mixture was stirred for 1 h and was extracted with dichloromethane (2 L). The layers were separated and the organic layer was washed with brine (2×1 L) and dried with sodium sulfate. The solvent was evaporated, and the residue was purified with an ISCO CombiFlash Companion using gradient elution from 100% hexane to 20% ethyl acetate in hexane to afford the title compound as a white solid (2.19 g, 27%): 1H NMR (300 MHz, CD2Cl2) 7.94 (d, 1H), 7.66 (m, 4H), 7.48 (t, 2H), 7.39 (m, 1H), 7.14 (dd, 4H), 6.82 (s, 1H), 5.37 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H); ES-MS m/z 380.2 (MH)+, HPLC RT (Method A) 4.25 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([O:37][CH3:38])[CH2:31][CH2:32][C:33](OC)=[O:34]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][CH:30]([O:37][CH3:38])[O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COC(=O)CCC(OC)OC
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: COC(CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)OC

Procedure:
The title compound, white solid (110 mg, 96%), MS (ISP) m/z=461.4 [(M+H)+], mp 204.5° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 4,4-dimethoxy-butanoate.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Cl-].[Na+].O.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.C(O)C>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:34]3[CH:33]=[C:32]([Br:31])[CH:37]=[CH:36][C:35]=3[O:41][CH3:42])[C@H:14]2[CH3:28])[CH:4]=[C:3]([C:2]([F:29])([F:30])[F:1])[CH:8]=1
Reactant: COc1ccc(Br)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(F)ccc1Br
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Br)cc1-c1ccc(F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (600 mg, 1.2 mmol), (5-bromo-2-methoxyphenyl)boronic acid (319 mg, 1.38 mmol), sodium carbonate aqueous solution (1.27 mL, 2M, 2.54 mmol), toluene (3.5 mL) and ethanol (400 μL) were mixed and stirred at room temperature for 45 minutes followed by addition of tetrakis(triphenylphosphine)palladium(0) (87 mg, 4.5 mol %). The resulting mixture was heated in a 90° C. oil bath for 24 hours to complete the reaction. The crude reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixtureaffording (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(5′-bromo-4-fluoro-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=607.04; found=607.98 (M+1)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>ClCCl>[CH2:26]([N:28]([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH2:29][CH2:30][OH:31])[CH3:27]
Reactant: CCNCCO
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(N(CC)CCO)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 31 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.40 g) and 2-(ethylamino)ethanol (0.64 g) in dichloromethane (12 ml) yielded the title compound, 137 mg, m.p. 141°-2° C. (recrystallised from isopropanol-ether).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12](=[O:35])[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][CH2:9][CH2:10][O:11][C:12](=[O:35])[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:32])([F:33])[F:34])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OCCO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
4.5 mg of 10% Pd/C was added to a methanol solution (5 ml) containing 44.9 mg (0.093 mmol) of 2-benzyloxyethyl[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]carbamate obtained in Example 130. The obtained mixture was intensively stirred under a hydrogen atmosphere at a room temperature for 2 hours 20 minutes. Thereafter, insoluble matters were removed by filtration, and the filtrate was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate), so as to obtain 33 mg (90%) of 2-hydroxyethyl[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]carbamate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CN1CCNCC1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)CC1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-Methyl piperazine (0.072 mmol). The mixture can be microwaved at 120 degrees. The reaction mixture can then be filtered through a syringe filter and can be purified by prep-HPLC.