Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:10][C@@H:4]2[CH2:3]1.Br[C:24]1[CH:29]=[N:28][C:27]([CH:30]2[CH2:32][CH2:31]2)=[CH:26][N:25]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH:30]1([C:27]2[N:28]=[CH:29][C:24]([O:1][C@@H:2]3[CH2:22][N:5]4[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][N:12]=5)[CH2:10][C@@H:4]4[CH2:3]3)=[N:25][CH:26]=2)[CH2:32][CH2:31]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](O)CN12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To (8S,9aS)-8-hydroxy-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (74 mg, 0.235 mmol, Part D), 2-bromo-5-cyclopropylpyrazine (79 mg, 0.4 mmol) in tetrahydrofuran (1.2 mL) was added potassium tert-butoxide (0.47 ml, 0.47 mmol, 1 M in tetrahydrofuran). The mixture was stirred at room temperature overnight. The mixture was purified by chromatography on silica gel (ethyl acetate) to give 48 mg (47%) of the titled compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.88-1.04 (m, 4H), 2.00 (m, 1 H), 2.15 (br d, J=14 Hz, 1 H), 2.66 (m, 1 H), 2.72 (m, 2 H), 3.36 (dd, J=14, 10 Hz, 1 H), 3.48 (m, 1 H), 3.83 (dd, J=12, 8 Hz, 1 H), 3.90 (br d, J=12 Hz, 1 H), 4.03 (m, 1H), 4.34 (br d, J=15 Hz, 1 H), 4.63 (d, J=14 Hz, 1 H), 5.44 (m, 1H), 6.65 (d, J=9 Hz, 1 H), 7.66 (dd, J=9, 2 Hz, 1 H), 7.95 (s, 1 H), 8.06 (s, 1 H), 8.41 (s, 1H); MS (ESI) m/z 434.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[CH:14]=2)=[C:8]([CH3:29])[CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[C:32]([O:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:29])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH:25]=[O:26])=[CH:27][CH:28]=3)[CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(C)(C)CCOc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-{[4′-(3-hydroxy-3-methylbutoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}benzaldehyde, acetic anhydride, pyridine, DMAP and chloroform was stirred at room temperature for 2 days to obtain 3-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)-1,1-dimethylpropyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])[C:8]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)=[N:9]2)=[CH:4][C:3]=1[C:27]([O:29]C)=[O:28].[OH-].[Na+].O>CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])[C:8]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)=[N:9]2)=[CH:4][C:3]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4[nH]ncc4c3)nc2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)c(O)cc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of (S)-methyl 7-hydroxy-2-(1H-indazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.30 mmol) in methanol (10 ml) was added NaOH (48 mg, 1.27 mmol) and water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-7-hydroxy-2-(1H-indazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (65.6 mg, 56%).
Reaction SMILES: C(O)[C:2](N)([CH2:5][OH:6])[CH2:3][OH:4].[O:9]=[CH:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12]>>[CH2:19]([OH:20])[C@H:17]1[O:18][C@H:10]([O:9][C@:2]2([CH2:3][OH:4])[O:12][C@H:11]([CH2:13][OH:14])[C@@H:10]([OH:9])[C@@H:5]2[OH:6])[C@H:11]([OH:12])[C@@H:13]([OH:14])[C@@H:15]1[OH:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(CO)(CO)CO
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
NAC and THAM were first granulated separately in mixtures with gum arabic and dextrose. The granulates were dried and then mixed together with saccharin, saccharose and flavour and then distributed into the bags.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CN1CCc2cccc(Cl)c2CC1
Agent: O=S(=O)(O)O
Product: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 67.2 g (0.34 mol, U.S. Pat. No. 4,265,890) of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 100 ml of sulfuric acid was added, dropwise over 2 hours, 40 ml of concentrated nitric acid. The mixture was stirred at room temperature overnight and quenched in ice. It was made basic with 10% sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed, dried and evaporated to leave a residue, which was chromatographed over a "Waters prep 500" high pressure liquid chromatographic silica gel column, using isopropanol-hexanediethylamine, to give pure 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH:13]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C@H:13]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCCCN1CC(C(=O)OCC)C(N)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCCCCN1C[C@@H](C(=O)OCC)[C@@H](NC(=O)Nc2ccc(Cl)cc2)C1=O
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of 4-chlorophenyl isocyanate (113 mg, 0.734 mmol) in CH2Cl2 (1 ml) was added the aminopyrrolidinone of Example R (178 mg, 0.734 mmol) in CH2Cl2 (1ml). After stirring for 18 h, the solvent was removed in vacuo and the resulting mixture was chromatographed on silica gel (5% EtOH/CH2Cl2) to give the title compound (210 mg, 72%). 'H NMR (300 MHz, CDCl3) δ7.99 (1H, s), 7.42 (2H, d), 7.24 (2H, t), 6.21 (1H, d), 4.92 (1H, q), 4.21 (1H, m), 4.11 (1H, m), 3.55 (2H, q), 3 32 (2H, m), 1.55 (2H, q), 1.29 (4H, m), 1.21 (2H, t), 0.89 (3H, t).
Reaction SMILES: [Na].[C:2]([NH:4][C:5]([CH:9]1[CH2:11][CH2:10]1)=[N:6][C:7]#[N:8])#[N:3].[ClH:12].CCCCCC>CC(=O)CC>[NH2:8][C:7]1[N:3]=[C:2]([Cl:12])[N:4]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:6]=1
Reactant: N#CN=C(NC#N)C1CC1
Reactant: Cl
Agent: [Na]
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: Nc1nc(Cl)nc(C2CC2)n1
Temperature: 10 °C

Procedure:
33 g of the sodium salt of N,N'-dicyano-cyclopropanecarbamidine (crude product) is suspended in 100 ml butanone. A solution of 20 g HCl in 400 ml butanone is dropped under stirring into this solution at 10° C. After the addition has been completed it is stirred for 1 h at ambient temperature. The reaction mixture is concentrated by evaporation and 200 ml of saturated aqueous NaHCO3 -solution and 300 ml diethylether are added. The organic phase is separated, washed, dried and concentrated by evaporation. One isolates 21 g of crude product which is treated with hexane to leave the pure title product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:28]=1[CH2:29]Br>C1COCC1.CS(C)=O>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:29][C:28]2[C:31]([C:35]([F:36])([F:38])[F:37])=[CH:32][CH:33]=[CH:34][C:27]=2[F:26])[N:18]=1)=[O:15]
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1Cl
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-chloro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 45)(22 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (26 mg, 0.1 mmol, Aldrich) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+=398, tRET=2.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[C:8]2=O)=[CH:4][C:3]=1[S:26]([NH2:29])(=[O:28])=[O:27].[Sn].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH2:8]2)=[CH:4][C:3]=1[S:26]([NH2:29])(=[O:28])=[O:27]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccccc3)CC1)C2=O
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: NS(=O)(=O)c1cc2c(cc1Cl)CN(C1CCN(Cc3ccccc3)CC1)C2=O

Procedure:
A mixture of the above part (a) 1,3-dioxoisoindole (4.4 g., 0.01 mole), and 30 mesh granulated tin (2.8 g., 0.024 mole) in 20 ml. of methanol and 12 ml. of concentrated hydrochloric acid was heated at 75°-80° for a 8 hr. period. Additional 1 g. portions of tin were added at the end of 5 hr. and 6 hr., respectively. After cooling, the reaction mixture was diluted with 40 ml. of methanol, heated to reflux and filtered through infusorial earth to remove unreacted tin. The filter-cake was washed with methanol and combined filtrates concentrated under reduced pressure. Residual oil slurried with warm methanol provided 1 g. of solid and cooling of the methanol decant an additional 2.1 g. of solid. The combined crude product was further purified by stirring with 65 ml. of 0.077N hydrochloric acid while slowly introducing a gaseous stream of hydrogen sulfide (H2S) during a 2.0 hr. period. Excess H2S was removed under reduced pressure, the mixture filtered through infursorial earth and the filter-cake extracted with warm methanol. Cooling the methanol filtrates provided 2.2 g. of product which crystallized from methanol-water gave analytically pure 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide hydrochloride as the monohydrate, m.p. 282°-284°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[O:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:43][C:39]3[O:38][CH:42]=[CH:41][N:40]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: Nc1ncco1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ncco3)ccc21
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB, 40.69 mg, 0.074 mmol), oxazole-2-amine (9.32 mg, 0.11 mmol, Ryan Scientific, Mt. Pleasant, S.C.) and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (155 μl, 0.155 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the flask was lowered into an ice bath for 1 h. Additional portions of oxazole-2-amine (ca. 5 mg) and LHMDS solution (0.05 mL) were added in sequence. After an additional 45 min, glacial acetic acid (1 drop) was added. The mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (br. s., 1 H), 8.38 (d, J=2.1 Hz, 1 H), 8.05 (dd, J=1.8, 8.8 Hz, 1 H), 7.71 (d, J=8.6 Hz, 1 H), 7.59 (d, J=1.7 Hz, 1 H), 7.31 (d, J=2.1 Hz, 1 H), 7.26-7.17 (m, 2 H), 6.80 (d, J=8.5 Hz, 1 H), 4.36-4.27 (m, 2 H), 3.87-3.82 (m, 2 H). m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[NH:24][N:39]=[C:25]3[S:26]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A suspension of 4-[4-amino-3-(1-naphthylsulfonylmethyl)phenoxy]piperidin-1-ylcarboxylic acid benzyl ester (3.2 g, 6.0 mmol) in ethanol and 1.0 N HCl (155 mL) was heated to aid dissolution, treated slowly with sodium nitrite (0.67 g, 9.7 mmol) in water, stirred at ambient temperatures for one hour, basified with solid sodium carbonate, stirred at ambient temperature for 1 hour and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and brine. The phases were separated; the organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. This residue was purified by flash chromatography with 35-40% ethyl acetate in hexane and 100% ethyl acetate to give 4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yloxy]piperidin-1-ylcarboxylic acid benzyl ester as a light orange foam, 1.79 g (55.9% yield), Mass spectrum (+EI, [M+H]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): δ14.07 (s, 1H), 8.71-8.73 (m, 1H), 8.55 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.26 (d, 1H, J=8.29 Hz), 8.01-8.03 (m, 1H), 7.70-7.74 (m, 1H), 7.51-7.62 (m, 3H), 7.27-7.35 (m, 5H), 7.23 (d, 1H, J=2.20 Hz), 7.09 (dd, 1H, J=9.03 Hz and 2.32 Hz), 5.06 (s, 2H), 4.59-4.61 (m, 1H), 3.63-3.72 (m, 2H), 3.29-3.33 (m, 2H), 1.83-1.88 (m, 2H), 1.50-1.55 ppm (m, 2H
Reaction SMILES: [K].[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1.[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[F:2][C:3]([F:20])([F:21])[C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH2:22][CH2:23][CH2:24][CH3:25])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: CCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1

Procedure:
In anhydrous dimethyl formamide was dissolved 3.2 g. of potassium salt of N-(3-trifluoromethylphenyl)anthranilic acid. To the solution was added 5.0 g. of n-butyl bromide. The mixture was heated at 100°-120° C. for 5 hrs. while stirring. The precipitated potassium bromide was taken out by filtration. The filtrate was concentrated and the residue obtained was distilled to obtain 3.1 g. of light yellow liquid having a boiling point of 190°-192° C. (5 mmHg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: Cn1cccc1CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: Cn1cccc1CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-nitrobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:31]=4)=[CH:24][C:23]=3[CH:36]=1)[N:13]=[C:12]2[C:37]([NH2:39])=[O:38])C1C=CC=CC=1>ClCCl>[C:32]([C:30]1[N:31]=[C:27]([C:25]2[O:26][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:14]4[C:15]5[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=5)[C:12]([C:37]([NH2:39])=[O:38])=[N:13]4)=[CH:36][C:23]=3[CH:24]=2)[S:28][CH:29]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4nc(C(N)=O)c5cc(OCc6ccccc6)ccc54)ccc3o2)n1
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4nc(C(N)=O)c5cc(O)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
5-Benzyloxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-1H-indazole-3-carboxamide (0.122 g) was added to a solution (1 M) of borontribromide in dichloromethane (0.57 ml) under ice-cooling and then the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxy-1H-indazole-3-carboxamide (0.08 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH:10]1[C:14]2([CH2:16][CH2:15]2)[CH2:13][N:12](CC2C=CC=CC=2)[CH2:11]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH:10]1[C:14]2([CH2:15][CH2:16]2)[CH2:13][NH:12][CH2:11]1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(NC(=O)OC(C)(C)C)C1CN(Cc2ccccc2)CC12CC2
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C1CNCC12CC2

Procedure:
A solution of [1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethyl]carbamic acid tert-butyl ester (Example A4a, 1.47 g) in methanol (30 mL) in a Parr shaker is treated with 10% palladium on carbon (0.5 g) and hydrogen introduced (50 psi) for 24 hours. The reaction mixture is filtered through celite, washed with methanol, and the combined filtrate concentrated in vacuo to afford the title compound. MS CI: m/z 241 (MH+).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C@H:18]([OH:23])[CH2:19][C:20](=[O:22])[CH3:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:35]2[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=2)[N:29]=[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])[N:27]=1.C(N(CC)CC)C>[Pd].CO>[OH:23][C@H:18]([CH2:19][C:20](=[O:22])[CH3:21])[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:35]3[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[N:27]=2)[CH2:16][CH2:15]1)=[O:24]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of 4-((R)-2-hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylic acid benzyl ester (0.13 g, 0.39 mmol) and MeOH (4 mL) was stirred with 10 mg of Pd/C (10% wt Pd on carbon) under H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent, the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.11 g, 0.39 mmol) and triethylamine (0.11 mL, 0.78 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentane-1,4-dione as a yellow solid (91 mg, 54%). LC/MS: m/z 435.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])[N:13]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: CN(C)CCNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Yield: 84 %

Procedure:
The product of Example 47, and N,N-dimethylethylenediamine were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (396 mg, 84% yield). 1H-NMR (CDCl3) δ 2.02-2.34 (m, 8H), 3.05 (m, 2H), 6.02 (br s, 1H), 6.39 (d, 1H, J=9.8 Hz), 7.24-7.62 (m, 9H). LC MS (m/e)=455 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[O:33][C:34]=1[CH3:35].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Reactant: Cc1oc(-c2cccs2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl]-1H-pyrazol-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 58.0 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-(2-thienyl)oxazole (310 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-methoxy-4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (500 mg, yield: 66%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).