Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[O:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>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.C1COCC1>[O:27]1[CH2:28][CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:31][CH2:32]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: [K+]
Solvent: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(C3=CCOCC3)cc12
Reaction time: 5 h

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), pd(ph3p)4 (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid. Step 2: A vial was charged with (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (68.1 mg, 0.166 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg, 0.498 mmol), tetrakis(triphenylphosphine)palladium (19.18 mg, 0.017 mmol), THF (830 μL), and potassium carbonate (415 μL, 0.830 mmol) (as a 2.0 M aq. solution). The vial was sealed and placed in a 110° C. for 5 hours. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:20]1([C:26]([CH2:34][CH2:35][CH3:36])([CH2:30][C:31](O)=[O:32])[C:27](O)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:1]3[C:31](=[O:32])[CH2:30][C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([CH2:34][CH2:35][CH3:36])[C:27]3=[O:28])[CH:19]=[CH:18][CH:17]=2)=[N:7][NH:8]1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: CCCC(CC(=O)O)(C(=O)O)c1ccccc1
Solvent: CO
Product: CCCC1(c2ccccc2)CC(=O)N(c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)C1=O
Temperature: 200 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1) and 2-phenyl-2-propylsuccinic acid (0.094 g, 0.4 mmol) was heated at 200° C. for 1.5 hours then it was allowed to stand at ambient temperature for 18 hours. Methanol (1 ml) was added, the mixture was heated under reflux for 5 minutes, then it was filtered and the collected solid was washed with hot methanol (3 ml). The combined filtrate and washings were concentrated in vacuo and the residue was triturated with water (5 ml). The resulting solid was collected by filtration and dried in vacuo to give 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-phenyl-3-propylpyrrolidine-2,5-dione (0.061 g) as a beige solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.95 (t, 3H) (CH3), 1.25 (m, 2H) (—CH2CH2CH3), 2.1 (m, 2H) (—CH2CH2CH3), 3.3 (d, 2H) (ring CH2), 4.4 (s, 2H) (ArCH2—), 7.2 (d, 1H) (ArH), 7.3–7.65 (m, 8H) (8×ArH), 7.85–8.1 (m, 3H) (3×ArH), 8.35 (d, 1H) (ArH), 12.7 (s, 1H) (CONH); m/z (M+H)+. 452, 93.6% purity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>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.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 54.4 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), (4-trifluoromethyl-phenyl)boronic acid (18.1 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), and tetrakis(triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (25 mg, 0.049 mmol, 55% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1H), 12.95 (s, 1H), 10.15 (t, J=6.06 Hz, 1H), 7.93 (d, J=8.08 Hz, 2H), 7.83 (d, J=8.59 Hz, 2H), 7.67 (dd, J=11.37, 1.77 Hz, 1H), 7.58 (dd, J=7.96, 1.89 Hz, 1H), 7.39 (t, J=7.96 Hz, 1 H), 5.36 (s, 2 H), 4.09 (d, J=5.56 Hz, 2H), 3.19 (m, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 508 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]2[N:27]=[CH:26][N:25](C3CCCCO3)[N:24]=2)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][NH:17][C:11]3=[N:10][CH:9]=2)[CH:7]=1>Cl.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[C:3]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][NH:17][C:11]3=[N:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(-c2nc[nH]n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Yield: 46.4 %

Procedure:
A solution of 7-(5-fluoro-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (200 mg, 0.44 mmol) in methanolic hydrochloride solution (20 mL, 2 M) was stirred for 5 h at room temperature. The reaction was diluted with saturated aqueous sodium bicarbonate solution (25 mL) and the aqueous mixture was extracted with ethyl acetate (25 mL×2). The organic phase was dried over sodium sulfate, filtered, evaporated under reduced pressure and purified on silica gel column (50-100% ethyl acetate in petroleum ether). The desired fractions were combined and concentrated under reduced pressure to give the title compound (75 mg, 46% yield). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 14.25 (br. s., 1H), 8.20 (br. s., 1H), 7.90 (m, 2H), 7.58 (s, 1H), 7.35 (s, 1H), 5.24 (m, 1H), 4.10 (s, 2H), 2.43 (s, 3H), 1.44 (d, J=7.2, 6H); MS (ESI) m/z 368.2 [M+1]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:7]2=1>>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:7]2=1
Reactant: COC(=O)c1cc2c3cc(C)ccc3n(C)c2s1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc2c(c1)c1cc(C(=O)O)sc1n2C
Yield: 100 %

Procedure:
Prepared from KOH (0.40 g), (52) (0.33 g) yielding (55) 0.312 g (100%). M.p. 216°-219° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]\[O:6][CH3:7].Br.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N\OC)c1ccccc1Oc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
(Z)-N-Methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (570 mg, 2 mmol) was dissolved in toluene (10 ml). Hydrobromic acid (47%, 0.52 g) was addd, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate (50 ml) was added for neutralization. The resulting mixture was extracted with methylene chloride (130 ml), washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (564 mg, Yield: 98.9%, E/Z=96/4).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].O.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([CH3:21])[C@@H:22]([C:23](=[O:25])[NH:47][CH2:46][C:45]([F:49])([F:48])[F:44])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: NCC(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.18 g, 11.4 mmol) was added to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (3.0 g, 11.4 mmol) and 1-hydroxybenzotriazole hydrate (1.54 g, 11.4 mmol) in N,N-dimethylformamide (2 ml) and dichloromethane (4 ml). The reaction mixture was stirred for 15 min at 0° C. 2,2,2-Trifluoroethylamine (0.91 ml, 11.4 mmol) and ethyldiisopropylamine (2.0 ml, 11.39 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (200 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silcia (240 g), using ethyl acetate/heptane 1:2 as eluent, to give 3.52 g of N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]([CH3:55])[O:29][C:30]1[CH:31]=[C:32]([CH:41]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[CH:47][CH:46]=2)[CH:43]=1)[C:33]([NH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=[O:34])(C(C)(C)C)(C)C>C1COCC1.C(OCC)C.Cl>[OH:26][CH2:27][C@H:28]([CH3:55])[O:29][C:30]1[CH:31]=[C:32]([CH:41]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:52])=[O:53])=[CH:47][CH:46]=2)[CH:43]=1)[C:33]([NH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=[O:34]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2nccs2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2nccs2)c1
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Tetra-n-butyl ammonium fluoride (1.0M in THF, 0.832 mL, 0.832 mmol) was added to a solution of 3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (425 mg, 0.756 mmol) in THF (5 mL) and the reaction stirred for 1.5 h. A further portion of tetra-n-butyl ammonium fluoride (0.83 mL) in THF was added and the reaction was stirred for a further 1.5 h. The reaction was then diluted with diethyl ether (40 mL) and 1M aqueous hydrochloric acid (20 mL) and the aqueous layer was re-extracted with diethyl ether (20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 50% to 100% ethyl acetate in hexanes, afforded the title compound as a foam (200 mg, 60%). 1H NMR δ (CDCl3): 1.30 (d, 3H), 3.08 (s, 3H), 3.77 (m, 2H), 4.47 (m, 1H), 6.85 (s, 1H), 7.00 (d, 1H), 7.13 (d, 2H), 7.20 (s, 1H), 7.32 (d, 1H), 7.37 (s, 1H), 7.92 (d, 2H). m/z 467 (M−H)−
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[N:10]([CH3:16])[CH2:9]1)(C)(C)C.Cl.CO>O1CCOCC1>[CH3:16][N:10]1[C:11]([CH3:15])([CH3:14])[CH2:12][CH2:13][C:8]([NH2:7])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1
Reactant: CN1CC(NC(=O)OC(C)(C)C)(c2ccccc2)CCC1(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CC(N)(c2ccccc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of 50 mg (0.157 mmol) (1,6,6-Trimethyl-3-phenyl-piperidin-3-yl)-carbamic acid tert-butyl ester in 0.3 ml dioxane was added 0.39 ml (1.57 mmol) of a 4M HCl solution in dioxane at room temperature. After 30 minutes 0.3 ml methanol was added to dissolve the product. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo. The residue was dissolved in water. The aqueous layer was extracted twice with ethyl acetate and then basified with a 2M sodium carbonate solution. The aqueous layer was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to provide 22 mg (64%) of the title compound as a brown oil. MS (m/e): 219.4 (M+H).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][C@H:34]2[CH2:39][CH2:38][C@@H:37]([Cl:40])[CH2:36][CH2:35]2)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][C@H:34]2[CH2:35][CH2:36][C@@H:37]([Cl:40])[CH2:38][CH2:39]2)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1
Reactant: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](Cl)CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](Cl)CC1)c1csc(N)n1

Procedure:
Ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(cis-4-chlorocyclohexyloxyimino)acetate (205 mg) was deprotected using formic acid as described in Example 1a. After chromatography the crystalline title compound (81 mg) was obtained, having identical m.p. and spectroscopic data to Example 53c.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2].[CH3:22]C(C)([O-])C.[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH:19]=[CH2:22])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CCC1CCC(C2CCC(C=O)CC2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(C2CCC(CCC(=O)OCC)CC2)CC1
Reaction time: 8 h

Procedure:
To 3-(4′-formyl-bicyclohexyl-4-yl)-propionic acid ethyl ester (7.8 g, 25 mmol) and methyltriphenylphosphoniumbromide (9.5 g, 26 mmol) in THF (150 ml) is added potassium-tert-butoxide portionwise at −10° C. The reaction mixture is stirred overnight, quenched with water and acidified with hydrochloric acid. The aq. layer is separated and extracted twice with MTB ether. The combined org. layers are washed with brine, dried (Na2SO4) and evaporated. The crude product is purified with heptane/ethyl acetate (19:1) on silica to give 3-(4′-vinyl-bicyclohexyl-4-yl)-propionic acid ethyl ester as a colourless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH2:12][CH3:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:18]2[NH:19][C:20](=[O:22])[S:21][C:17]=2[CH:16]=1.Cl>C(OCC)C.C(O)C>[CH2:12]([C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:14][C:15]3[CH:24]=[CH:23][C:18]4[NH:19][C:20](=[O:22])[S:21][C:17]=4[CH:16]=3)[C:3]=2[C:10]=1[CH3:11])[CH3:13]
Reactant: CCc1[nH]c2ncnc(Cl)c2c1C
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCc1[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c2c1C
Yield: 85.4 %

Procedure:
A mixture comprising 60.0 mg (307 μmol) 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate example 1a), 51 mg 6-amino-1,3-benzothiazol-2(3H)-one (CAS-No: 56354-98-4), 1.75 mL ethanol and 16.9 μL hydrochloric acid (4M in dioxane) was reacted at 110° C. for 10 hours. The residue was digested in a mixture of diethyl ether and ethanol and dried to give 85.3 mg (85%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[CH:15]([O-])([O-])[O:16]CC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][OH:16]
Reactant: CCOC([O-])[O-]
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Product: COc1cc2c(cc1OC)C(=CO)C(=O)N2

Procedure:
As illustrated above in Scheme (A), the intermediate, 5,6-dimethoxy oxindole (I) is reacted with ethyl ortho formate (II) to provide 5,6-dimethoxy-3-hydroxymethylene oxindole (III). This oxindole (III) is then reacted with primary or secondary amines in refluxing benzene in the presence of acetic acid or toluene sulfonic acid to yield 5,6-dimethoxy-3-(substituted amino methylene) oxindoles (IV) or (V), respectively.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([C:26]([O:28][CH3:29])=[O:27])=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]3[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=3[CH:15]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1>CCOC(C)=O.[Pd]>[CH:1]1([C:6]2[C:7]([C:26]([O:28][CH3:29])=[O:27])=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]3[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=3[CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C2C=CCC2)cc2c(c1-c1ccc(F)cc1)C(=O)CC(C)(C)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C2CCCC2)cc2c(c1-c1ccc(F)cc1)C(=O)CC(C)(C)C2
Reaction time: 5 h

Procedure:
A mixture of 1.17 g (2.98 mmol) of the compound of Example XVI and 150 mg of Pd/C (10%) in 80 ml of EtOAc is hydrogenated under an atmosphere of hydrogen (1 atm) for 5 h. The mixture is filtered through diatomaceous earth, concentrated and purified over silica gel 60 (EtOAc/petroleum ether 1:10).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:6]=[C:7]([CH3:12])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:4]=[CH2:5]>CO>[CH2:3]([NH:6][CH:7]([CH3:12])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:4]=[CH2:5]
Reactant: C=CCCC(C)=NCC=C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCC(C)NCC=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (2.7 g, 71 mmol) was added portionwise to a stirred solution of allyl-(1-methyl-pent-4-enylidene)-amine (6.5 g, 47 mmol) in MeOH (100 ml) at 0 C. The reaction mixture was stirred for 30 minutes, then warmed to RT. Approximately 90 ml of MeOH was removed from the reaction mixture by rotary evaporation, then the reaction mixture was diluted with ether (200 ml), then extracted with water then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation to give a pale yellow liquid that was used in the next reaction without further purification (5.2 g, 80%).
Reaction SMILES: C(O)C=C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](O)=[O:13])=[CH:10][CH:11]=1>CC(C)=O>[C:6]1([CH3:5])[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CC(C)=O
Solvent: C=CCO
Product: Cc1ccc(C=O)cc1

Procedure:
Epoxidation of allyl alcohol is carried out with 200 g of the per-p-toluic acid product solution containing 31.6% by weight of per-p-toluic acid, obtained by autooxidizing p-tolualdehyde with air in the absence of catalyst in acetone as a solvent. That is to say, the per-p-toluic acid product solution contains 63.2 g (0.415 moles) of per-p-toluic acid, 13.2 g (0.097 moles) of p-toluic acid and the solvent acetone. 24.4 g (0.420 mole) of allyl alcohol, which is equimolar to the per-p-toluic acid, is fed to an autoclave containing the per-p-toluic acid product solution, the autoclave being provided with a rotating stirrer and a reflux cooler, and subjected to reaction at a temperature of 50° to 52°C at a stirring speed of 500 rpm for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([NH2:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:10]([NH:28][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNc1nc(N)nc(N)n1
Temperature: 100 °C
Yield: 18.1 %

Procedure:
2,6-Diamino-4-chloro-s-triazine (100 g., 0.7 mole), octadecyl amine (207 g., 0.7 mole), and sodium carbonate (100 g) were dissolved in 1000 mls of dimethyl formamide and heated at 100° C. for 4 hours. While still hot, the contents of the reactor was filtered to remove the inorganic salts. When the hot filtrate was allowed to cool, the crude octadecyl melamine precipitated. With filtration, 208 grams (M.P. 78°-82° C.) of a pale yellow solid was recovered. Addition of the second filtrate to cold water yielded an additional 48 grams of solid (M.P. 60°-80° C.).