Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:16][CH:17]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1[N+](=O)[O-]
Yield: 72 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv.), 2-amino-5-chloropyridine (9.02 g, 1.3 equiv.), in 80 mL of pyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv.) for 30 minutes. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The product was triturated with diethyl ether to give N-(5-chloro-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (11.5 g, 72%). MS found for C12H7ClFN3O'(M+H)+: 296, (M+2+H): 298.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Cl[C:15]1[C:20]([S:21]([N:24]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[C:25]2[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=2)(=[O:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C>[CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:15]3[C:20]([S:21]([N:24]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[C:25]4[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=4)(=[O:22])=[O:23])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(CC2CC2)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2CC2)cc1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
4-(cyclopropylmethyl)benzeneboronic acid (1.5 g), 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (2.99 g) and sodium carbonate (912 mg) were added to a mixture of toluene (66 ml), ethanol (33 ml) and water (24 ml). The mixture was deoxygenated by alternatively bubbling argon through and evacuating (3 cycles) and tetrakis(triphenylphosphine) palladium(0) (347 mgs) was added. The reaction mixture was heated to 80° C. for 18 hours with efficient stirring and, after cooling, ethyl acetate (50 ml) and water (30 ml) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with brine (15 ml), dried (MgSO4) and evaporated. The residue was purified by chromatography on a Mega Bond Elut column, eluting with a gradient of ethyl acetate in hexane (0-100%) to give 2-(4-cyclopropylmethylphenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.85 g); 1H NMR (d6 -DMSO): 0.25 (q, 2H), 0.54 (m, 2H), 1.03 (M, 1H), 1.64 (m, 1H), 2.55 (s, 3H), 2.60 (d, 2H), 3.83 (d, 2H), 3.98 (s, 3H), 7.33 (d, 2H), 7.46 (d, 2H), 7.77 (dd, 1H), 8.15 (s, 1H), 8.10-8.95 (m, 2H); mass spectrum (+ve ESP) 511 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[S:22][C:23]([C:27](=[O:37])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[C:24]([NH2:26])[N:25]=2)=[CH:16][CH:15]=1)[CH2:8][CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:24]1[N:25]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][NH:7][CH2:8][CH3:9])=[CH:15][CH:16]=2)[S:22][C:23]=1[C:27]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=1)=[O:37]
Reactant: CCN(CCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc(OC)c(F)c3)s2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc(OC)c(F)c3)s2)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of (3-[4-[4-Amino-5-(3-fluoro-4-methoxybenzoyl)-thiazol-2-ylamino]-phenoxy]-propyl)-ethyl-carbamic acid tert-butyl ester (220.5 mg) (from Step A above) in dichloromethane (6 mL) at 0° C. was added trifluoroacetic acid (3 mL). After stirring for 1 hour, the mixture was concentrated and the residue was purified on HPLC to [4-Amino-2-[4-(3-ethylamino-propoxy)-phenylamino]-thiazol-5-yl]-(3-fluoro-4-methoxyphenyl)-methanone (159.8 mg, 89% yield) as a light yellow solid. HRMS, observed: 445.1707; Calcd for M+H: 445.1704.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][N:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 92%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21](Cl)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH:84]1([NH2:89])[CH2:88][CH2:87][CH2:86][CH2:85]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:19]1[CH:20]=[C:21]([NH:89][CH:84]2[CH2:88][CH2:87][CH2:86][CH2:85]2)[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=1
Reactant: NC1CCCC1
Reactant: Fc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To a solution of N-cyclopentyl-4-[5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (0.04 g, 0.1 mmol) in cyclopentylamine (4 mL) was added racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25 mg), cesium carbonate (50 mg) and palladium (II) acetate (5 mg). The resulting mixture was stirred at 80° C. for 24 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (3:7 ethyl acetate-hexane) to give 30 mg (68%) of N-{4-[5-chloro-7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine as a yellow foam. 1H NMR (CDCl3): δ 8.00 (d, 1H), 7.82 (s, 1H), 7.61 (m, 2H), 7.15 (t, 2H), 6.23 (d, 1H), 6.06 (d, 1H), 6.00 (s, 1H), 5.11 (d, 1H), 4.35 (m, 1H), 3.95 (m, 1H), 2.0-2.1 (m, 4H), 1.5-1.9 (m, 12H); 19F NMR (CDCl3): δ−113.0; MS m/z 491 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH:6]1[C:14]([NH:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])=[O:15])=[O:4].[C:31]([O:35][C:36]([N:38]([CH3:44])[C@@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:14]([CH:6]1[N:5]([C:3](=[O:4])[C@@H:2]([NH:1][C:40](=[O:41])[C@@H:39]([N:38]([CH3:44])[C:36](=[O:37])[O:35][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:43])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:15]
Reactant: N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101 %

Procedure:
To a solution of 1-((S)-2-amino-2-(tetrahydropyran-4-yl)acetyl)-N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (37 mg, 88.9 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (27.1 mg, 133 μmol, Eq: 1.5) and diisopropyl-ethylamine (62 μL, 355 μmol, Eq: 4) in DMF was added HATU (60.8 mg, 160 μmol, Eq: 1.8) and the resulting solution was stirred at rt. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was then washed with 0.1 M aqueous NaOH and brine and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 100% EtOAc in hexanes) to give tert-butyl (2S)-1-((1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (54 mg), m/z=602 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][C:20]#[N:21])=[C:17]([N+:22]([O-])=[O:23])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:25])[CH3:2].C(N(CC)CC)C.C[Si](Cl)(C)C>CN(C)C=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]4[C:17](=[N:22][O:23][C:19]=4[C:20]#[N:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:25])[CH3:2]
Reactant: CCN1CN(C)CN(c2nc3ccc([N+](=O)[O-])c(CC#N)c3s2)C1=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CN(C)CN(c2nc3ccc4noc(C#N)c4c3s2)C1=O
Temperature: 25 °C

Procedure:
0.2 g of [2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-6-nitro-1,3-benzothiazol-7-yl]methyl cyanide was charged into about 2 ml dimethylformamide. About 15 equivalents of triethylamine were then added followed by about 15 equivalents of trimethylsilyl chloride. The solution was stirred at room temperature for about 4–20 hours. The reaction was quenched by pouring into dilute aqueous hydrochloric acid then extracted well with ethyl acetate. The combined organics were back extracted with dilute sodium bicarbonate then dried over magnesium sulfate and concentrated. The dark oil was further purified by preparative HPLC to yield 2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl) [1,3]thiazolo[5′,4′: 3,4]benzo[c]isoxazol-8-yl cyanide.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH2:22](I)[CH3:23].[OH-].[Na+].Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:22][CH3:23])=[O:8])=[CH:18][CH:19]=1)#[N:2]
Reactant: CCOC(=O)CCCNC(=O)c1ccc(C#N)cc1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCC(=O)O)C(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
To a solution of the compound obtained in Step 1 (200 mg, 0.77 mmol) in DMF (4 mL) were added sodium hydride (50% oil, 111 mg, 2.31 mmol) and ethyl iodide (0.093 mL, 1.15 mmol) at room temperature, and the mixture was stirred at 60° C. for 14 hr. To the reaction solution was added 1N aqueous sodium hydroxide solution (3 mL, 3.00 mmol), and the mixture was stirred at 60° C. for additional 2 hr. The reaction solution was cooled, and neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give 4-(4-cyano-N-ethylbenzamido)butanoic acid (0.23 g, 0.76 mmol, 98.7%) as a crude product.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1.CCOCC>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([B:17]([OH:18])[OH:16])=[CH:6][CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a suspension of 0.68 g (28.15 mmol) of magnesium turnings in 50 mL of tetrahydrofuran under argon, a crystal of iodine was added and a solution of 4-bromo-isobutylbenzene (6.0 g, 28.15 mmol) in 25 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The mixture was refluxed for an additional 1 hour, cooled to room temperature and added in portions over 15 min to a solution of trimethylborate (2.93 g, 28.15 mmol) in 50 mL of ether at -78° C. under argon. After 30 min at -78° C., the solution was warmed to room temperature, stirred for 90 minutes and 10% aqueous hydrochloric acid (100 mL) was added. After 10 minutes, the solution was extracted with ether (3×100 mL) and the combined ether extracts were extracted with 1 M sodium hydroxide (3×100 mL). The aqueous extracts were acidified with dilute hydrochloric acid to pH 2 and extracted with ether (3×100 mL). The combined ether extracts were washed once with water (100 mL), dried and evaporated to afford 3.5 g of a white solid. Crystallization from ether/hexanes provided 2.3 g (46%) of compound A as a white solid in two crops, m.p. 134-135° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=1)(=O)C.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9](=[O:11])[C:8]2=[CH:14][CH:15]=1
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(O)cc2C1=O
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
4-Hydroxy-N-isobutylphthalimide is prepared as described in Example 2, starting with 7.26 g of 4-acetoxyphthalic anhydride, 7.35 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 75 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 4 hours and then cooled to a temperature in the region of 40° C. and concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in 175 cm3 of ethyl acetate and 150 cm3 of saturated sodium hydrogen carbonate solution. The aqueous phase is separated out after settling has taken place and then extracted twice with 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 200 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up and stirred in 100 cm3 of cyclohexane at a temperature in the region of 20° C. for 1.5 hours and then filtered. The solid is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 4.0 g of 4-hydroxy-N-isobutylphthalimide are thus obtained in the form of a white solid. (Rf=0.25, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.CS(Cl)(=O)=O.O.[OH:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>CN(C=O)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:25]2[C:24](=[O:36])[C:18]3[C:17](=[CH:22][C:21]([OH:23])=[CH:20][CH:19]=3)[O:16][CH:5]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: CCOCC
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1OC
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
In a similar manner to Example 2.1 above, 1-(2,4-dihydroxyphenyl)-2-(3,4-dimethoxy-phenyl)-ethanone dissolved in DMF had added boron trifluoride diethyl etherate followed by methanesulfonyl chloride in DMF. Addition of water to the reaction mixture afforded 3-(3,4-dimethoxyphenyl)-7-hydroxychromen-4-one.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:30]([O:32]/[CH:33]=[CH:34]/[Sn](CCCC)(CCCC)CCCC)[CH3:31].C(N(CC)CC)C>CN(C=O)C.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>[CH2:33]([O:32]/[CH:30]=[CH:31]/[C:15]1[C:14]([C:24]([O:26][CH3:27])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:34]
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](/C=C/OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a stirred solution of methyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.4 g, 3.24 mmol) and (E)-2-ethoxyvinyl tributyltin [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (2.2 g, 6.48 mmol) in DMF (10 mL) under a nitrogen atmosphere were added triethylamine (0.48 mL, 3.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.24 g, 0.32 mmol). The resulting mixture was heated to 140° C. for 2 hours. It was quenched with water, and extracted with ethyl acetate three times. The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as brown glue (0.40 g, 35% yield). 1H NMR (MeOD) δ; 8.50 (s, 1H), 7.64 (d, 1H, J=3.3 Hz), 7.22 (t, 2H, J=6.8 Hz), 7.05 (t, 2H, J=6.8 Hz), 6.89 (d, 1H, J=3.3 Hz), 5.53 (s, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.37 (t, 3H, J=7.1 Hz). LCMS (APCI, M+H+): 355.2.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH:19]=O)=[CH:14][N:13]=1>>[C:2]1([CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[C:5]([NH2:6])=[N:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[CH:14][C:15]=2[CH:19]=1
Reactant: Cc1ccccc1CC#N
Reactant: Nc1ncc(C=O)c(N)n1
Product: Cc1ccccc1-c1cc2cnc(N)nc2nc1N

Procedure:
The title compound was prepared according to Example 1, starting from 2-methylbenzyl cyanide and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 300°-302° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[CH3:12][C:13]1[C:14]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:24][CH2:25]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 94.5 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (310 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (383 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (620 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(OCc3ccccc3)cccc21
Reaction time: 16 h
Yield: 40.6 %

Procedure:
4′-Hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.25 g, 0.77 mmol), benzyl bromide (0.13 mL, 1.1 mmol), and cesium carbonate (0.751 g, 2.30 mmol) were combined in anhydrous N,N-dimethylformamide (10 mL) at ambient temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was taken up in water (25 mL) and extracted with dichloromethane (3×25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane, followed by recrystallization from methanol/dichloromethane to afford 4′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.130 g, 41%) as a colorless solid: mp 198-200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-7.23 (m, 4H), 7.03-7.01 (m, 2H), 6.81 (d, J=8.5 Hz, 1H) 6.74 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.20 (s, 1H), 5.06 (s, 2H), 4.70 (ABq, 2H), 4.19-4.11 (m, 4H), 3.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.8, 154.4, 145.0, 144.3, 137.8, 137.3, 130.6, 128.5, 127.9, 127.0, 120.5, 117.6, 111.5, 108.1, 102.8, 98.8, 77.5, 69.1, 64.7, 64.1, 57.7, 27.1; MS (ES+) m/z 416.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:15]([CH3:18])([O-:17])=[O:16].Cl.CN.C([O-])(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:18][N+:15]([O-:17])=[O:16])=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1
Reactant: COc1nc(C(F)(F)F)ccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: COc1nc(C(F)(F)F)ccc1C=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.3 %

Procedure:
2-methoxy-6-(trifluoromethyl)nicotinaldehyde (300 mg, 1.46 mmol) (Example 139, Step A) was treated with nitromethane (790 μl, 14.6 mmol) at ambient temperature. Solid methylamine hydrochloride (77.0 mg, 1.14 mmol) and sodium acetate (93.6 mg, 1.14 mmol) were added and the colorless reaction mixture was stirred rapidly at ambient temperature for 14 hours. The reaction mixture was applied directly to silica gel and eluted with 2 to 20% ethyl acetate-hexanes to provide the desired compound (193 mg, 0.778 mmol, 53.2% yield) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.CS[C:10]1[N:11]=[N:12][CH:13]=[CH:14][N:15]=1.N1(C2N=NC=CN=2)CCNCC1>>[N:12]1[CH:13]=[CH:14][N:15]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]2)[N:11]=1
Reactant: NC1CCNCC1
Reactant: CSc1nccnn1
Agent: c1cnc(N2CCNCC2)nn1
Product: NC1CCN(c2nccnn2)CC1

Procedure:
Intermediate 5b is synthesised from piperidin-4-ylamine and the precursor 2a according to the procedure described for the synthesis of 5a. Intermediate 5b is isolated in solid form with a 71% yield.