Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].CO[C:22](OC)([CH3:24])[CH3:23].CC(C)=O>CCCCCC>[CH3:23][C:22]1([CH3:24])[O:3][CH:2]2[CH:4]([CH:6]([CH2:7][OH:8])[O:9][CH:1]2[N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:5]1
Reactant: COC(C)(C)OC
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC1(C)OC2C(CO)OC(n3cnc4c(N)ncnc43)C2O1
Reaction time: 3 h

Procedure:
A solution of adenosine (43 g) and 2,2-dimethoxypropane (5 eq.) in acetone (75 eq.) was treated with D-camphorsulphonic acid (1 eq) at and the resulting reaction was allowed to stir for 3 hr. The reaction mixture was concentrated in vacuo and diluted with a mixture of saturated aqueous NaHCO3 (250 mL) and ethyl acetate (250 mL). The resulting solution was transferred to a separatory funnel and the organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide a solid residue. The solid residue was suspended in hexane, filtered, washed with hexane and dried to provide 2′,3′-Isopropylidene-adenosine (43 g). 1H NMR (DMSO-d6, 300 MHz): δ 4.12-4.17 (m, 1H), 4.22-4.26 (m, 1H), 4.59 (d, J=4.8 Hz, 1H), 4.74-4.85 (m, 2H), 5.49-5.52 (m, 1H), 5.51 (d, J=5.1 Hz, 1H), 5.84 (d, J=5.1 Hz, 1H), 7.85 (s, 2H), 8.33 (s, 1H). MS m/z 347.11 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 92.2 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), piperidine (0.099 mL, 0.998 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (189 mg, 0.460 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H); 8.17 (s, 1H); 7.79 (dd, J=8.84, 2.56 Hz, 1H); 6.75 (d, J=8.77 Hz, 1H); 6.63 (s, 1H); 3.94 (s, 3H); 3.57-3.73 (m, 4H); 1.47-1.69 (m, J=4.68 Hz, 6H). m/z (ESI, +ve ion) 412.0 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].CN(C=O)C.Br[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>C(OCC)(=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)=[O:19]
Reactant: BrCC1COc2ccccc2O1
Reactant: COC(=O)c1ccc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Yield: 55.2 %

Procedure:
To 4.19 g cesium carbonate and 1.37 g methyl 1-hydroxy-2-naphthoate in 25 ml abs. DMF was added 1.62 g 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine and the mixture was reacted for 16 h at 50° C. The reaction was poured unto ice, the resulting precipitate was isolated by filtration, dissolved in ethyl acetate and washed with brine. The organic phase was dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to yield 1.31 g of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5](COCC[Si](C)(C)C)[N:4]=1)=C.FC1C(OC=O)=C(F)C(F)=C(F)C=1F>C(Cl)Cl.CCOC(C)=O>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:4]1
Reactant: C=Cc1nn(COCC[Si](C)(C)C)c2ccccc12
Agent: O=COc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc2[nH]ncc2c1
Reaction time: 3 h
Yield: 190.5 %

Procedure:
6-(3-Benzamidobenzoyl)-3-E-2-aminophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.17, 0.28 mmol) was dissolved in 3 mL of methylene chloride. To this was added formic acid pentafluorophenyl ester (0.12 g, 0.56 mmol) dropwise. After 3 h, the reaction mixture was diluted with 40 mL of EtOAc and was washed with 50/50 NaHCO3 (2×30 mL) and the organic layer was filtered through a silica plug. The residue was purified by radial chromatography through silica eluting with hexane:EtOAc/CH2Cl2 (1:1:1) which afforded 6-(3-benzamidobenzoyl)-3-E-(2-formamidophenyl)ethenyl]-(2-trimethylsilanyl)-ethoxymethyl)-1H-indazole as a clear oil (63 mg, 40%). 1H NMR (CDCl3) δ 8.48-8.36 (m, 1H), 8.20-7.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26-7.01 (m, 4H), 6.82 (t, 1H, J=14.2 Hz), 3.48-3.23 (m, 2H), 0.95-0.87 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:10](=O)[CH3:11].[NH2:13][NH2:14]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10]([CH3:11])=[N:13][NH:14]2
Reactant: NN
Reactant: CC(=O)c1c(F)ccc(C)c1Cl
Solvent: CS(C)=O
Product: Cc1ccc2[nH]nc(C)c2c1Cl

Procedure:
A solution of 1-(2-chloro-6-fluoro-3-methylphenyl)ethanone (10 g, 53.6 mmol) and hydrazine (5.05 mL, 161 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide crude 4-chloro-3,5-dimethyl-1H-indazole as a white solid, which was used in the next step directly. MS (ESI+) m/z 180.9 (M+H)+. NaH (60% dispersion in mineral oil, 3.87 g, 97 mmol) was added portion wise to a solution of crude 4-chloro-3,5-dimethyl-1H-indazole (9.7 g, 53.7 mmol) in THF (200 mL) at −20° C. The mixture was allowed to warm to 0° C. and stir for 20 min, then TsCl (14.33 g, 75 mmol) was added. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was cooled to −20° C. and sat. NH4Cl aqueous solution was added to quench excess base. The resulting mixture was extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with EtOAc and filtered to provide 4-chloro-3,5-dimethyl-1-tosyl-1H-indazole. 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J=8.34 Hz, 1 H) 7.84 (m, J=8.34 Hz, 2 H) 7.39 (d, J=8.59 Hz, 1 H) 7.25 (m, J=7.83 Hz, 2 H) 2.73 (s, 3 H) 2.46 (s, 3 H) 2.38 (s, 3 H); MS (ESI+) m/z 334.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[O:16][CH3:15])=[O:11]
Reactant: COc1ccccc1N
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccccc1NC(=O)c1cc(C(N)=O)ccc1OC

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-methoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][O-:13].[Na+].O>O1CCOCC1>[CH3:12][O:13][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccnc(OC)c1
Yield: 75 %

Procedure:
A mixture of methyl 2-chloroisonicotinate (5.23 g, 0.030 mol) and sodium methoxide (2.47 g, 0.045 mol) in 15 mL of dioxane was heated at reflux for 1.5 hours. After the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 3.76 g (75%) of product as a yellow oil: Anal. Calc'd. for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.07; H, 5.54; N, 8.34.
Reaction SMILES: [C:1](O)(=O)C.[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][NH:16][CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:5].[ClH:5].[ClH:5].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][N:16]([CH3:1])[CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:22][CH2:23]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic acid (3 ml, 52 mmol) was added to a solution of the amine of example 4b (10 g, 26 mmol) in dichloromethane (100 ml) followed by formaldehyde (37% w/v aqueous, 3.2 ml, 39 mmol). In a separate vessel sodium triacetoxyborohydride (6.7 g, 31 mmol) was slurried in dichloromethane and cooled to <10° C. The imine solution was then added dropwise to the cold slurry over 15 minutes. The reaction mixture was stirred at room temperature for 0.5 hours, after which time the reaction mixture was partitioned between 2N aqueous sodium hydroxide solution and dichloromethane. The organic phase was then washed three times with a 50% aqueous solution of sodium metabisulfite, followed by a final water wash. The dichloromethane solution was distilled to half volume before adding EtOAc and further distilled to remove the remaining dichloromethane. EtOH was added and the reaction mixture heated for a further 0.5 hours, before cooling to 10° C. and isolating the product as a white solid. The solid was dried under vacuum at 50° C. for 16 hours to afford the title compound (7.48 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][NH:8][CH3:9]
Reactant: COc1nn(C)c(CN(C)C(=O)OC(C)(C)C)c1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1c(Br)c(OC)nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.1 %

Procedure:
To a solution of compound 91 (1613 mg, 4.826 mmol) in DCM (10 ml) was added 4N HCl in dioxane. (10 ml). The solution was allowed to stir at room temperature for 2 hours, then the reaction mixture was concentrated to give compound 196 (1357 mg, 104%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH2:24]([O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH3:25]>CCOCC.CCCCC.C1COCC1>[CH2:24]([O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([OH:39])([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)[C:35]([F:36])([F:37])[F:38])[CH3:25]
Reactant: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1
Reactant: CCOCCn1cccc1C(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CCOCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 75 mg (0.23 mmol) of N-(4-bromophenyl)-N-methyl-benzenesulfonamide in 4 mL of Et2O at −78° C. was added dropwise 285 μL (0.49 mmol) of a 1.7 M solution of tert-BuLi in pentane and the resultant mixture was stirred at −78° C. for 10 min. To this mixture was then added a solution of 81 mg (0.34 mmol) of N-ethoxyethyl-2-trifluoroacetylpyrrole in 3 mL THF and the mixture was allowed to gradually warm to room temperature over an 18 h period. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N-:14]1.[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[O:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 91.5 %

Procedure:
4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) and potassium 1,3-dioxoisoindolin-2-ide (2.0 g, 10.9 mmol) were placed in microwave vial (0.5-2 ml) and NMP (12.0 ml) was added. The reaction mixture was heated at 200° C. using microwave (Biotage, Initiator) for 1 min. After cooling to rt, the reaction mixture was added dropwise to stirring water which resulted in formation of precipitate. The solid was collected, washed with water and dried under stream of nitrogen to afford the title compound (2.89 g, yield: 92%). 1H-NMR (400 MHz, CDCl3) δ 7.26 (s, 2H) 7.43 (d, 2H) 7.81-7.87 (m, 3H) 7.91 (dd, 2H) 7.95-8.05 (m, 3H) 8.33 (d, 1H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCCl)cc1
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(CCc2ccc(F)cc2)CCN1
Temperature: 85 °C
Yield: 48.3 %

Procedure:
Piperazinone (1.20 g, 12.1 mmol), 1-fluoro-4-(2-chloroethyl)benzene (2.45 g, 12.1 mmol) and i-Pr2NEt (3.25 g, 4.5 ml, 25 mmol) were combined in acetonitrile (25 mL) and heated to 85° C. for 2 h. The mixture was concentrated and partitioned between H2O (20 mL) and CH2Cl2 (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH2Cl2 (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH2Cl2 (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.30 g, 48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 7.00-6.94 (m, 2H), 6.45 (s, 1H), 3.39-3.35 (m, 2H), 3.20 (s, 2H), 2.78-2.62 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.O.Cl.C(O[CH:18](OCC)[CH2:19][CH:20](OCC)OCC)C>C(O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([N:9]2[CH:20]=[CH:19][CH:18]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cccc(-n2cccn2)c1
Yield: 80 %

Procedure:
Into a 500 ml., 2-neck flask, fitted with a condenser and a magnetic stirrer, is successively added 35.2 g. (0.2 M.) of m-trifluoromethylphenyl hydrazine, 15 ml. of water, 20 ml. of 100% ethanol, 16.5 ml. of concentrated hydrochloric acid (slowly) and 44.0 g. (0.2 M.) of 1,1,3,3-tetraethoxypropane. The reaction mixture is then heated slowly to between 80° C. and 90° C., and after maintaining the mixture at this temperature range for a period of between 2 and 3 hours, the reaction mixture is cooled, quenched on ice water, extracted with ethylacetate and washed several times with water. After drying the organic solution over sodium sulfate, the solvent is evaporated on a rotary evaporator to obtain a very dark liquid which is then distilled at 70° to 80° C. and a pressure of about 100 microns to yield a light yellow oil (Yield: 80%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].CC1C=CC(S(O[CH2:35][C@H:36]2[CH2:40][CH2:39][CH2:38][O:37]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:35][C@H:36]5[CH2:40][CH2:39][CH2:38][O:37]5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione was obtained (32%) as a colorless solid: mp>250° C. (toluene/hexanes); 1H NMR (300 MHz, CDCl3) δ7.38-7.29 (m, 1H), 7.17-7.03 (m, 3H), 6.90-6.85 (m, 1H), 6.40-6.28 (m, 1H), 4.99-4.92 (m, 1H), 4.75-4.67 (m, 1H), 4.36-4.25 (m, 1H), 4.01-3.67 (m, 4H), 3.25-3.21 (m, 3H), 2.14-1.85 (m, 3H), 1.79-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.0, 156.9, 155.0, 143.5 (2C), 143.1, 142.6, 132.2, 131.9, 129.3, 129.2, 126.2, 124.1, 123.8, 123.6, 109.8, 109.8, 103.1, 103.0, 94.7 (2C), 80.5, 80.4, 77.1, 76.3, 68.4, 68.2, 58.2 (2C), 45.0, 44.7, 29.3, 29.2, 28.3, 28.2, 25.7; MS (ES+) m/z 393.0 (M+1).
Reaction SMILES: C(OP([CH2:9][C:10](=[O:15])[N:11]([O:13][CH3:14])[CH3:12])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH:24]1([O:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[O:38][CH3:39])[CH:33]=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.O>[CH3:14][O:13][N:11]([CH3:12])[C:10](=[O:15])[CH:9]=[CH:33][C:32]1[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:31]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)N(C)OC)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a stirred solution of diethyl(N-methoxy-N-methyl-carbamoylmethyl)phosphonate (2.60 g, 10.90 mmol) in dry tetrahydrofuran (50 ml) at -78° C. was added lithium diisopropylamide (1.5M solution in cyclohexane, 7.33 ml, 11 mmol) dropwise over 3 minutes. The resulting solution was stirred at -78° C. for 30 minutes, after which time 3-cyclopentyloxy-4-methoxybenzaldehyde (1.5 g, 6.81 mmol) in dry tetrahydrofuran (5 ml) was added in one portion. The reaction was allowed to warm to room temperature and stirring continued overnight. After which time the reaction mixture was diluted with water (25 ml) and the tetrahydrofuran removed in vacuo. The aqueous residue was diluted with brine (25 ml) and extracted with methylene chloride (3×60 ml). The organic extracts were dried (Na2SO4) and evaporated in vacuo to give a yellow liquid. The liquid was purified by flash chromatography (SiO2 ; hexane/ethyl acetate (65:35)) to afford the title compound as a pale yellow liquid (1.986 g).
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([O:18][C:14](=[O:17])/[CH:15]=[CH:16]/[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=c1[nH]c(=O)c2cc(Br)cnc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Yield: 83.5 %

Procedure:
A suspension of 6-bromo-1H-pyrido[2,3-d]pyrimidine-2,4-dione (430 mg, 1.59 mmol) in propionitrile (8 mL) and DMF (2 mL) was treated with tert-butyl acrylate (0.93 mL, 6.4 mmol), (i-Pr)2EtN (0.6 mL, 3.3 mmol) and P(o-tol)3 (100 mg, 0.32 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (36 mg, 0.16 mmol) was added and the mixture was deoxygenated with a stream of Ar for 10 min. The mixture was heated to reflux for 17 h, then allowed to cool. The resulting precipitate was isolated by filtration to give the title compound (384 mg, 83%) as a gray solid: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.54 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 6.72 (d, J=16.1 Hz, 1H), 1.49 (s, 9H); ESI MS m/e 290 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[CH:10]([C:13]([CH3:15])=O)([CH3:12])[CH3:11].[CH:16](C=C)=O>>[CH3:1][C:2]1([CH3:9])[CH2:3][CH2:4][CH:5]2[CH:6]([CH:15]([CH3:16])[CH:13]=[C:10]([CH3:12])[CH2:11]2)[CH:7]1[OH:8]
Reactant: C=CC=O
Reactant: CC1(C)CCC=CC1=O
Reactant: CC(=O)C(C)C
Product: CC1=CC(C)C2C(CCC(C)(C)C2O)C1

Procedure:
6,6-Dimethyl-cyclohex-2-en-1-one, used as starting material in the above described process, can be prepared starting from isopropyl-methyl ketone and acrolein according to a condensation reaction in the presence of an acidic dehydrating agent as indicated hereinbelow: ##STR12##
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][NH:19][C:18]=3[CH:23]=2)=[O:13])=[CH:7][CH:6]=1)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[F:25][C:26]1[CH:27]=[C:28]([S:32]([N:19]2[C:18]3[CH:23]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:24])=[CH:6][CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:22][CH2:21][CH2:20]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.1 %

Procedure:
Step 7 and 8. A solution of 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (27 mg, 0.085 mmol) in pyridine (0.4 mL) was treated with a solution of 3-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) in pyridine (0.2 mL). The resulting mixture was stirred at room temperature for 18 hours. The pyridine was evaporated, and the residual crude 4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester was dissolved in ethanol (0.6 mL) and treated with KOH 3N (0.15 mL). The resulting mixture was stirred at room temperature overnight. The mixture was acidified with HCl 3N and evaporated. The residue was purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). 4-{[4-(3-Fluorobenzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid (17.1 mg, 44%) was obtained as an off-white solid, MS (ISP): m/e=455.0 (M−H).