Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([N:21]2[CH2:42][CH2:41][C:24]3([NH:28]/[C:27](=[N:29]/[C:30]([C:32]4[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=4)=[O:31])/[NH:26][CH2:25]3)[CH2:23][CH2:22]2)=[O:20])[CH:14]=1)(=[O:12])=[O:11])(C)(C)C.CCCC(C)C>Cl.O1CCOCC1>[NH2:38][C:37]1[C:32]([C:30](/[N:29]=[C:27]2/[NH:28][C:24]3([CH2:41][CH2:42][N:21]([C:19]([C:15]4[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][C:6]([OH:43])=[O:5])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=4)=[O:20])[CH2:22][CH2:23]3)[CH2:25][NH:26]/2)=[O:31])=[N:33][C:34]([Cl:40])=[C:35]([NH2:39])[N:36]=1
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1
Agent: Cl
Solvent: CCCC(C)C
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)O)c4)CC3)N2)nc1Cl

Procedure:
A solution of 3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid tert-butyl ester (step 1) (900 mg, 1.415 mmol) in 4N HCl in dioxane (10 ml) was stirred for 16 h at RT. Iso-hexane (10 ml) was added to the reaction mixture and resulting suspension was sonicated for 1 hour at RT. The solvent was decanted off and the solids washed with iso-hexane (10×25 ml). The resulting pale yellow crystals were dried under vacuum @ 45° C. for 36 h to afford the title compound; LC-MS Rt 0.80 mins; 580.0 [M+H]+, Method 2minLC_v003.
Reaction SMILES: CC1(C)CO[C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:14]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:27][C:28]([O:30]C)=[O:29])[C:6]2=[O:32])[O:4]C1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(OCC)(=O)C.CCCCCC>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:27][C:28]([OH:30])=[O:29])[C:6](=[O:32])[C:5]3=[O:4])[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:22][CH2:23]1
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of methyl 2-(5,5-dimethyl-5′-(N-(2-morpholinoethyl)-methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (0.450 g, 0.880 mmol) and TFA (0.678 ml, 8.80 mmol) in dioxane/water 1/1 (15 ml) was heated at 80° C. for 24 hours. Additional TFA (1.356 ml, 17.6 mmol) was added over 5 days with stirring at the same temperature. The volatiles were removed under vacuum, and the crude was triturated with diethyl ether. The insoluble was collected by filtration and dried under vacuum affording 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid 2,2,2-trifluoroacetic acid salt (0.319 g, 0.607 mmol, 69.0% yield, MS/ESI+ 412.0 [MH]+).
Reaction SMILES: C([Li])CCC.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])(=O)=O)(C)C.[CH:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl>CCCCCC.COCCOC.C(OCC)C>[CH:39]1([CH:38]([OH:45])[C:26]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=Cc1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: COCCOC
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 1.5M solution (29 cc) of n-butyllithium in hexane is added to a solution of β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (9.15 g) in 1,2-dimethoxyethane (100 cc) kept under a nitrogen atmosphere at a temperature in the region of -75° C. The orange solution obtained is then stirred for 15 minutes at a temperature in the region of 0° C., and then cooled to a temperature in the region of -40° C. Benzaldehyde (2.2 cc) is then added, and then the reaction mixture is stirred for 1 hour at a temperature in the region of 20° C. A 1N aqueous solution (100 cc) of hydrochloric acid is then added with stirring, followed by ethyl ether (100 cc). The aqueous phase is separated; the organic phase is extracted with a 0.1N aqueous solution (25 cc) of hydrochloric acid. The aqueous phases are combined, washed with ether (2×50 cc) and then made alkaline to a pH in the region of 10 with sodium hydroxide solution, and then extracted with ethyl acetate (3×50 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. In this way 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) (5.2 g) is obtained in the form of white crystals melting at 75° C.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.O[C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]2[S:27][CH2:26][CH2:25][N:20]2[C:21](=[O:24])[C:22]=1[CH3:23].C(OC(=O)C)C>C(Cl)Cl.CCCCCC>[CH3:23][C:22]1[C:21](=[O:24])[N:20]2[CH2:25][CH2:26][S:27][C:19]2=[C:18]([N+:28]([O-:30])=[O:29])[C:17]=1[O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCS2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCS2
Reaction time: 2 h
Yield: 22.8 %

Procedure:
Triflic anhydride (3.4 g, 12.06 mmol) was added to a stirred solution of 7-hydroxy-6-methyl-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (2.5 g, 10.96 mmol) and TEA (2.3 mL, 16.44 mmol) in DCM (20 mL) at −70° C. The resulting mixture was stirred at −70° C. to −50° C. for 2 hours. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was diluted DCM and quenched with bicarbonate solution. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 0.9 g of the product (38% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1.[OH-].[NH4+:20].O.C(OCC)(=O)C>O1CCOCC1>[NH2:20][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: [NH4+]
Reactant: COc1ccccc1C(=O)c1ccc(Cl)nc1Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1C(=O)c1ccc(Cl)nc1N
Temperature: 150 °C
Yield: 50.7 %

Procedure:
A solution of (2,6-Dichloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (50.3 mg, 0.178 mmol, Example 4) in 1,4-dioxane (2 mL) was treated with concentrated ammonium hydroxide (0.24 mL, 29.4%) and heated to 150° C. in the microwave for 3 hrs. The resulting mixture was treated with water and ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with hexanes/ethyl acetate to give (2-Amino-6-chloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone as a off-white solid (23.7 mg, 50.7% yield). HRMS, observed: 262.0502, Calcd for M+: 262.0509.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([C:18]3[CH:23]=[C:22]([C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:36]CC6C=CC=CC=6)=[C:31]([O:34][CH3:35])[CH:32]=5)[CH:27]=[C:26]([CH2:44][OH:45])[C:25]=4[CH2:46][OH:47])[CH:21]=[CH:20][N:19]=3)[N:8]=2)[CH:2]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C.[Cl:62]CCl>>[ClH:62].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([C:18]3[CH:23]=[C:22]([C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[CH:27]=[C:26]([CH2:44][OH:45])[C:25]=4[CH2:46][OH:47])[CH:21]=[CH:20][N:19]=3)[N:8]=2)[CH:2]=1
Reactant: COc1cc2c(-c3ccnc(-n4nc(-c5cccnc5)c5ccccc5c4=O)c3)c(CO)c(CO)cc2cc1OCc1ccccc1
Reactant: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2c(-c3ccnc(-n4nc(-c5cccnc5)c5ccccc5c4=O)c3)c(CO)c(CO)cc2cc1O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 1-[2-{4-(3-pyridyl)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-2,3-bis(hydroxymethyl)-6-benzyloxy-7-methoxynaphthalene (0.73 g) in dichloromethane (10 ml) are added dropwise acetic anhydride (0.7 ml) and triethylamine (1.3 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, washed with water, dried, and concentrated under reduced pressure to remove the solvent. The residue is dissolved in acetic acid (50 ml) and thereto is added 10% palladium-carbon (0.1 g), and the mixture is subjected to medium-pressure catalytic hydrogenation at room temperature overnight with using a Parr reduction apparatus. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in methanol (10 ml), and thereto is added sodium methoxide (0.2 g) under ice-cooling. The mixture is stirred at room temperature for three hours, and thereto is added diluted hydrochloric acid under ice-cooling. The mixture is concentrated under reduced pressure to remove the solvent. Water is added to the residue, and the mixture is extracted with dichloromethane. The extract is washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is crystallized from ethyl acetate, and thereto is added 4M hydrogen chloride in ethyl acetate to give 1-[2-{4-(3-pyridyl)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-2,3-bis(hydroxymethyl)-6-hydroxy-7-methoxynaphthalene hydrochloride (0.15 g, yield; 25%), which is listed in Table 12.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH:10]([N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester (10.4 g, 41.4 mmol), phthalimide (5.2 g, 36.6 mmol), and PPh3 (14.6 g, 55.5 mmol) in THF (204 mL) was added dropwise DEAD (8.9 mL, 55 mmol) with stirring at 0° C. Then the resulting mixture was warmed to room temperature for an additional 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate, 3:1) to give [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acid tert-butyl ester. (Yield 10.5 g, 66.8%). 1H NMR (300 MHz, CDCl3): δ 7.81-7.75 (m, 2H), 7.69-7.64 (m, 2H), 7.53-7.50 (m, 2H), 7.34-7.23 (m, 3H), 5.44-5.38 (m, 1H), 4.74 (brs, 1H), 3.29-3.07 (m, 2H), 2.83-2.75 (m, 1H), 2.51-2.42 (m, 1H), 1.42 (s, 9H). LC-MS: [M-Boc+H]+ 281.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45]/[CH:46]=[CH:47]/[CH2:48][CH2:49][CH3:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:44]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[N:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:13])([F:43])[C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])=[CH:25][N:24]=2)=[CH:31][CH:30]=1)[CH2:45]/[CH:46]=[CH:47]/[CH2:48][CH2:49][CH3:50]
Reactant: CCC/C=C/CCO
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/CCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mol) in THF (20) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.693 g, 1.50 mmol), trans-3-hepten-1-ol (0.171 g, 1.50 mmol) and triphenylphosphine (0.399 g, 1.50 mmol) in THF (30) and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:27])/[CH:16]=[CH:17]/[C:18]1[CH:26]=[CH:25][C:23]([OH:24])=[C:20]([O:21][CH3:22])[CH:19]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:27])/[CH:16]=[CH:17]/[C:18]1[CH:26]=[CH:25][C:23]([O:24][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:20]([O:21][CH3:22])[CH:19]=1)[CH3:13]
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 85 °C
Yield: 69.7 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.5 g, 3.02 mmol), ferulic acid ethyl ester (0.97 g, 4.37 mmol), anhydrous potassium carbonate (1.0 g, 7.25 mmol), and DMF (40 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stirring to react for 8 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.5), filtering to obtain filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain solid, 0.75 g (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-3-methoxyphenyl)acrylic acid ethyl ester, a yield is 69.7%, m.p. 111.5-111.9° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([CH2:25][C:26](=O)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:33])=[N:13]2)=[CH:8][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:3][N:2]=[C:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:25][CH:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:33])[N:16]1[C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[N:15][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:13]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(CCC(C)C)=NO)nc2n1
Yield: 22.4 %

Procedure:
Hydroxylamine hydrochloride (0.9 g) is added to a suspension, maintained at 0° C. with a bath of ice-cold water, of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (4.3 g) in a mixture (100 cc) of water and ethanol (50:50 by volume). The suspension obtained is allowed to return to a temperature in the region of 20° C. and a solution of sodium carbonate (0.7 g) in distilled water (10 cc) is added. The suspension obtained is heated to reflux for 22 hours. During this period, ethanol (80 cc) is added in two portions. Refluxing is maintained for 12 hours, adding in three portions further hydroxylamine hydrochloride (1.35 g) and sodium carbonate (1.05 g). The reaction mixture is then poured into water (1 litre). The aqueous phase is extracted with methylene chloride (3×300 cc). The organic phases are combined, washed with distilled water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness. After recrystallization in 2-propanol, 3-(2-hydroxyimino-5-methylhexyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (1 g), m.p. 200° C., is obtained.
Reaction SMILES: C(OC[C:6]1[CH:11]=[C:10]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[N:14]=2)[CH:9]=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=O)C.[OH-:37].[Li+].[CH2:39]1[CH2:43][O:42]CC1.CO>O>[Cl:27][C:24]1[S:23][C:22]([C:15]2[N:14]=[C:13]([NH:12][C:10]3[CH:11]=[CH:6][C:7]([CH2:39][C:43]([OH:37])=[O:42])=[CH:8][CH:9]=3)[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[N:16]=2)=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(COC(C)=O)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(Nc2nc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A 18-mL vial was charged with [5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl acetate (8.6 mg, 0.016 mmol) and lithium hydroxide (10 mg, 0.23 mmol). THF (1 ml), MeOH (0.2 ml) and water (0.2 ml) was added to the vial. The resulting mixture was stirred at rt overnight. Then the volatile material was removed. The residue was treated with THF (0.5 ml) and 2N HCl aq. (0.5 ml) for 1 hr. The mixture was neutralized by addition of NaHCO3 aq. to pH=7. Then the mixture was extracted with ethyl acetate (3×2 ml). The ethyl acetate layers were combined and solvent was removed to dryness and the residue was purified by chromatography on silica gel using DCM followed by 0.4% MeOH in DCM as eluent to afford 2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetic acid (4.2 mg, 68% yield). MW=385.68. 1H NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.67 (d, J=4.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.95 (d, J=4.0 Hz, 1H), 6.68 (brs, 1H), 5.18 (s, 2H), 2.68 (q, J=8.0 Hz, 2H), 2.51 (s, 3H), 1.27 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[C:18]12([C:28](O)=[O:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>>[CH:12]1([CH2:11][CH2:10][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/2=[N:8]\[C:28]([C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:29])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1nc(N)sc1C
Reactant: BrCCC1CCCCC1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCC2CCCCC2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, (2-bromoethyl)-cyclohexane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 0.93-1.05 (m, 2 H) 1.10-1.26 (m, 3 H) 1.29-1.38 (m, 1 H) 1.48-1.57 (m, 2 H) 1.58-1.75 (m, 9 H) 1.75-1.83 (m, J=12.79 Hz, 2 H) 1.85 (d, J=2.50 Hz, 6 H) 1.94-2.02 (m, 3 H) 2.15 (s, 3 H) 2.20 (s, 3 H) 4.07-4.18 (m, 2 H); MS (ESI) m/z 401 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:12])[C:6]2=[O:11].[CH2:13]=[C:14]([O:17][Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]1([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:6]2=[O:11]
Reactant: C=C1Cc2c(F)cccc2C1=O
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC2(CC1)Cc1c(F)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 4-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (249b) (3.71 g, 22.9 mmol) and (buta-1,3-dien-2-yloxy)trimethylsilane (5.2 mL, 29.8 mmol) in DCM (200 mL) at 0° C., there was added BF3.Et2O (0.5 mL dropwise. The resulting solution was stirred at 0° C. for another 30 min, quenched with MeOH (0.3 mL), warmed to room temperature, acidified with 2N HCl aqueous solution (15 mL) and extracted with DCM (10 mL×4). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the residue was purified by flash chromatography (0 to 50% EtOAc/Hexane) to give 4′-fluorospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (249c) (2.77 g, 49%). LC-MS tR=1.41 min in 3 min chromatography, MS (ESI) m/z 233 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:11][C:12]1[CH:13]=[C:14](CN)[CH:15]=[CH:16][CH:17]=1.[CH2:20]([N:22](CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:14]([N:22]([CH3:20])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10])[CH:15]=[CH:16][CH:17]=1
Reactant: NCc1cccc(Br)c1
Reactant: CCN(CC)CC
Reactant: CCCCCCCN=C=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
3.2 mL (20 mmol) of heptyl isocyanate are added to a solution of 2.5 g (13 mmol) of (3-bromophenyl)methylamine (prepared according to Example 24f) in 10 mL of tetrahydrofuran in the presence of 2 mL of triethylamine. The reaction mixture is stirred for 12 hours at room temperature. The reaction is stopped by addition of 2 mL of water and extraction with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 3.4 g (77%) of 1-(3-bromophenyl)-3-heptyl-1-methylurea are obtained in the form of a solid.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[C:4]([CH:3]([C:2](=[O:7])[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])[CH3:5]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCCCCC(C(C)=O)C(C)=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 458.4 %

Procedure:
A mixture of pentane-2,4-dione (5.0 g), ethyl 7-bromoheptanoate (11.1 g), potassium carbonate (13.8 g), and cesium carbonate (1.63 g) in a mixture of acetonitrile (150 ml) and dimethylsulfoxide (30 ml) was stirred at 20° C. overnight, then pentane-2,4-dione (5 g) was added. After stirring at 20° C. overnight, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 8-acetyl-9-oxodecanoate (55 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].N.[N:16]1C=CC=CC=1>S(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:16])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1F
Reactant: c1ccncc1
Agent: N
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-3-sulphamoylbenzoic acid (5.4 mmol) in thionyl chloride (10 mL) is refluxed for 4 hours. The reagent is then removed by distillation under reduced pressure and the residue is re-dissolved in dry toluene (10 mL). The solvent is removed by distillation under reduced pressure. This operation is repeated twice, and then the residue is dissolved in dry dioxane (10 mL), and ammonia (6 mmol) and pyridine (6 mmol) are added. After one hour, the solvent is removed under reduced pressure and the residue is taken up in methanol (5 mL), and then water (30 mL) is added. The precipitate obtained is collected by filtration, washed with water and dried.