Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:3]2[N:4]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[N:5]=1
Reactant: CCOC(=O)c1cn2nc(Cl)cc(Br)c2n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cn2nc(Cl)cc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 5a (10.6 g, 34.8 mmol) in acetonitrile (150 mL) was added DIEA (10.9 mL, 62.6 mmol) and morpholine (3.60 mL, 42.0 mmol). The reaction mixture was stirred at rt for 1 h, during which time the entire solution solidified. The resulting mixture was left at rt for 3 h, then was poured into ice water (200 mL), and the precipitates were collected by filtration, and dried under high vacuum. Compound 5b was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.25 (s, 1H), 6.10 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.99-4.17 (m, 4H), 3.86-3.96 (m, 4H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([C:27](=[O:28])[CH2:26][O:25][CH3:24])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.2 %

Procedure:
A slurry of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (Intermediate B99, 3.2 g, 13.87 mmol) in THF (100 mL) was treated with diisopropylethylamine (4.83 mL, 27.7 mmol), followed by (methyloxy)acetyl chloride (1.903 mL, 20.81 mmol). The resulting yellow slurry was stirred at rt for 3 days, then diluted with CH2Cl2 (300 mL), washed with water (150 mL), a saturated NaCl solution (150 mL), dried (Na2SO4) and concentrated to obtain 5-(methyloxy)-1-[(methyloxy)acetyl]-6-nitro-2,3-dihydro-1H-indole as an orange solid (3.96 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (t, J=8.42 Hz 2H), 3.36 (s, 3H), 3.89 (s, 3H), 4.07 (t, J=8.42 Hz 2H), 4.19 (s, 2 H), 7.35 (s, 1H), 8.47 (s, 1H); ESIMS (M+H)+=266.87.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].ClC[CH2:16][C:17](Cl)=[O:18].Cl[CH2:21][Cl:22]>>[Cl:22][CH2:21][C:17](=[O:18])[CH2:16][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C(Cl)CCCl
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)Cc1ccc2c(c1)CCO2
Yield: 80.2 %

Procedure:
To the solution of 2,3-dihydrobenzofuran (0.05 mol) dissolved in dichloromethane (30 mL), AlCl3 (0.10 mol) is added batch by batch and 3-chloropropionyl chloride (0.055 mol) is added dropwise, while the internal temperature is maintained below 5° C. Following procedures described in General Method One-Method A, 3-chloro-1-(2,3-dihydrobenzofuran-5-yl)-acetone is obtained as a white solid (8.4 g). The yield is 80.2%. MS(m/z): 211.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:15][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:30][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (3.29 g, 15.2 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (4.56 g, 15.2 mmol) in dry DCM (70 mL) was added EDC×HCl (3.49 g, 18.22 mmol) and DMAP (0.37 g, 3.03 mmol) under nitrogen atmosphere. After stirring for 1 h at ambient temperature the mixture was extracted with saturated aq. NaHCO3, aq. HCl (0.05N) and with saturated aq. NaHCO3 again. The organic layer was dried and the remaining crude product purified by HPLC. The title compound was obtained as an oil (4.15 g, 54.7%). 1H NMR (400 MHz, CDCl3): δ 7.99-7.80 (d, 2H), 7.25-7.43 (m, 8H), 7.18-7.20 (d, 2H), 6.99-7.01 (d, 2H), 5.12 (s, 2H), 4.01-4.04 (m, 1H), 3.80 (s, 2H), 3.57-3.61 (m, 1H), 3.31-3.35 (m, 1H), 2.98-3.00 (m, 2H), 2.41 (s, 3H), 1.11-1.15 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:2].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)[C@@H](C)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](C)Oc1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
2.50 g of 3-hydroxybenzaldehyde, 2.77 g of methyl L-(−)-lactate, and 6.44 g of triphenylphosphine were dissolved in 25.0 mL of THF, and 22.2 mL of a 2.2 M diethyl azodicarboxylate/toluene solution was added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1) to obtain 1.67 g of methyl (2R)-2-(3-formylphenoxy)propionate. The obtained methyl (2R)-2-(3-formylphenoxy)propionate was dissolved in 33.3 mL of methanol, and 394 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 30 minutes. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1.68 g of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]34[CH2:22][NH:21][CH2:20][C@H:19]3[CH2:18][S:17][C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15]4)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:21]2[CH2:20][C@@H:19]3[C@@:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([C:7]5[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=5)[CH:9]=4)([N:15]=[C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[S:17][CH2:18]3)[CH2:22]2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CNC[C@H]2CS1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CN(c3ccc(F)cc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (±)-{(4aR*,7aS*)-7a-[3-(2-fluoropyridin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}carbamate obtained in Preparation Example 18-(9) (72 mg) was mixed with 4-fluorobenzeneboronic acid (24.7 mg), copper (II) acetate (6.1 mg), triethylamine (93.2 μL, specific gravity: 0.73 g/cm3) and molecular sieves 4A (powder) (57.6 mg) in dichloromethane (3 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 11 hours and 30 minutes. 4-Fluorobenzeneboronic acid (23.5 mg) and copper (II) acetate (12 mg) were further added. The atmosphere was changed to an open system, followed by further stirring. After 23 hours and 45 minutes, the reaction suspension was purified by NH-silica gel column chromatography. The resulting product was purified again by pTLC to obtain the title compound (15 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:2](=[O:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6][NH:5][C:4]=1[CH3:11]
Reactant: Cc1cc(O)c(C(=O)O)cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxy-6-methyl-nicotinic acid (10.00 g, 65.3 mmol) in glacial acetic acid (35 mL) is added bromine (4.00 mL, 78.1 mmol). After stirring for 18 h at room temperature, additional bromine (0.5 mL) is added and the reaction mixture is stirred for an additional 24 h. The reaction mixture is evaporated under reduced pressure and the remaining residue is co-evaporated with toluene. The remaining residue is treated with a small amount of MeOH and then triturated with water. The precipitate is filtered off and dried. Yield: 13.8 g (92% of theory); ESI mass spectrum: [M+H]+=232 (bromine isotope pattern); Retention time HPLC: 0.61 min (Z002_002).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].C(N(CC)C(C)C)(C)C.[C:20]1([C:26]2[O:27][CH2:28][C:29](=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([C:26]2[N:30]=[C:29]([CH2:28][OH:27])[N:3]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=3)[N:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1COC(c2ccccc2)=N1
Reactant: NNc1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OCc1nc(-c2ccccc2)nn1-c1cccnc1

Procedure:
To a solution of 3-hydrazinylpyridine dihydrochloride (336 mg, 1.84 mmol) and N,N-diisopropylethylamine (476 mg, 644 μL, 3.69 mmol) in ethanol (7 mL) was added 2-phenyloxazol-4(5H)-one (300 mg, 1.68 mmol, example 55, step 1) and the reaction mixture was refluxed for 2 h. All volatiles were removed in vacuo, and the product was obtained after purification by flash chromatography (using silica gel and a methanol/ethyl acetate gradient) as light yellow solid (390 mg, 1.546 mmol, 92.3%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCOCC1.C(OCC)C.C(Cl)[Cl:40]>>[ClH:40].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Reactant: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cl
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.4 g, 3.7 mmol) in DCM (3 was added 4.0M HO in dioxane (4.6 mL, 18.56 mmol) and stirred at rt for 3 h. Diethylether (200 mL) was then added and the mixture was stirred at rt for 30 min and then filtered and washed with diethylether and dried to give the title compound (1.3 grams).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([OH:18])=[O:17].C(O)(=O)C.Br>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(-c2ccc(O)c(C(=O)O)c2)cc1
Agent: Br
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(O)cc2)ccc1O
Yield: 48.3 %

Procedure:
A solution of 4-hydroxy-4′-methoxy-3-biphenylcarboxylic acid (5.3 g; 21.6 mmol), tetrabutylphosphonium bromide (0.8 g; 2.3 mmol), acetic acid (35 ml) and hydrobromic acid (35 ml of a 48% solution) was heated at reflux for 6 h. The reaction mixture was cooled and poured into water (400 ml). The resulting precipitate was isolated and recrystallised from ethyl acetate to give 2.4 g (47%) of 4,4′-dihydroxy-3-biphenyl-carboxylic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([N:15]=[C:16]=[S:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1.O>[C:5]1([N:15]2[C:16](=[S:17])[N:1]=[N:2][NH:3]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: S=C=Nc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: S=c1nn[nH]n1-c1cccc2ccccc12
Temperature: 102 °C
Yield: 63.1 %

Procedure:
To a solution of NaN3 (1.76 g, 27.0 mmol) in a mixture of 1,4-dioxane (25 mL) and water (25 mL) was added 1-naphthalenylisothiocyanate (5.00 g, 27.0 mmol) at room temperature. The yellow solution containing a white solid was heated at 102° C. for 2 h. The reaction mixture was then cooled to room temperature and aqueous 1 N HCl solution was added until pH 2 was reached. The aqueous mixture was extracted with EtOAc (250 mL). The organic layer was extracted with aqueous 1 N NaOH solution. The aqueous layer was acidified with aqueous 6 N HCl solution and a white precipitate formed. The suspension was filtered and the resulting solid was triturated with Et2O/hexane (1/1) to give the title compound (3.89 g, 63% yield) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[Cl:17])[CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[Br:19]Br>C(O)(=O)C>[BrH:19].[NH2:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[Cl:17])[CH:9]=[C:10]([Br:19])[C:5]=2[NH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1n[nH]c2ccn(-c3ccncc3Cl)c(=O)c12
Solvent: CC(=O)O
Product: Br
Product: Nc1n[nH]c2c(Br)cn(-c3ccncc3Cl)c(=O)c12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-5-(3-chloropyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-4(5H)-one obtained in Step D (0.25 g) and acetic acid (30 mL) was slowly added bromine (0.10 mL) at 60° C., and the reaction mixture was stirred at 60° C. for 3 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized from acetic acid to give the title compound (0.27 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[S:28]([O:38][NH2:39])([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C)C=O.ClCCl>[S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O-:38])(=[O:30])=[O:29].[NH2:39][N+:3]1[C:4]2[C:9](=[CH:8][C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:6][CH:5]=2)[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([C:12]#[N:13])[C:2]=1[NH2:1]
Reactant: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N#Cc1c(NCc2ccccc2)c2cc(N3CCOCC3)ccc2[n+](N)c1N
Reaction time: 5 h

Procedure:
To the solution of 3 g 2-amino-3-cyano-4-benzylamino-6-morpholino-quinoline in 20 ml dimethylformamide, 2.2 g of O-tosylhydroxylamine dissolved in 25 ml dichloromethane is added dropwise at 20° C. in 15 minutes. After 5 hours of stirring the precipitated crystalline material is filtered off. After drying 3.8 g of the title compound is obtained (MH+:376).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]([CH3:16])[CH3:15])=[O:11])[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([B:17]2[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]([CH3:16])[CH3:15])=[O:11])[C:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)B1OC(C)(C)C(C)(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(B2OC(C)(C)C(C)(C)O2)C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 2 (0.30 g) in dichloromethane (7 mL) was added triethylamine (0.11 mL) and acetyl chloride (55 uL). The reaction mixture was stirred overnight at room temperature. Evaporation gave a green-grey foam which was purified by chromatography, with chloroform:methanol (gradient, 50:1, 30:1) as the eluent, to yield the title compound (0.19 g) as a white powder; TLC: Rf =0.35, methanol:chloroform (5:95); NMR: 0.84 (d,3, J=6.7), 0.85 (d,3, J=6.8), 1.17 (s,12), 1.7-1.8 (m,1), 2.15 (s,3), 2.66 (t,1), 4.48 (s,2), 7.46-7.55 (m,5), 8.29 (d,1, J=5), 8.82 (s,1), 9.54 (s,1); MS: m/z=469(M+1). Analysis for C24H33BN4O5 : Calculated: C, 61.55; H, 7.10; N, 11.96; Found: C, 61.55; H, 7.23; N, 11.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[CH2:23](Br)[C:24]#[CH:25]>>[CH2:23]([O:22][C:15]1[C:14]2[C:12](=[O:13])[CH:11]=[C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][C:3]#[CH:8])[CH:7]=3)[O:20][C:19]=2[CH:18]=[C:17]([O:21][CH2:7][C:6]#[CH:5])[CH:16]=1)[C:24]#[CH:25]
Reactant: C#CCBr
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Product: C#CCOc1cc(OCC#C)c2c(=O)cc(-c3ccc(OC)c(OCC#C)c3)oc2c1

Procedure:
30 g of diosmetin are alkylated with propargyl bromide under the conditions of Example 3 to yield, after recrystallisation from isopropanol, 32 g of the title compound in pure form, m.p.: 196° C.
Reaction SMILES: C([O:8][C:9]1[C:13]2[CH:14]=[N:15][C:16]([NH:18][C:19]([NH:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[O:20])=[CH:17][C:12]=2[N:11]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[O:8]=[C:9]1[C:13]2[CH:14]=[N:15][C:16]([NH:18][C:19]([NH:21][C@@H:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:23])=[O:20])=[CH:17][C:12]=2[N:11]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:10]1
Reactant: CCOC(=O)n1nc(OCc2ccccc2)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)n1[nH]c(=O)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21

Procedure:
(R)-Ethyl 3-(benzyloxy)-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (177.2 mg, 0.386 mmol) and Pd/C (4.10 mg, 0.039 mmol) were stirred in EtOAc (3.86 mL), under a balloon of hydrogen gas for 72 h. The reaction mixture was filtered through Celite, eluting with EtOAc. The filtrate was concentrated in vacuo to afford (R)-ethyl 3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate, which was carried onto the next step without further purification. MS ESI calc'd. For C18H19N5O4 [M+1]+370. found 370.
Reaction SMILES: [CH3:1][N:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=1)[CH:3]1[C:7]2[C:8](C)=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[N:11](OC(=O)C(C)(C)C)[C:10]3=[O:24].[OH-].[Na+].O>CO>[CH3:1][N:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:24]
Reactant: COC(=O)c1ccc(N(C)C2CCc3cc4nc(C)n(OC(=O)C(C)(C)C)c(=O)c4c(C)c32)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)O)nc1)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylate (0.185 g), sodium hydroxide (0.06 g), water (2 ml) and methanol (10 ml) was stirred at ambient temperature for 18 hours. The mixture was evaporated. Water (20 ml) was added and the mixture was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylic acid (0.01 g).
Reaction SMILES: C1C=NC=[C:3]([CH:7]=[O:8])C=1.[CH3:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12]/[C:11]/1=[N:19]/[N:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.[Br:28]C(O)C>C(#N)C>[Br-:28].[OH:8][CH2:7][CH2:3][N+:24]1[CH:25]=[CH:26][CH:27]=[C:22](/[CH:21]=[N:20]\[N:19]=[C:11]2\[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]\2[CH3:9])[CH:23]=1
Reactant: CC(O)Br
Reactant: O=Cc1cccnc1
Reactant: Cn1/c(=N\N=Cc2cccnc2)sc2ccccc21
Solvent: CC#N
Product: Cn1/c(=N\N=C/c2ccc[n+](CCO)c2)sc2ccccc21
Product: [Br-]

Procedure:
1.21 g (4.51 mmol) of nicotine aldehyde ((2E)-3-methyl-1,3-benzothiazol-2(3H)-ylidene hydrazone from Step 1 and 0.85 g (6.76 mmol) of bromoethanol in acetonitrile were heated at reflux for 2 hours. After the solvent was removed, the precipitate was suction-filtered off, washed with ethyl acetate and dried under vacuum.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:31]>ClC1C=CC=CC=1Cl>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([C:4]2[CH:3]=[CH:2][C:1]3[O:31][C:11]4[C:12](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:13][C:14]=3[CH:5]=2)=[O:21])=[CH:18][CH:17]=1)=[O:25]
Reactant: O
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccc(C(=O)c2ccc3c(c2)Cc2ccccc2O3)cc1)c1ccc2c(c1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1,4-Bis-(2-xanthenoyl)benzene was synthesized in this fashion: To a solution of 11.84 g of xanthene and 2.64 g of terephthaloyl chloride in 79 cc of o-dichlorobenzene chilled at 11° C. for 40 min,.was added, in a nitrogen atmosphere and without further cooling, 8.40 g of aluminum chloride portionwise so that the temperature did not rise above 26° C. The resulting deep reddish-brown solution was stirred for 45 min. It was then mixed with 240 cc of o-dichlorobenzene, and water was added. The mixture was heated to 98°-100° C. with stirring, and kept at that temperature for 30 min. Two layers formed. The organic layer was separated, and after cooling to room temperature, the solid that separated was collected by filtration. The solids were washed with methanol, methylene chloride, twice again with methanol, and dried under vacuum at ~90° C. for several hours. Mass spectrometry showed this solid to be the desired compound and indicated no impurities.