Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>O.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([N:32]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)[N:36]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(N4CCN(C)CC4)n3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Yield: 32 %

Procedure:
A stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide, 3 (200 mg, 0.464 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (154 mg, 0.510 mmol) and Na2CO3 (123 mg, 1.160 mmol) in a mixture of water (3 mL) and DMF (15 mL) was degassed with argon gas for 30 min. Then PdCl2(PPh3)2 (16.28 mg, 0.023 mmol) was added and heated to 120° C. for 3 h. Then the reaction mixture was filtered through Celite bed and the Celite bed was washed with ice cold water (2×100 mL). The filtrate was extracted with EtOAc (20 mL), dried over anhydrous sodium sulphate, filtered, and concentrated to afford 150 mg of crude product. The crude product was purified by silica gel chromatography over (eluent: 5% MeOH/DCM) to afford the title compound as an off-white solid (85 mg, 32%). 1H NMR (DMSO-d6, 400 MHz): δ 0.889 (t, J=14.4 Hz, 3H), 1.554-1.483 (m, 8H), 2.134 (s, 3H), 2.55 (s, 3H), 4.411 (d, J=1.6 Hz, 2H), 5.059 (m, 1H), 5.913 (s, 1H), 7.830 (s, 1H), 8.047 (s, 1H), 8.08 (s, 1H), 8.306 (s, 1H), 8.462 (s, 1H), 11.53 (s, 1H), 13 (brs, 1H). LCMS (ES+) m/z=528.2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:8](=[O:22])[N:7]([CH3:23])[CH:6]=[N:5][C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:10]2[C:9]3[C:8](=[O:22])[N:7]([CH3:23])[CH:6]=[N:5][C:4]=3[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][O:24][CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2nc(Cl)cc3ncn(C)c(=O)c23)cc1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(COc2nc(-c3ccc(N4CCOCC4)cc3)cc3ncn(C)c(=O)c23)cc1
Temperature: 140 °C

Procedure:
To a solution of 7-chloro-5-(4-methoxybenzyloxy)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (750 mg, 2.26 mmol) in 1,4-dioxane (11 mL) were added 4-morpholinophenylboronic acid pinacol ester (654 mg, 2.26 mmol), 2M aqueous Na2CO3 solution (3.39 mL, 6.78 mmol), and Pd(dppf)2Cl2 (36.9 mg, 0.045 mmol). The reaction mixture was purged with N2 and heated at 140° C. by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure to afford crude 5-(4-methoxybenzyloxy)-3-methyl-7-(4-morpholinophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one.
Reaction SMILES: Br.[C:2]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][N:13]2[CH:21]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[CH2:23][N:24]=[C:25]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CNC>CN(C=O)C.C1COCC1>[C:2]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:24]([CH3:25])[CH3:23])=[O:20])=[CH:14][N:13]2[CH:21]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc2nc(C(=O)c3ccccc3)cn2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Br
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2nc(C(=O)c3ccccc3)cn2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
A solution of 0.21 g of 2-benzoylimidazo[1,2-a]pyridine-6-carboxylic acid hydrobromide, 0.35 g of EDCI hydrochloride and 0.294 g of HOBT in 7 mL of DMF is stirred for 30 minutes at 20° C., followed by addition of 1 mL of a 1 M solution of dimethylamine in THF, and the mixture is stirred for 2 hours at 20° C. The reaction mixture is concentrated to dryness and then taken up in 100 mL of water and 200 mL of ethyl acetate. The organic phase is separated out, dried and evaporated. The residue is purified by flash chromatography on a column of 20 g of silica, eluting with a 99/1 mixture of dichloromethane and methanol. The fractions containing the expected product are combined and concentrated under vacuum to give 40 mg of 2-benzoyl-N,N-dimethylimidazo[1,2-a]pyridine-6-carboxamide in the form of a beige-colored solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[N:7]([Si](C(C)C)(C(C)C)C(C)C)[C:6]=2[CH2:5][CH2:4]1.[ClH:30].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1.[N-]=C=O.Cl>CN(C)C=O.O1CCCC1.ClCCl>[ClH:30].[ClH:30].[N:56]1[CH:57]=[CH:58][C:53]([NH:52][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:29])[CH3:1])[CH2:15][C:14]3=2)=[O:18])=[CH:54][CH:55]=1
Reactant: Nc1ccncc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(C(=O)O)ccc31)CC(N(C)C)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)Nc4ccncc4)cc3c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
A mixture of 0.41 gm (1.0 mMol) 3-dimethylamino-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid, 0.77 gm (4.0 mMol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.54 gm (4.0 mMol) 1-hydroxybenzotriazole, and 0.38 gm (4.0 mMol) 4-aminopyridine in 10 mL dimethylformamide and 50 mL tetrahydrofuran were stirred together at room temperature for 3 days. Polystyrene bound isocyanate resin was added to the reaction mixture which was stirred at 40° C. for 6 hours to scavenge excess 4-aminopyridine. The reaction mixture was filtered, concentrated under reduced pressure and the residue subjected to preparative centrifugal thin layer chromatography (PCTLC), eluting with chloroform containing 5% methanol and 0.5% ammonium hydroxide. Fractions containing the desilylated product were combined and concentrated under reduced pressure to provide a yellow oil. This oil was dissolved in dichloromethane and treated with ethanolic hydrogen chloride. The resulting mixture was concentrated under reduced pressure to provide 0.22 gm (54%) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([OH:13])[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:21][CH3:22])[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)cc1Cl
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of ethyl 6-chloro-4-hydroxynicotinate (3.7 g), powdered potassium carbonate (3.7 g), iodoethane (5 ml) and dimethylformamide (50 ml) is well stirred for 7 hours at 90° C. After cooling, the reaction mixture is filtered and the solvent evaporated off. The residue is treated with icy water (30 ml) and extracted with dichloromethane (2×30 ml). The combined extract are dried and evaporated to dryness. The residue is boiled 90 minutes with 1N sodium hydroxide (18 ml). After cooling the solution is extracted with diethyl ether (30 ml), that is discharged. The alkaline solution is concentrated to small volume, cooled and acidified to pH 4 with 1N hydrochloric acid. The white material that precipitates is collected and crystallized from ethanol to give 6-chloro-1,4-dihydro-1-ethyl-4-oxo-3-pyridine-carboxylic acid (3 g) m.p. 155°-57° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 69.6 %

Procedure:
N-tert-butoxycarbonyl glycine (10.57 g, 60.33 mmol) and glycine methyl ester hydrochloride (7.58 g, 60.4 mmol) were dissolved in DMF (60 mL). N,N-diisopropylethyl amine (7.80 g, 60.4 mmol) and HOBt hydrate (9.24 g, 60.3 mmol) dissolved in DMF (40 mL) were added. The solution was cooled to 0° C. (icebath) and EDC hydrochloride (12.72 g, 66.35 mmol) added in small portions. The reaction mixture was stirred for 15 hours before the solvent was evaporated. The residue was taken up in EtOAc (300 mL) and washed with 2 M aqueous H2SO4 (3×50 mL), 7.5% (w/w) aqueous K2CO3 (3×50 mL) and saturated brine (50 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a clear liquid (10.34 g, 70%) with spectral characteristics in accordance with literature data8; δH (300 MHz; d6-DMSO) 8.17 (1H, t, J 6, NH(Gly2)), 6.97 (1H, t, J 6, NH(Gly1)), 3.85 (2H, d, J 6, CαH2(Gly2)), 3.62 (3H, s, OCH3), 3.57 (2H, d, J 6, CαH2(Gly1)), 1.38 (9H, s, (CH3)3); δC (75 MHz; d6-DMSO) 170.2, 169.9, 155.7, 78.0, 51.6, 42.9, 40.4, 28.1; m/z (ESI) 269.1110 ([M+Na]+; C10H18N2O5 requires 269.1113)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>O>[CH2:12]([NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Solvent: O
Product: C=CCNc1cc(C)nc2cn[nH]c12
Yield: 88.5 %

Procedure:
A mixture of 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) (1.0 g, 0.006 mole) and allylamine (60 g) in water (100 ml) was heated under reflux for 12 days. On cooling the reaction mixture was evaporated to dryness, basified to pH8 with 10% sodium carbonate solution and the resulting solid filtered off. Recrystallisation from chloroform/pentane gave the product as white solid (1.0 g). m.p. 172°-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[C:8]1(=[O:12])[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)CBr
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O
Reaction time: 18 h

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.62 g) in acetone (50 ml) was added anhydrous potassium carbonate (2.23 g) followed by methyl bromoacetate (1.52 ml) and the resulting mixture was stirred for 18 hours. The mixture was filtered and the solvent was evaporated to give a yellow solid. Recrystallisation from ethyl acetate gave methyl tetralone-6-oxyacetate (2.28 g): NMR (d6DMSO) δ1.95-2.05(m,2H), 2.45-2.55(m,2H), 2.9(t,2H), 3.7(s,3H), 4.9(s,2H), 6.85-6.9(m,2H), 7.8(d, 1H); m/e 235(M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[CH2:32]([O:34][C:35](=[O:44])[CH2:36][N:37]1[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]1)[CH3:33]>C1C=CC=CC=1>[CH2:32]([O:34][C:35]([CH2:36][N:37]1[C:41](/[CH:42]=[C:10]2\[CH2:9][N:8]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][C:11]\2=[O:14])=[CH:40][N:39]=[CH:38]1)=[O:44])[CH3:33]
Reactant: CCOC(=O)Cn1cncc1C=O
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Yield: 18.5 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (3.66 g) in benzene (40 ml) was added pyrrolidine (0.97 ml), and the mixture was heated under reflux for 3.5 hours. To this mixture was added a solution of ethyl(5-formyl-1H-imidazol-1-yl)acetate (1.95 g) in benzene (10 ml) under cooling using an ice bath. Then, the whole was heated further under reflux for 8.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography using hexane and ethyl acetate (1:3) as an eluent to afford the title compound (1.0 g, yield: 19%) as a yellow oil.
Reaction SMILES: CCO[C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=O.C(#N)C=C.CCCCCC.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>O1CCOCC1>[O:11]=[C:10]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:4][CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: C=CC#N
Solvent: C1COCCO1
Product: CCOC(=O)CCC1CCCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
Namely, to a solution of 50 ml (0.35 mol) of ethyl cyclopentanone-2-carboxylate in 130 ml of dioxane was added 3.8 ml of Triton B. Then, to the solution was added 27.1 ml (0.242 mol) of acrylonitrile in 50 ml of dioxane. The solution was stirred at room temperature for 12 hours, and extracted with ether after 100 ml of 10% hydrochloric acid was added thereto. An organic layer was dried over anhydrous magnesium silfate. After removinq the solvent, 300 ml of conc. hydrochloric acid was added to the residue and the mixture was heated under reflux for 24 hours. After cooling, the mixture was extracted with ether and 5% aqueous solution of sodium hydroxide was added to the ether layer and the mixture was stirred. An aqueous layer was made acidic with addition of 10% hydrochloric acid, and then the mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, the residue was dissolved in 150 ml of ethanol and 10 ml of conc. sulfuric acid was added thereto. The mixture was heated under reflux for 14 hours, and then ethanol was removed therefrom after cooling, and ethyl acetate was added thereto. The mixture was washed with 10% aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 45 g (yield 70%) of ethyl 2-oxocyclopentanepropionate from hexane-ethyl acetate (4:1) eluate. In 150 ml of 80% ethanol was dissolved 5.5 g (30 mmol) of this compound. To the solution were added 4.17 g (60 mmol) of hydroxylamine hydrochloride and 2.7 g (33 mmol) of sodium acetate and the mixture was stirred at room temperature over night. After removing ethanol, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 5 g (yield 84% ) of ethyl 2-hydroxyiminocyclopentanepropionate from hexane-ethyl acetate (6:1) eluate. In 15 ml of anhydrous ethanol was dissolved 4.4 g of this compound and the solution was stirred at 50° C. for 4 hours under a hydrogen pressure of 120 atm. with use of Raney nickel (W2) as a catalyst. After removing Raney nickel by filtration and removing the solvent, the resulting residue was chromatographed over silica gel to obtain 0.95 g (yield 31%) of 2-azabicyclo[4.3.0]nonane-3-one from ethyl acetate eluate.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1([CH3:41])[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[C:22]2[N:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH:18]([CH:29]([OH:40])[C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=4)[C:19]3=[O:28])=[N:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][C:12]1([CH3:41])[CH2:25][CH2:24][C:23]([CH3:26])([CH3:27])[C:22]2[N:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH:18]([C:29]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=4)=[O:40])[C:19]3=[O:28])=[N:14][C:13]1=2
Reactant: COC(=O)c1ccc(C(O)C2CCc3nc4c(nc3C2=O)C(C)(C)CCC4(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)C2CCc3nc4c(nc3C2=O)C(C)(C)CCC4(C)C)cc1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
A solution of 0.2 ml of dimethyl sulfoxide in 1 ml of methylene chloride was dropped into a solution of 0.124 ml of oxalyl chloride in 10 ml of methylene chloride cooled to −60° C., followed by the stirring for 5 minutes. A solution of 0.5 g of methyl 4-[(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl)hydroxymethyl]benzoate in 10 ml of methylene chloride was dropped into the solution prepared above. The obtained mixture was stirred for 15 minutes, followed by the dropwise addition of 0.954 ml of triethylamine. The temperature of the reaction mixture was raised to room temperature. The resulting mixture was stirred for 30 minutes, followed by the addition of water. The obtained mixture was extracted with methylene chloride. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium. sulfate and concentrated in a vacuum. The residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 0.248 g of the title compound as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])=[CH:5][N:4]([CH3:16])[C:3]=1[C:17]#[N:18].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:26][O:25][C:19]([C:20]1[C:17]([NH2:18])=[C:3]2[N:4]([CH3:16])[CH:5]=[C:6]([C:7]3[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=3[CH3:15])[C:2]2=[N:1][C:21]=1[CH3:23])=[O:24]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(C)c(-c2cn(C)c(C#N)c2N)c(C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c2c1N

Procedure:
A mixture of 3-amino-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole-2-carbonitrile (2 mmol), methyl acetoacetate (4 mmol) and SnCl4 (4 mmol) in 1,2-dichloroethane was heated at reflux for about six hours until all the starting material were consumed. The mixture was quenched with acetone, basified with saturated NaHCO3, then filtered through Celite?. The filtrate was concentrated to dryness. The residue was quenched with water and extracted with chloroform. The chloroform layer was washed with brine, dried and concentrated to dryness to give 7-amino-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester. The product may be purified by trituration.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1.[I-].[Na+]>CN(C)C=O>[C:13]1([C:10]2[C:9]3[C:19](=[O:20])[CH:5]([CH2:4][CH2:3][CH2:2][N:24]4[CH2:21][CH2:23][CH2:29][CH2:27]4)[CH2:6][CH2:7][C:8]=3[O:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCCC1
Temperature: 25 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.75 g) and dimethylformamide (37.0 ml) was added diisopropylethyl amine (6.81 ml), pyrrolidine (2.17 ml) and sodium iodide (5.85 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 73°-76° C. for 1.25-2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ether) afforded 3.10 g of 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The salicylate was prepared with 1.07 eq. salicylic acid in ether. The resulting solid was redissolved with methanol. Addition of pentane led to precipitation of the target salt. Filtration and washing with pentane gave 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one salicylate, m.p. 106°-107° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=[O:8].C(O[CH:13](OCC)[CH:14]([CH3:22])[CH:15](OCC)OCC)C.Cl>>[CH3:22][C:14]1[CH:13]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:15]=1
Reactant: Nc1[nH]ncc1C(=O)O
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Agent: Cl
Product: Cc1cnc2c(C(=O)O)cnn2c1
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
A suspension of 5-amino-1H-pyrazole-4-carboxylic acid (271 mg, 2.1 mmol) and 1,1,3,3-tetraethoxy-2-methyl-propane (prepared accordingly to the procedure described in JACS126(7), 2004, 2194) (0.5 g, 2.1 mmol) in an aqueous solution of hydrochloric acid (6 M, 1.3 mL) was heated at 95° C. in a sealed tube. The solid material completely dissolved when the temperature reached 82° C. and then a solid precipitate crushed out of solution, stirring was continued for 5 minutes. The resulting mixture was cooled to room temperature and the solid was collected by filtration, rinsed with water and dried in vacuum oven to afford 305.1 mg (81% yield) of 6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:15]2[O:16][C:17]3[C:22]([C:23]4([CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[CH:21][CH:20]=[C:19]([O:30][CH3:31])[CH:18]=3)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[C:15]2[O:16][C:17]3[C:22]([C:23]4([CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[CH:21][CH:20]=[C:19]([O:30][CH3:31])[CH:18]=3
Reactant: COc1ccc2c(c1)Oc1c(OCc3ccccc3)cccc1C21CCN(C)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)Oc1c(O)cccc1C21CCN(C)CC1

Procedure:
A solution of 4-benzyloxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (1.5 g.) in ethanol (200 ml.) is hydrogenated using 5% w/w palladium-on-carbon catalyst at 1 atmosphere and 25° C. The catalyst is filtered off and the ethanol evaporated to give a gummy residue which is crystallised from ethanol-ether to give 4-hydroxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 223°-224° C.