Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:24][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][CH:13]1[O:12][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[CH2:15][CH2:14]1
Reactant: CCCCCC(O)C=CC1CCC(CCCCCCCC(=O)OC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(O)C=CC1CCC(CCCCCCCC(=O)O)O1

Procedure:
IV (1.77 g, 0.00500 mole), methanol 20 ml), and 20% aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 90 minutes. The methanol was removed from a water bath (60° C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. The resulting emulsion was extracted with ether (25 + 25 ml). The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (60° C, 1 mm Hg) to give 1.60 g (94%) of V as a colourless oil, nD25 1.4778.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:31]2[CH2:32][CH2:33][CH:29]([CH2:28][C:27]3[CH:34]=[CH:35][C:24]([C:23]([F:22])([F:36])[F:37])=[CH:25][CH:26]=3)[CH2:30]2)=[O:15])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CC2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)benzyl]pyrrolidine oxalate (19.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.5 mg). Calcd for C23H21F3N2O2: 414.1555, found 414.1562.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].I[C:6]1[C:7]([CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[N:8][N:9](COCC[Si](C)(C)C)[CH:10]=1.CCO.CCO.C(N(CC)CC)C>CCO.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:4][C:6]1[C:7]([CH:19]2[CH:24]3[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]3)[CH2:20]2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCO
Reactant: C[Si](C)(C)CCOCn1cc(I)c(C2CN3CCC2CC3)n1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCOc1c[nH]nc1C1CN2CCC1CC2

Procedure:
Compound 52B was prepared following the procedure as described for the synthesis of compound 52A (see Scheme 10) using propanol and 3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane (50). Work-up and flash chromatography (gradient EtOH to EtOH/triethylamine 300/1) followed by a second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51B as an oil (14%). LCMS (method B): Rt: 7.15 min, ([M+H]+=366). Compound 51A was subsequently deprotected (TBAF/THF) and purified by flash chromatography (gradient EtOH to EtOH/triethylamine 97/3), followed by a preparative TLC purification (CH3CN/H2O) to afford the title compound 52B as an oil. (51%). LCMS (method A); Rt: 0.91 min, ([M+H]+=236). 1H-NMR (600 MHz, D6DMSO): δ 7.34 (s, 1H), 3.74 (t, J=7 Hz, 2H), 3.24-3.19 (m, 1H), 3.03-2.96 (m, 1H), 2.92-2.87 (m, 1H), 2.86-2.74 (m, 3H), 2.69-2.62 (m, 1H), 1.88-1.84 (m, 1H), 1.67-1.55 (m, 5H), 1.26-1.20 (m, 1H), 0.92 (t, J=7 Hz, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:18][C:17]3([O:36][C:21]4=[CH:22][N:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH:31]=5)[CH:25]=[C:20]4[CH2:19]3)[CH2:16]2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:4]([C:3]1[N:7]=[C:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:18][C:17]4([O:36][C:21]5=[CH:22][N:23]=[C:24]([C:26]6[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH:27]=6)[CH:25]=[C:20]5[CH2:19]4)[CH2:16]3)[CH2:14][CH2:15]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Zinc chloride (0.7 mol/L in tetrahydrofuran, 0.42 mL) is added to a solution of N-hydroxy-isobutyramidine (30 mg) and 1″-cyano-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (100 mg) in tetrahydrofuran (4 mL) and ethyl acetate (4 mL) at room temperature. The solution is heated to 60° C. and stirred at this temperature for 2 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37][CH2:38]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (75 mg), potassium carbonate (51 mg), and 1,3-dibromopropane (76 μl) was dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 74 mg (yield 78%) of N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (74 mg), potassium carbonate (51 mg), and morpholine (130 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 49 mg (yield 63%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[C:32]([Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:33]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCN(Cc2ccc(N)cc2[Si](C)(C)C)CC1
Reactant: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c([Si](C)(C)C)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid (0.22 mmol) in dry pyridine (5 mL) is added 4-(4-methylpiperazin-1-ylmethyl)-3-trimethylsilylaniline (60 mg, 0.22 mmol) and EDCI (62 mg, 0.325 mmol). The resulting mixture is stirred at r.t. overnight. The solvent is removed on rotavap and the residue is partitioned between DCM and aq. NaHCO3. The combined organic layers from extraction are dried (Na2SO4), filtered, concentrated, and the resulting residue is purified by silica gel flash chromatography [eluted with 5% MeOH (pre-saturated with NH3) in DCM] to give the desired product.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1

Procedure:
Using an analogous procedure to Example 1 3[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with p-toluenesulphonyl chloride to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([Br:38])=[CH:40][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(Br)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 84.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-bromobenzyl chloride (0.75 g) as starting materials, 5-benzyloxy-N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) was obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([NH:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[ClH:19]>O>[ClH:19].[CH2:17]([NH:16][S:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][NH2:1])=[CH:7][CH:8]=1)(=[O:15])=[O:14])[CH3:18]
Reactant: CCNS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCNS(=O)(=O)Cc1ccc(NN)cc1
Reaction time: 0.25 h

Procedure:
Sodium nitrite (1.01) in water (12 ml) was slowly added to a stirred suspension at -5° of the finely ground product of stage (a) (3.14 g) in concentrated hydrochloric acid (30 ml) keeping the temperature below 0°. The resulting mixture was stirred at -5° for 15 min. the slowly added to a cold (-5°) stirred solution of stannous chloride (16.52 g) in concentrated hydrochloric acid (30 ml) keeping the solution below 0°.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:22])[CH:20]=[O:21])=[CH:17][CH:18]=1
Reactant: CC(CO)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)c1ccc(Cl)cc1

Procedure:
To a solution of 19.8 g (0.092 mole) of pyridinium chlorochromate in 80 mL of methylene chloride is added a solution of 7.8 g (0.046 mole) of 2-(4-chlorophenyl)propanol in 20 mL of methylene chloride. After one hour this mixture is diluted with 100 mL of diethyl ether, and the remaining solution is decanted from the insoluble material. Additional diethyl ether is added to the solids, and, after being mixed thoroughly, the solution is decanted from the solids and combined with the original solution. The combination is washed sequentially with 10 mL of a 10% aqueous solution of sodium hydroxide, 10 mL of 10% hydrochloric acid, and finally with 10 mL of water. After being dried over an hydrous magnesium sulfate, this solution is evaporated under reduced pressure, leaving a residue. This residue is passed through a column of silica gel, eluting with ethyl acetate/hexane (5:95). Product-containing fractions are combined, and the solvent is evaporated from the combined fractions under reduced pressure, leaving 2-(4-chlorophenyl)propionaldehyde as the residue.
Reaction SMILES: [CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:28][O:29][CH2:30][O:31][CH3:32])[N:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH2:11][C:12]=2OS(C(F)(F)F)(=O)=O)=[O:6])[CH2:3][CH2:2]1.[OH:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:28][O:29][CH2:30][O:31][CH3:32])[N:9]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:10][CH2:11][C:12]=2[C:46]2[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(OS(=O)(=O)C(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(c2ccc(O)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
Into a 20 mL microwave vial was added 4G (1.33 g, 2.05 mmol) and 4-hydroxyphenyl boronic acid (425 mg, 3.1 mmol, 1.5 eq). Dioxane (12 mL) and saturated sodium bicarbonate (4 mL) was added and the mixture was degassed by bubbling N2 through the solution for 10 minutes. After degassing, 1,1′-bis-diphenyl phosphinoferrocene dichloro palladium (II) (Pd(dppf)Cl2) (150 mg, 206 μmol, 0.05 eq) was added and the reaction was capped. The reaction was microwaved at 150° C. for 20 minutes, and the reaction was transferred to a round bottom and the solvent was removed under vacuum. Saturated ammonium chloride (25 mL) and ethyl acetate (25 mL) was added to the residue and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2×25 mL). The organic layers were combined and dried over sodium sulfate. Solution was filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (40% ethyl acetate/hexanes) to give 4H (948 mg, 37%). ESI-MS:m/z 591.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([O:20]C)=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 68.9 %

Procedure:
A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (4.05 g) in 1 N sodium hydroxide solution (58.3 ml) and methanol (80 ml) was refluxed for 1 hour and evaporated in vacuo. The residue was dissolved in water and washed with chloroform. The aqueous layer was acidified with 1 N hydrochloric acid. The resulting precipitates were filtered and recrystallized from isopropyl alcohol to give crystals of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (2.65 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.3 %

Procedure:
To a solution of 8-bromo-5-methoxycarbonyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (256 mg, 0.76 mmol) in a mixture of THF (5 mL) and methanol (5 mL) was added aqueous 1N NaOH (2.5 mL) and the mixture was stirred for 12 h at room temperature. Aqueous 1N HCl was added and the resulting mixture was concentrated to ca. 5 mL. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 256 mg of the title compound (quant): mp 285° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ13.45 (bs, 1H), 12.09 (s, 1H), 7.22 (d, 1H, J=1Hz), 7.08 (d, 1H, J=1 Hz), 5.18 (dd, 1H, J=11, 4 Hz), 3.79 (dd, 1H, J=17, 11 Hz), 3.33 (dd, 1H, J=17, 4 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([CH2:15][N:16]4[CH2:21][CH2:20][C:19]([NH:23]C(=O)OCC5C=CC=CC=5)([CH3:22])[CH2:18][CH2:17]4)[N:3]1[C:4]=23.[H][H]>C(O)C.[Pd]>[NH2:23][C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([CH2:15][C@H:14]2[N:3]3[C:4]4[N:5]([C:6](=[O:12])[CH2:7][CH2:8][C:9]=4[CH:10]=[CH:11][C:2]3=[O:1])[CH2:13]2)[CH2:21][CH2:20]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(N)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Yield: 99.8 %

Procedure:
A solution of phenylmethyl (1-{[(2R)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl}-4-methyl-4-piperidinyl)carbamate (1.848 g, 4.10 mmol) in ethanol at rt under argon was treated with palladium on carbon (10% paste) (0.462 g, 4.34 mmol) (20% w/w) and stirred under 1 atmosphere of hydrogen for 2 h, reaction mixture was filtered through a thin pad of Kielselguhr eluting with ethanol (100 ml). The filtrate was treated with palladium on carbon (10% paste) (0.462 g, 4.34 mmol) and stirred under 1 atm of hydrogen for 18 h. The reaction mixture was filtered through a thin pad of Kielselguhr eluting with ethanol (500 ml) and the filtrate was then evaporated to give the product as a yellow solid (1.294 g, 100%).
Reaction SMILES: [CH2:1]([N:5]1[CH:21]=[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH:11]=[N:12][C:7]2=[N:6]1)[CH2:2][CH2:3]C.[K+].[Br-]>>[CH2:1]([N:5]1[CH:21]=[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH:11]=[N:12][C:7]2=[N:6]1)[CH2:2][CH3:3]
Reactant: CCCCn1cc2c(ncn3nc(-c4ccco4)nc23)n1
Agent: [Br-]
Agent: [K+]
Product: CCCn1cc2c(ncn3nc(-c4ccco4)nc23)n1

Procedure:
8-Butyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (Compound 21) yield 50%, pale yellow solid m.p. 245-247° C. (EtOAc-light petroleum); IR (KBr): 1610, 1500 cm−1; 1H NMR (DMSO-d6) δ 0.9 (m, 3H); 1.3 (m, 2H); 1.9 (m, 2H); 4.5 (t, 2H, J=7.2); 6.2 (m, 1H); 7.3 (m, 1H); 8.0 (m, 1H); 8.9 (s, 1H); 9,4 (s, 1H).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[C:12]([O:16][C:17]([N:19]1[CH2:53][CH2:52][CH2:51][C:21]2([CH2:50][CH2:49][N:24]3[C:25]4[C:30]([C:31]([C:32]5[C:33](=[O:48])O[C:35](=[O:47])[C:36]=5[C:37]5[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]([CH3:46])[CH:38]=5)=[C:23]3[CH2:22]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:53][CH2:52][CH2:51][C:21]2([CH2:50][CH2:49][N:24]3[C:25]4[C:30]([C:31]([C:32]5[C:33](=[O:48])[NH:3][C:35](=[O:47])[C:36]=5[C:37]5[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]([CH3:46])[CH:38]=5)=[C:23]3[CH2:22]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC3(CCCN(C(=O)OC(C)(C)C)C3)C4)C(=O)OC2=O)c2ccccc21
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC3(CCCN(C(=O)OC(C)(C)C)C3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 1.08 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.11 g of methanol was added to a solution of 380 mg of 3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 10 ml of DMF and the mixtue was stirred for 16 hours and subsequently poured into 50 ml of water. The resulting mixture was extracted with dichloromethane and the extracts were washed with sodium chloride solution, dried and concentrated. Chromatography of the residue on silica gel using dichloromethane/methanol (9:1) for the elution gave 220 mg of 3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cncc1-c1cc2nc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-Benzyl-5-chloro-2-(1-methyl-1H-imidazol-5-yl)-1H-pyrrolo[3,2-b]pyridine (33 mg, 0.10 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (36 mg, 0.15 mmol) and Cs2CO3 (50 mg, 0.15 mmol) were combined in toluene (3.6 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (8.0 mg, 0.010 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 120° C. overnight. The mixture was diluted with DCM, filtered and concentrated. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded intermediate di-tert-butyl 1-[1-benzyl-2-(1-methyl-1H-imidazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate as 10 mg of light yellow oil. The oil was dissolved in AcOH (1.6 mL) and heated in the microwave to a temperature of 180° C. for 7 minutes. The AcOH was removed in vacuo and the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (4.5 mg, 13%).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]([O:19][CH3:20])=[N:17][C:16]3[C:11]2=[N:12][C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:14][C:15]=3[NH2:21])[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC1N=C2C(N=C(OC)N2CCCCCCl)=C(N)N=1)CCC.N1CCCC1>>[CH2:23]([O:22][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[C:18]([O:19][CH3:20])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:1]2[CH2:27][CH2:2][CH2:3][CH2:4]2)=[C:15]([NH2:21])[N:14]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Solvent: C1CCNC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and pyrrolidine.