Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-:6].[K+].[K+].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>O.C(Cl)Cl>[CH3:2][O:3][N:4]([C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11])[OH:6]
Reactant: O=C([O-])[O-]
Reactant: CON
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CON(O)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred mixture of 30.3 g (0.363 moles) methoxyamine hydrochloride and 51 g (0.37 moles) potassium carbonate in about 300 ml water/methylene chloride maintained at a temperature below -5° C., 50 g (0.32 moles) 2-fluoro-benzoylchloride were dropped in. The reaction mixture was then allowed to stir at room temperature overnight. The aqueous and methylene chloride layers were separated. The methylene chloride layer was dried over magnesium sulfate, filtered and stripped to give about 45 g of the above-identified product, as a clear amber liquid.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31]C)=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][C@H:21]([OH:23])[C@H:20]([OH:24])[C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([OH:31])=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][C@H:21]([OH:23])[C@H:20]([OH:24])[C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Temperature: 90 °C
Yield: 93.8 %

Procedure:
Sodium hydroxide (0.2′ 1 mL of 1 N, 0.2 mmol) was added to a solution of methyl (5R,6S)-rel-13-cyclohexyl-6,7-dihydro-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20 mg, 0.049 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 7 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid and a precipitate was observed to form. The solid was collected by filtration and purified on the Prep. reverse phase HPLC. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (18 mg, 94%). ESI-MS m/z 392 (MH+) 1H NMR (500 MHz, MeOD) δ 1.25–1.34 (m, 1 H) 1.39–1.54 (m, 2 H) 1.60–1.67 (m, 1 H) 1.77–1.86 (m, 2 H) 1.93–2.00 (m, 1 H) 2.01–2.17 (m, 3 H) 2.93–3.02 (m, 1 H) 3.36 (m, 1 H) 4.43 (d, J=4.27 Hz, 1 H) 4.54 (m, 1 H) 4.72 (dd, J=14.19, 7.17 Hz, 1 H) 7.46 (m, 2 H) 7.53 (m, 1 H) 7.74 (dd, J=8.39, 1.37 Hz, 1 H) 7.79 (d, J=7.63 Hz, 1 H) 7.90 (d, J=8.24 Hz, 1 H) 8.19 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH2:22]([P:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([O:35][CH3:36])[CH:29]=1)([CH2:26][CH3:27])=[O:25])[CH3:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([P:24]([CH2:26][CH3:27])([CH2:22][CH3:23])=[O:25])=[CH:29][C:30]=2[O:35][CH3:36])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CCP(=O)(CC)c1ccc(N)c(OC)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CCP(=O)(CC)c1ccc(Nc2nnc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Diethylphosphoryl)-2-methoxyaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](=O)[CH2:14][C:15]#[N:16].[NH2:18][NH2:19]>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:14]=[C:15]([NH2:16])[NH:18][N:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CC#N
Reactant: NN
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cc(N)[nH]n1

Procedure:
3-(5-Methyl-3-phenyl-isoxazol-4-yl)-3-oxo-propionitrile (0.391 g, 1.73 mmol) in Ethanol (3 mL) was treated with hydrazine (0.168 mL, 3.46 mmol) and heated to reflux. Evaporation in vacuum gave 5-(5-Methyl-3-phenyl-isoxazol-4-yl)-2H-pyrazol-3-ylamine used without purification. To the resulting amine (0.039 g, 0.16 mmol) in dioxane was added triethyl amine followed by benzyl chloride (0.019 mL, 0.16 mmol). The reaction was stirred at 10° C. for 1 hr and 2 hr at ambient temperature. The solution was diluted with water extracted with ethyl acetate, washed with saturated NaHCO3, Brine, dried over MgSO4 and concentrated in vacuum. HPLC purification afforded 1.4 mg of title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCNCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(F)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 was dissolved in N,N-dimethylformamide (3 ml). 1-Methylpiperazine (36 mg, 0.36 mmol), EDC (90 mg, 0.47 mmol) and HOBT (75 mg, 0.55 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (78 mg, Yield 64%).
Reaction SMILES: CN.[CH3:3][N:4](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]=1[CH2:37][OH:38]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([NH:4][CH3:3])=[O:35])=[CH:28][C:27]=1[CH2:37][OH:38]
Reactant: O=C(O)CCc1ccc(Cl)c(CO)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CNC(=O)CCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.6 %

Procedure:
MeNH2 (2M in THF, 28.0 mL, 56.1 mmol) and TBTU (1.98 g, 6.17 mmol) were added to a sol. of 3-(4-chloro-3-hydroxymethyl-phenyl)-propionic acid (1.20 g, 5.59 mmol) in CH2Cl2 (42 mL). The mixture was stirred at rt for 2.5 h, and CH2Cl2 (150 mL) was added. The mixture was washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:9) yielded the title compound (250 mg, 20%). LC-MS: tR=0.67 min; ES+: 269.34.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13](CO)=[C:12](O)[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:26])=O.[CH:29]([Cl:32])(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH2:12][Cl:26])=[C:29]([Cl:32])[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: ClC(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2ccc3c(O)c(CO)cnc3c2=O)cc1
Product: COc1ccc(Cn2ccc3c(Cl)c(CCl)cnc3c2=O)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
7-(4-methoxybenzyl)-4-hydroxy-3-(hydroxymethyl)-1,7-naphthyridin-8(7H)-one (1.1 g, 3.5 mmol) was suspended in chloroform and treated with phosphorous oxychloride (4.9 ml, 53 mmol) and the mixture was stirred at 85° C. After 3 hours, the reaction was cooled down to room temperature and the volatiles were removed under vacuum. Residual phosphorous oxychloride was azeotroped with toluene. The residue was dissolved in chloroform and washed with cold water (2×). The organic layer then washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 0 to 5% metahnol in DCM to give 7-(4-methoxybenzyl)-4-chloro-3-(chloromethyl)-1,7-naphthyridin-8(7H)-one as a yellow film. MS(M+H)+ 350.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].COC1C=CC(C=CC(O)=O)=CC=1.S(Cl)(Cl)=O.Cl.[CH3:34][NH:35][CH3:36]>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([N:35]([CH3:36])[CH3:34])=[O:8]
Reactant: CNC
Reactant: COc1ccc2c(Cl)c(C(=O)O)sc2c1
Agent: COc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(Cl)c(C(=O)N(C)C)sc2c1

Procedure:
3.0 g of 3-chloro-6-methoxy-benzo(b)thiophene-2-carboxylic acid (7.0 g) synthesized from 4-methoxycinnamic acid (10.0 g) and thionyl chloride (15 ml) according to the method described in J. Med. Chem. 1992, 35, 958–965 was reacted with dimethylamine hydrochloride and triethylamine in THF to give the title compound (1.9 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([N:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][O:20][C:14]=3[CH2:13]2)=[O:11])=[CH:8][CH:7]=1)=[O:5].[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:19]1[O:20][C:14]2[CH2:13][N:12]([C:10](=[O:11])[C:9]3[CH:21]=[CH:22][C:6]([C:4](=[O:5])[C:3]4[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=4[CH3:1])=[CH:7][CH:8]=3)[CH2:17][CH2:16][C:15]=2[CH:18]=1)[CH3:29]
Reactant: CNC
Reactant: Cc1ccccc1C(=O)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)c1ccc(C(=O)N2CCc3cc(CN(C)C)oc3C2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 0.250 g (0.724 mmol) of 6-[4-(2-methylbenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.098 ml (1.09 mmol) of 50% aqueous dimethylamine and 0.088 ml (1.09 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 120 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/methanol=5/1) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:46])[CH2:19][CH:20]1[CH2:25][NH:24][C@H:23]([C:26]([N:28]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29]2)=[O:27])[C@@H:22]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:46])[CH2:19][CH:20]1[CH2:25][NH:24][C@H:23]([C:26]([N:28]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:29]2)=[O:27])[C@@H:22]([C:39]([OH:41])=[O:40])[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(CC(=O)NCCCCCNC(=O)OCc2ccccc2)CN[C@@H]1C(=O)N1CCC(c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CC1CN[C@H](C(=O)N2CCC(c3ccccc3)C2)[C@@H](C(=O)O)C1)NCCCCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of tert-butyl (2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate (40 mg, 0.063 mmol) in methylene chloride (2 mL) was added a drop of water and trifluoroacetic acid (4 mL). After stirring the reaction mixture overnight, the volatiles were removed in-vacuo and the residue was azeotropically washed with benzene (2×3 mL) and heptane (2×3 mL). The crude product was dried under high vacuum and used directly in the following coupling reaction without purification. MS (ESI): 579 (M+H).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[OH:31][C:32]1[C:37]([C:38]([NH:40][NH2:41])=O)=[CH:36][CH:35]=[CH:34][N:33]=1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:38]([C:37]3[C:32]([OH:31])=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:40][N:41]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1cccnc1O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cccnc2O)C1
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
Triethyloxonium tetrafluoroborate (215 mg, 1.134 mmol) was added under argon to a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (300 mg, 1.031 mmol) in Dichloromethane (DCM) (2.5 mL). The mixture was stirred at room temperature for 1 h 15 min—after 55 min, the mixture became clear. 2-Hydroxy-3-pyridinecarbohydrazide (I92) (189 mg, 1.237 mmol) was added to the solution and the mixture was stirred at room temperature for one day. The solvent was evaporated under reduced pressure and the residue was dissolved in tert-butanol (2.500 mL).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9].CCOC(C)=O>C1COCC1>[S:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:11]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccsc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
EtMgBr (3 M, 1.2 eq, 18.6 mL) was added to a solution of N-methoxy-N-methylthiophene-3-carboxamide (8 g, 1.0 eq) in dry THF. Once the addition was complete, the mixture was stirred at rt overnight. The reaction mixture was washed with saturated NH4Cl (aq), dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=5:1 to give the desired product as a yellow oil (3.4 g, 52% yield). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 2.92 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: [ClH:1].CC(C)(OC([NH:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)C>CCOC(C)=O>[ClH:1].[NH2:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)c1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ 1.03 (t, J=7 Hz, 3H), 3.02 (dd, J=10 Hz, J=15 Hz, 1H), 3.25 (dd, J=6 Hz, J=15 Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[NH2:54][CH2:53][CH2:52][NH:55][C:24](=[O:26])[CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH3:27])=[CH:17][CH:18]=1
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1 h

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylamino]acetic acid (754 mg, 1.87 mmol) in dimethylformamide (20 mL) and treat with N-hydroxysuccinimide (215 mg, 1.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (751 mg, 3.92 mmol). Stir for 1 hour and add to a stirring solution of ethylenediamine (20 mL of a 10% solution in methanol). Stir for 1 hour and dilute with chloroform (600 mL). Separate the organic phase, wash with 5% sodium carbonate (200 mL), then brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo. Purify by radial chromatography to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C(O[N:21]1N=N[C:23]2C=CC=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(=NO)(N)C>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:27]=[C:22]([CH3:23])[N:21]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(I)ccc1C(=O)O
Agent: CC(N)=NO
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(I)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
A mixture of 4-iodo-2-methoxy benzoic acid (83 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), DIEA (26 μL, 0.15 mmol), and HOBt (8 mg, 0.06 mmol) in DMF was stirred at room temperature for 5 minutes. Acetamide oxime (22 mg, 0.3 mmol) was added, and reaction was stirred for 30 minutes at room temperature. The reaction was then heated to 110° C. for 16 hours. Cooled to room temperature. Partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by HPLC to provide 37 mg (39%) of desired product. MS (ESI) m/e 317 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 7.70 (d, J=8.14 Hz, 1H), 7.64 (d, J=1.36 Hz, 1H), 7.53 (dd, J=8.31-1.53 Hz, 1H), 3.94 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][CH3:25])[C:21]([CH2:26][O:27][CH2:28][CH3:29])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>[Pd].C(O)C>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:26][O:27][CH2:28][CH3:29])[N:22]([CH2:23][CH2:24][CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(COCC)nc2c(N)nc3cc(O)ccc3c21
Reaction time: 18 h
Yield: 80 %

Procedure:
7-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.9 g, 9.99 mmol) was mixed with ethanol and added to a Parr flask charged with 10% palladium on carbon (0.390 g) in ethanol. The flask was placed under hydrogen pressure and shaken for 18 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with warm DMF. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to yield 2.4 g of 4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol as a white solid, mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1Cl
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1Cl

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-chloro-4-methoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 3-(3-Chloro-4-methoxy-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 205-208° C.; HPLC: TRet (Grad20-100)=12.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62])=[O:9]
Reactant: COc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(C)C1CCOCC1
Yield: 62.6 %

Procedure:
To a solution of 5-chloro-2-methoxy-3-[methyl(oxan-4-yl)amino]benzoic acid (200 mg, 0.67 mmol) in DMF (2 ml) at room temperature under nitrogen was added HBTU (304 mg, 0.80 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (174 μl, 1.0 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 125 mg, 0.73 mmol). After stirring for 2 hours at room temperature EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 96:4 DCM:MeOH) to give 182 mg (63%) of the title compound as an off-white solid. LC-MS 98%, m/z=434.1/436.1, 1H NMR (500 MHz, Chloroform-d) δ ppm 12.52 (br s, 1H), 8.76 (t, J=5.8 Hz, 1H), 7.69 (d, J=2.6 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 5.94 (s, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.99 (dd, J=11.2, 3.9 Hz, 2H), 3.72 (s, 3H), 3.49 (tt, J=11.5, 3.7 Hz, 1H), 3.36 (t, J=11.2 Hz, 2H), 2.67 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3H), 1.93-1.73 (m, 2H), 1.64-1.52 (m, 2H).