Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Mg].[B:19](OC)([O:22]C)[O:20]C>BrCCBr.C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[C:3]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: COc1ccc(Br)c(OCc2ccccc2)c1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A 2 L three-necked flask equipped with thermometer, reflux condenser and mechanical stirrer was charged with 1-bromo-4-methoxy-2-(phenylmethoxy)benzene (43.0 g, 0.147 mol), anhydrous THF (600 mL) under nitrogen. Magnesium turnings (4.2 g, 0.17 mol) and 1,2-dibromoethane (0.5 mL, 6 mmol) was then added and the mixture heated to reflux. After 1.5 h, the reaction was cooled to -78° C. and B(OMe)3 (33.4 mL, 0.294 mol) added dropwise while maintaining an internal temperature below -60° C. Upon complete addition, the reaction was quenched with 5% HCl (15 mL) to pH=3.0, portioned with EtOAc (100 mL), the organic phase separated, washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo giving a pale yellow solid. The solid was triturated with hexane (90 mL), filtered and dried to afford [4-methoxy-2(phenylmethoxy)phenyl] boronic acid as a pale white solid (32 g, 85%): mp 127.0-129.0° C.; 1H NMR δ 7.8 (d, J=8.2 Hz, 1 H), 7.5-7.3 (m, 5 H), 6.6 (dd, J=8.2, 2.7 Hz, 1 H), 6.55 (d, J=2.7 Hz, 1 H), 5.65 (s, 2 H), 5.15 (s, 2 H), 3.85 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+].BrBr>CC(O)=O.O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-aminobenzoic acid (1.37 g, 14 mmol) in AcOH (16 mL) may be added with potassium thiocyanate (3.9 g, 40 mmol) and may be stirred for 15 minutes. A solution of bromine (0.5 mL, 10 mmol) in AcOH (6 mL) may then be added slowly into the reaction mixture in water bath, where the temperature may be maintained at about 25° C. The resulting mixture may be stirred overnight. The mixture may then be filtered, and the pale yellow precipitate may then be further recrystallized with the minimal volume of aqueous hydrochloric acid (6 M). A pale yellow product of formula (2) may be collected with the following characterization: 1H NMR (CD3OD, 500 MHz): δ 4.96 (2H, brs), 7.58 (1H, d, J=8.0 Hz), 8.14 (1H, dd, J=8.5 Hz and 1.5 Hz), 8.47-8.47 (1H, m); 13C NMR (CDCl3): δ 12.1, 23.7, 54.6, 85.0, 85.1, 122.5, 123.9, 127.9, 128.3, 132.7, 151.9, 155.3, 168.0, 178.7.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[Na+].[I-].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1)([CH3:42])[CH3:43]
Reactant: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of Intermediate A (102 mg, 0.63 mmol) in DMF (1.5 mL) was added NaI (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was stirred at RT for 5 min, then a solution of Intermediate 94b (240 mg, 0.57 mmol) in DMF (1.5 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (219 mg, 68%). LCMS (Method 3): Rt 2.65 min, m/z 565 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: COc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1
Yield: 90 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-methoxyphenyl boronic acid instead of phenyl boronic acid to obtain the title compound (90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1/[CH:8]=[CH:16]/[N:17]([CH3:19])[CH3:18]
Reactant: COc1ncc([N+](=O)[O-])c(C)c1Br
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc([N+](=O)[O-])c(/C=C/N(C)C)c1Br
Temperature: 90 °C

Procedure:
To a solution of 3-Bromo-2-methoxy-4-methyl-5-nitro-pyridine (3.00 g, 12.1 mmol) in DMF (0.6M) was added via syringe N,N-dimethylformamide-dimethylacetal (3.0 mL, 22.4 mmol, 1.8 eq) in a fast dropwise manner. The solution was heated for 2 hr at 90° C., cooled to 23° C., then diluted with Ethyl Acetate (200 mL). The washed reaction mixture was washed with water, brine, dried (Na2SO4), and concentrated giving [(E)-2-(3-Bromo-2-methoxy-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine as a red solid which was used without further purification (3.45 g, 10.9 mmol, 89%). MS ESI m/z 304.2 (M+2H)+. 1NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.03 (d, J=13.5 Hz, 1H), 5.30 (d, J=13.5 Hz, 1H), 4.05 (s, 3H), 2.97 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12]([NH:14][CH3:15])=[O:13].[C:26](Cl)(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:43]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CNC(=O)c1ccc(NCCCN(C)C)c(N)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)NC)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Triethylamine (0.77 ml) was added to a solution containing 3-amino-4-{[3-(dimethylamino)propyl]amino}-N-methylbenzamide (1.44 g) in chloroform (10 ml), and then a solution containing stearoyl chloride (1.51 g) in chloroform (5 ml) was added thereto while being cooled with ice. After being stirred for 1.5 hours at room temperature, the reaction mixture was diluted with chlorofonr, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.00 ml) was added to a solution containing the residue (2.78 g) in ethanol (25 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 4N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.77 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-10:1), thereby yielding the entitled compound (2.11 g) as grayish yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[CH3:12][C:13](OC(C)=O)=[O:14].N1C=CC=CC=1>ClCCl>[C:13]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][CH:9]=1)(=[O:14])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 4-n-butylphenol, 10 ml of Ac2O and 8 ml of pyridine is stirred at reflux in 10 ml of dichloromethane. After 2 hours, the medium is cooled to ambient temperature, diluted in dichloromethane, washed with water, washed with a 1M HCl solution, washed in a saturated CuSO4 solution, washed with water, and dried over MgSO4. After evaporation, 10.8 g of the expected compound are recovered in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](B1OC(C)(C)C(C)(C)O1)([CH3:14])=[CH2:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CCCCO.O>[C:12]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)([CH3:14])=[CH2:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: C=C(C)c1ccc2c(c1)CC(=O)N2
Temperature: 110 °C
Yield: 46.2 %

Procedure:
A mixture of 5-bromoindolin-2-one (106 mg, 0.500 mmol), isopropenylboronic acid pinacol ester (0.14 mL, 0.750 mmol), K3PO4 (212 mg, 1.00 mmol), water (1 mL) and n-BuOH (4 mL) was briefly sonicated in a microwave vial and then purged with argon for 15 min. Tris(dibenzyldeneacetone)dipalladium (9.2 mg, 0.010 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (19 mg, 0.040 mmol) were added, the vial sealed and heated in microwave reactor at 110° C. for 1 hour. The solvent was removed and the residue purified by column chromatography (silica gel, 2:1, hexanes/EtOAc) to give 40 mg, 46% of 5-isopropenylindolin-2-one as a beige solid; 5-isopropenylindolin-2-one (15 mg, 0.0866 mmol) was then dissolved into MeOH and the solution purged with N2 (g). 2 mg of 10% Pd/C (Degussa type) was then added and the mixture purged briefly with H2 (g). The mixture was stirred under 1 atm of H2 (g) for 3 hours and then filtered through a pad of celite. The solvent was removed to give 15 mg, 99% of the product as an off-white solid. MS ESI 176.0 [M+H]+, calcd for [C11H13NO+H]+ 176.11.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ6 10.31 (bs, 1H), 10.04 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.75 (t, 1H, J=3.0 Hz), 7.54 (td, 1H, J=3.0 and 9.0 Hz), 7.34 (s, 1H), 7.20-7.15 (m, 2H), 6.80 (d, 1H, J=8.1 Hz), 5.38-5.31 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.49 (dd, 1H, J=11.1 and 16.5 Hz); LCMS: purity: 99%; MS (m/e): 446 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:31])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (27.5 mg, 0.1 mmol), as prepared in Example 1d, in anhydrous DMF, was added 4-dimethylamino-phenylisocyanate (25 mg, 0.15 mmol) and the mixture was stirred at rt overnight. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to yield 19 mg (44%) of pure 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-dimethylamino-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): 9.07 (s, 1H), 7.33 (s, 1H), 7.28-7.17 (m, 3H), 6.9-6.56 (bs, 2H), 6.50-6.22 (bs, 1H), 4.26 (m, 2H), 4.06 (s, 6H), 3.57 (m, 1H), 3.14 (m, 2H), 3.02-2.76 (m, 6H), 2.22-1.90 (m, 4H). LC/MS (ESI): calcd mass 435.2, found 436.5 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(O)CC5)c34)cc2Cl)cn1
Yield: 36 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 36% yield; NMR Spectrum: 1.32-1.38 (m, 2H), 1.67-1.69 (m, 2H), 2.16 (t, 2H), 2.45 (s, 3H), 2.79 (m, 4H), 3.40-3.44 (m, 1H), 4.43 (t, 2H), 4.52 (br s, 1H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.71 (d, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.35 (s, 1H), 8.61 (br s, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:29])[CH:14]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:15](=O)[CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:29])[CH:14]([C:15]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=12)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:11]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C(=O)C1CCCC1=O)C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Yield: 51 %

Procedure:
(4-Chloro-phenyl)-hydrazine (5.63 g, 31 mmol; CAS Reg. No. 1073-69-4) was added to a solution of 2-cyclohexyl-3-oxo-3-(2-oxo-cyclopentyl)-propionic acid ethyl ester (8.8 g, 31 mmol) in ethanol (200 ml). The reaction mixture was heated under reflux conditions for 6 h. The solvent was removed under reduced pressure. The residue was suspended in dichloromethane and filtered off. The filtrate was brought to dryness under reduced pressure to give a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (6.26 g, 16 mmol; 51%) as orange oil. MS: m/e=388.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[N:8][C:9]=2[NH2:12])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38]OS(C)(=O)=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][N:4]2[C:3]([O:2][CH3:1])=[N:11][C:10]3[C:5]2=[N:6][C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[N:8][C:9]=3[NH2:12])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: COCCOc1nc(N)c2[nH]c(OC)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
8-Methoxy-2-(2-methoxyethoxy)adenine (3.27 g, 13.7 mmol) was dissolved in DMF (75 ml), and thereto were added potassium carbonate (1.89 g, 13.7 mmol) and 4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (4.21 g, 13.7 mmol), and the mixture was stirred at 60° C. for 2.5 hours. The mixture was cooled to room temperature, and the carbonate salt was removed by filtration, and the filtrate was concentrated. To the residue was added water, and the mixture was extracted three times with chloroform. The resultant was dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column (chloroform/methanol=200/1 to 100/1) to give the subtitle compound (3.62 g, 8.04 mmol) as a white solid. Yield: 60%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:5][C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([O:10][CH3:11])=[C:8]([CH3:12])[CH:7]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1c(C)cc(C=O)cc1C
Product: COc1c(C)cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C

Procedure:
3,5-Dimethyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(4-methoxy-3,5-dimethylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 3-trifluoromethyl-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.47 (br s, 1H), 8.12 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.74 (s, 1H), 7.57-7.69 (m, 4H), 4.67 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297. Found 297.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[NH2:22][C:23]1[C:24]([C:31](O)=[O:32])=[N:25][C:26]([Cl:30])=[C:27]([NH2:29])[N:28]=1>>[NH2:22][C:23]1[C:24]([C:31]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:32])=[N:25][C:26]([Cl:30])=[C:27]([NH2:29])[N:28]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Cl)c(N)nc2N)C1
Yield: 57 %

Procedure:
Following method 11, tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 3,5-diamino-6-chloropyrazine-2-carboxylic acid yielding (S)-tert-butyl 1-(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (57%). LCMS (m/z): 463.1 (MH+); LC Rt=2.36 min.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[F:6])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: O=C(Nc1cc(F)ccc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 15 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 4 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][OH:10])[C:5]([F:13])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([F:13])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CO)c1cc(Br)ncc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(COS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propane-1,2-diol (17.45 g, 69.8 mmol) and triethylamine (19.45 ml, 14.12 g, 140 mmol) in DCM (350 ml) at 0° C. was added dropwise methanesulfonyl chloride (5.71 ml, 8.39 g, 73.3 mmol) over a period of 10 min. The reaction mixture was stirred at 0° C. for 30 min, then quenched with 1M aq. NaHCO3 soln. The phases were separated, the aq. phase was twice reextracted with DCM and the combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (gradient heptane: EtOAc 0-5 min 88:12, 5-37.5 min 24:76) yielded the title compound as a clear oil. HPLC RtH4=0.76 min; ESIMS: 328, 330 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, 1H), 7.82 (d, 1H), 4.58-4.47 (m, 2H), 3.04 (s, 3H), 3.00 (s, 1H), 1.64 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(N(CC)CC)C>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2ccccc2n1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-2-carbonyl chloride were combined in dichloromethane and triethylamine (3 equivalents) to provide N2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-2-quinolinecarboxamide as a white solid, m.p. 78.1-79.9° C. 1H NMR (300 MHz, DMSO-d6) δ9.02 (t, J=6.1 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.10 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.75-7.70 (m, 1H), 7.58 (dd, J=8.3, 1.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.48 (broad s, 2H), 4.58 (m, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.44 (m, 2H), 3.22 (m, 5H), 1.91-1.78 (m, 4H); MS (EI) m/e 468.2276 (468.2274 calcd for C27H28N6O2).