Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:14]2[CH:27]=1.[CH3:28][O:29][CH2:30][CH2:31]Br.[F-].[K+]>CO.CN(C)C=O>[CH3:28][O:29][CH2:30][CH2:31][O:26][CH2:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:14]([CH:27]=[C:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[N:12]=3)[CH:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cccc(-c2ccc3nc(-c4ccc5ccccc5c4)cn3c2)c1
Reactant: COCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COCCOCc1cccc(-c2ccc3nc(-c4ccc5ccccc5c4)cn3c2)c1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
100 mg of [3-(2-naphthalen-2-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol (Example 2) and 120 mg of 2-bromoethanol methyl ether are dissolved in 5 ml of a 1/1 methanol/dimethylformamide mixture, in a pressure tube, and 1 g of potassium fluoride on alumina is added thereto. The tube is closed and heated for 16 h at 80° C. After cooling, the mineral is removed by filtration and washed with dichloromethane. The filtrate is concentrated under reduced pressure and purified by silica gel chromatography, elution being carried out with a 99/1 dichloromethane/methanol mixture. An oil which crystallizes from 5 ml of diisopropyl ether is obtained. The precipitate is recovered by filtration, washed with diisopropyl ether and dried under reduced pressure. 44 mg of compound are obtained. Mp=80-82° C. 1H NMR (DMSO-d6, δ in ppm): 3.25 (m, 3H) 3.55 (m, 4H); 4.57 (s, 2H); from 7.27 to 7.80 (m, 8H); from 7.82 to 8.16 (m, 4H); 8.52 (m, 2H); 8.89 (m, 1H). M+H=409.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[OH:4].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:23]=[CH:22][N:21]=1
Reactant: OC(c1ccccc1-c1ccncc1)C(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccncc1
Temperature: 110 °C
Yield: 79.1 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)ethanol (100 mg, 0.40 mmol), 4,6-dichloro-pyrimidine (54 mg, 0.38 mmol), cesium carbonate (468 mg, 1.44 mmol) and 1,4-dioxane (1 ml). The mixture was heated at 110° C. overnight. The reaction mixture was cooled to room temperature. 10 ml of ethyl acetate was added, and then the mixture was filtered through Celite. The filtrate was concentrated to give 110 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)-ethoxy]-pyrimidine, yield: 76%.
Reaction SMILES: CO.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][C:13]3[C:17]([OH:30])([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[O:16][C:15](=[O:31])[C:14]=3[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:11][C:6]=2[O:5][CH2:4]1>O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12]/[C:13](/[C:17](=[O:30])[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[C:14](/[C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)\[C:15]([OH:31])=[O:16])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COc1ccc(C2=C(Cc3ccc4c(c3)OCO4)C(O)(c3cc(OC)c(OC)c(OC)c3)OC2=O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(/C(C(=O)O)=C(/Cc2ccc3c(c2)OCO3)C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 16 h

Procedure:
To 250 mL methanol was added 4-benzo[1,3]dioxol-5-ylmethyl-5-hydroxy-3-(4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-5H-furan-2-one 4.0 g (7.89 mmol), giving solution. To the solution was added 250 mL water containing 15.8 mL 1.001N NaOH. The solution was irradiated with a Hanovia ultraviolet light contained in a quartz reactor (Ace Glass, Catalog 1200, #7840-180) for 16 hours at ambient temperature. The solution was evaporated in vacuo to remove the methanol. The residual aqueous solution was extracted repeatedly with ethyl ether, while the pH of the aqueous phase was adjusted incrementally between 7.5 and 8 by addition of 3N HCl. The aqueous phase was then acidified to pH 1 with HCl and extracted with ethyl ether. The ether extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether solution under reduced pressure gave a foam, 1.44 g. The residue was purified by chromatography on 50 g silica gel eluted with 1% methanol in chloroform. The appropriate fractions were evaporated to a solid, 0.77 g. The product was identified by 1H NMR, MS [M-H]+ =505.4 Da. and microanalysis.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][C:8]2([CH2:13][CH:12]([CH2:14][CH2:15][CH2:16][CH3:17])C(=O)[C:10]2=[O:19])[C:7](=[O:20])C1=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>NC1C=CC=CC=1>[CH2:14]([CH:12]1[CH2:13][C:8]2([CH2:9][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]2=[O:20])[C:10](=[O:19])[N:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC1CC2(CC(CCCC)C(=O)C2=O)C(=O)C1=O
Reactant: Nc1ccccc1
Agent: Cl
Product: CCCCC1CC2(CC(CCCC)N(c3ccccc3)C2=O)C(=O)N1c1ccccc1
Yield: 86 %

Procedure:
A mixture of 53.6 g (0.02 mole) of 3,8-dibutyl-2,7-dioxospiro-[4.4]nonane-1,6-dione, 10.32 g (0.08 mole) of aniline hydrochloride and 40 ml of aniline was placed in a 500 ml round bottom flask and heated to reflux. After refluxing for 6 hours, the aniline was removed by distillation at reduced pressure. The resulting mixture was subjected to column chromatography employing a 2:1 mixture of diethyl ether and petroleum ether as eluent. The product, 3,8-dibutyl-2,7-diphenyl-2,7-diazaspiro[4.4]nonane-1,6-dione, was isolated as a viscous oil in a yield of about 86%. The infrared, 13C-NMR and mass spectra of the product were consistent with this structure.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](OCC)(OCC)(OCC)[CH3:13]>C(O)CC>[CH3:12][C:13]1[O:9][C:1]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[N:10][N:11]=1
Reactant: NNC(=O)c1ccccc1O
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCO
Product: Cc1nnc(-c2ccccc2O)o1
Yield: 44.5 %

Procedure:
90 g (0.6 mole) of salicylic acid hydrazide and 388.8 g (2.4 moles) of triethyl orthoacetate in 500 ml of n-propanol are refluxed for 84 hours. When the mixture has cooled, the precipitate is filtered off and recrystallized from a mixture of toluene and petroleum ether. 47 g of colorless crystals (26.7% of theory) are obtained; melting point 74°-76° C.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62](Br)=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:48]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:47]1[CH:48]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([B:25]([OH:27])[OH:26])=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:50]=[CH:51][CH:52]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Product: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Yield: 70 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 34D (800 mg, 1.37 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 34E (530 mg, 70%) as an oily brown solid. 1H NMR (400 MHz, MeOD) δ ppm 1.16 (t, J=7.20 Hz, 3 H) 2.36 (s, 3 H) 2.67-2.85 (m, 2 H) 3.01 (t, J=7.07 Hz, 2 H) 4.06 (q, J=7.16 Hz, 2 H) 4.31 (t, J=7.07 Hz, 2 H) 4.96-5.11 (m, J=12.55, 12.55, 12.55 Hz, 3 H) 6.99 (d, J=7.33 Hz, 1 H) 7.15-7.25 (m, J=7.83, 7.83 Hz, 3 H) 7.31 (s, H) 7.35-7.43 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([CH3:22])=[CH:4][N:3]=1>CO.CN(C=O)C.O=[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([CH3:22])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1C#Cc1ccccc1C1(C(N)=O)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A mixture of 1-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide A39 (1.85 g, 5.93 mmol) and PtO2 (0.404 g, 1.78 mmol) in MeOH (10 mL) and DMF (40 mL) was stirred under an atmosphere of H2 for 110 hours at room temperature. The mixture was filtered through Celite and the volatiles were removed in vacuo. The residue was purified by column chromatography (Biotage Isolera, 40 g SiO2, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A40 as a white solid (1.65 g, 88%). LCMS-D: rt 3.20 min; m/z 316 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 41.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.34 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:5][C:2]([NH:1][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])([CH3:6])[CH2:3][OH:4]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: CC(C)(CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (2.0 g, 21.4 mmol) in tetrahydrofuran (15 mL) was added 1,3-propane sultone (2.66 g, 21.4 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The crude product was collected by filtration, washed with acetone (2×25 mL). The solid was suspended in EtOH (50 mL). The suspension was stirred at reflux for 5 minutes. The solid was collected by filtration and dried in a vacuum oven (50° C.), affording compound DH (2.5 g, 58%): 1H NMR (D2O, 500 MHz) δ ppm 3.48 (s, 2H), 3.04 (t, 2H, J=7.8 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.18 (s, 6H). 13C NMR (D2O, 125 MHz) δ ppm 64.88, 60.27, 48.19, 40.10, 21.92, 20.02. ES-MS 210 (M−1).
Reaction SMILES: [ClH:1].[CH2:2]([N:9](C)[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13])C1C=CC=CC=1>CO.O.[Pd]>[ClH:1].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH3:2])=[CH:19][CH:18]=1
Reactant: CN(CCC(=O)c1ccc(F)cc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNCCC(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 42.15 g (0.137 mole) of compound VI dissolved in 221 mL of a MeOH-water (1:1) mixture were added 9.68 g of Pd over 5% carbon (56.5% water). The mixture was hydrogenated at atmospheric pressure for 1 hour. The catalyst was filtered and the solvent was evaporated to dryness. The solid formed was recrystallized from AcCN and acetone to give 28.6 g (96%) of compound VII as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:21]1([C:24]2[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1.[S].C(O)(=O)C>C(O)C>[CH:21]1([C:24]2[N:29]=[C:28]([C:30]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: CCN(C)C(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reactant: O=Cc1ccnc(C2CC2)n1
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Yield: 13.7 %

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (200 mg, 0.722 mmol) in ethanol (10 mL) was added 2-cyclopropylpyrimidine-4-carbaldehyde (106 mg, 0.722 mmol), sulfur powder (69 mg, 2.16 mmol), and acetic acid (0.2 mL). The reaction mixture was heated to 80° C. for 18 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative HPLC to afford the title compound (40 mg, 13.5%). 1H NMR (300 MHz, CDCl3) δ 1.09-1.18 (m, 3H), 1.19-1.31 (m, 4H), 1.65-1.73 (m, 1H), 1.84 (d, 1H), 1.88-1.98 (m, 2H), 2.31 (d, 1H), 2.69-2.87 (m, 1H), 2.99 (br s, 1H), 3.03 (br s, 1H), 3.11 (br s, 1H), 3.14-3.27 (m, 1H), 3.37-3.57 (m, 2H), 4.37 (d, 1H), 4.45-4.59 (m, 1H), 6.76 (d, 1H), 7.79-7.96 (m, 1H), 8.67 (d, 1H), 10.25 (br s, 1H). MS (ES+APCI) (M+H) 406.3; LCMS retention time 3.055 min (Method U1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][NH:31][C:32](=O)[O:33]C1C=CC=CC=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:23]([O:30][NH:31][C:32]([N:11]1[CH2:12][CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[C:10]1=[O:14])=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Reactant: O=C(NOCc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C=C2CCN(C(=O)NOCc3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 61 %

Procedure:
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (600 mg, 2 mmole) and phenyl N-benzyloxycarbamate (490 mg, 2.01 mmole) were dissolved into 8 ml of pyridine and the solution was heated under reflux for 12 hours. The reaction mixture was evaporated and the obtained residue was dissolved into ethyl acetate, which was washed with an aqueous solution of 0.1N hydrochloric acid, water, and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=10:1) and recrystallized from dichloromethane/n-hexane, whereby 550 mg of the objective compound (Ia-10) was obtained in 61% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:8](=[O:15])[NH:9][C:10]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CSc1ncc(Oc2ccc(Cl)cc2)c(=O)[nH]1
Product: CN1CCN(c2ncc(Oc3ccc(Cl)cc3)c(=O)[nH]2)CC1
Yield: 37.2 %

Procedure:
A solution of of 5-(4-chlorophenoxy)-2-(methylmercapto)pyrimidin-4(3H)-one (158 g, 5.87 mmoles) and 1-methylpiperazine (Aldrich) (6.1 mL, 55 mmoles) was heated at 135° C. for 18 hours. The dark brown mixture was spin evaporated in vacuo. The residue was dissolved in ethyl acetate and applied to a column (d=5 cm) of Silica Gel 80 that was equilibrated with ethyl acetate. The column was eluted with ethyl acetate by flash chromatography to remove unreacted starting material. Elution with 10% methanol-dichloromethane and spin evaporation in vacuo of the combined fractions gave a beige solid that was triturated with ethyl acetate to give 0.70 g (37% yield) of 5-(4-chlorophenoxy)-2-(4-methylpiperazino)pyrimidin-4(3H)-one. Recrystallization from ethyl acetate gave off-white flakes that had an NMR spectrum consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH2:23][NH2:24]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:15]([CH3:16])[CH3:17])=[O:18])=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:19]([NH:23][NH2:24])=[O:21]
Reactant: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Reactant: NN
Solvent: CCO
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a stirred solution of methyl 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylate (1.7011 g, 5.664 mmol) in EtOH (10.21 mL) was added hydrazine (726.1 mg, 711.2 μL, 22.66 mmol). The resultant solution was heated to reflux for 30 minutes and then allowed to cool to RT. The precipitate was filtered off and dried (1.47 g, 87% Yield). 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 4.58 (d, J=4.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 8.27-8.29 (m, 2H), 8.88 (s, 1H) and 10.09 (s, 1H) ppm; MS (ES+) 301.13
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1,4-dibenzyl-2-(hydroxymethyl)piperazine (1.51 g), phthalimide (0.790 g) and triphenylphosphine (1.40 g) in tetrahydrofuran (20 ml) was added a 40% toluene solution (2.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. Furthermore, 1,4-dibenzyl-2-(hydroxymethyl)piperazine (0.87 g), phthalimide (0.486 g), triphenylphosphine (0.81 g) and tetrahydrofuran (5 ml) were added to the reaction mixture, followed by the addition of a 40% toluene solution (1.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 18.5 hours. Phthalimide (0.405 g) and a 40% toluene solution (1.10 ml) of diethyl azodicarboxylate were added under ice cooling, followed by stirring at room temperature for 20 hours. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography twice (3% methanol—methylene chloride for the first time and ethyl acetate/hexane=1/3 for the second time) using as a carrier silica gel, whereby a crude product was obtained. The crude product was crystallized from hexane - methylene chloride, collected by filtration and washed with hexane, whereby the title compound (0.243 g) was obtained as colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@@H:9]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:8]1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@@H](c2ccccn2)C1
Solvent: CCO
Product: N[C@@H]1CC[C@@H](c2ccccn2)C1
Yield: 69.8 %

Procedure:
A mixture of (1R,3R)-N-[3-(2-pyridyl)cyclopentyl]phthalimide (4.17 g, 14.3 mmol), and hydrazinemonohydorate (2.0 mL, 41.2 mmol) in EtOH (100 mL) was stirred at reflux for 4 h. After cooling, the reaction mixture was filtered followed by the removal of solvent. The residue was suspended in EtOAc and stirred at reflux for 1 h. After cooling, the precipitate was filtered followed by the removal of solvent to yield (1R,3R)-3-(2-pyridyl)cyclopentylamine (1.62 g, 70%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][OH:25])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([NH:55][C@H:56]([C:60](O)=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[CH2:48]([O:47][C:45]([NH:55][C@H:56]([C:60]([O:25][CH2:24][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)=[O:61])[CH:57]([CH3:59])[CH3:58])=[O:46])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
To a stirred suspension of N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (2.1 g, 5.8 mmol) in THF was added triphenylphosphine (1.5 equivalents, 8.7 mmol, 2.2 g) followed by CBZ-L-valine (1.5 equivalents, 8.7 mmol, 2.3 g). The suspension was stirred for 5 min after which it was cooled in an ice-bath. To this cooled reaction mixture diisopropyl azodicarboxylate (DIAD, 1.8 equivalents, 10.4 mmol, 2.0 mL) was added and the reaction was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude solid was purified by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-8% methanol in dichloromethane with 1% ammonium hydroxide) to provide a solid. The solid was heated in diethyl ether and filtered to afford (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl N-[(benzyloxy)carbonyl]-L-valinate (2 g) as a beige solid, mp 99-100° C.; MS (ESI) m/z 597 (M+H)+; Anal. Calcd for C29H36N6O6S: C, 58.37; H, 6.08; N, 14.08; Found C, 57.98; H, 6.31; N, 13.82.