Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26]([NH:28]C(OC2C=CC=CC=2)=O)=O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(O)C.[CH:41]([Cl:44])(Cl)Cl>>[Cl:12][C:26]1[N:28]=[C:41]([Cl:44])[C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:22]([O:23][CH3:24])[CH:21]=2)[N:25]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(NC(=O)NC(=O)Oc2ccccc2)cc1OC
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
One ml. of N,N-dimethylaniline is added to 10 ml. of phosphorus oxychloride at 20°-25°. After a period of 5 min. 1-(3,4-dimethoxyphenyl)-3-phenoxycarbonylurea (0.785 g., 2.4 mmole) is added and the solution heated to reflux for a period of 4 hours. After the reflux period, excess phosphorus oxychloride is removed under reduced pressure providing a dark oily residue which is dissolved in chloroform. The chloroform solution is added cautiously to an ice/water mixture and after 10 min. the organic layer is separated and the aqueous phase extracted with additional chloroform. Combined chloroform extracts are sequentially washed with water, aqueous 1.0 N hydrochloric acid, water, aqueous 0.5 N sodium hydroxide and finally water. After drying the solution over sodium sulfate, the chloroform extract is concentrated under reduced pressure to provide 0.92 g. of a yellow-brown solid. Chromatographic purification of this material employing an aluminum oxide column eluted with toluene affords 0.504 g. of yellow solid. Trituration of this material with cold ethanol affords 0.368 g. (58% yield) of 2,4-dichloro-6,7-dimethoxyquinazoline, m.p. 175°-177°; mixture melting point (174°-177°; with sample: m.p. 158.5°-162°, prepared according to Curd, et al., J. Chem. Soc., 1765, (1948) and otherwise identical according to infrared, nuclear magnetic resonance and vaporphase chromatograph analysis.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.C[CH2:14][N:15](C(C)C)C(C)C.ClC(OCC1C=CC=CC=1)=O>C1COCC1>[C:14]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 2 (0.376 mol), DIEA (196 mL, 1.13 mol) and THF (200 mL) was added benzyl chloroformate (59.0 mL, 0.414 mol) dropwise. After the reaction solution was stirred at room temperature for 1 hr, the solution was concentrated on a rotovap. The residue was partitioned between sat. NaHCO3 (300 mL) and dichloromethane and the aqueous phase extracted with additional dichloromethane (100 mL×3). The combined dichloromethane layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give product 3 (0.376 mol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1O)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].OC1C=C2C(CCC2)=CC=1C1(CO)C2C(=CC=CC=2)N(CC(OCC)=O)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 1.45, and making non-critical variations using ethyl [4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace ethyl [3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (41%): mp 133-134° C.; 1H NMR (300 MHz, CDCl3) δ 7.26-7.15 (m, 3H), 6.78-6.58 (m, 2H), 5.08 (d, 1H), 4.91 (d, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.24 (q, 2H), 1.29 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.5, 166.8, 157.1, 143.7, 130.7, 129.0, 127.8, 120.0, 111.8, 111.6, 107.5, 99.8, 99.5, 62.2, 59.1, 41.7, 14.1; MS (ES+) m/z 438 (M+1), 440 (M+1), 460 (M+23), 462 (M+23).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][O:18]C1=O)=[O:14])#N.[OH-:21].[K+].Cl.[OH2:24]>>[OH:18][CH2:19][CH2:20][CH2:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]([OH:24])=[O:21]
Reactant: N#CCCCCCCCCCCC(=O)C1CCOC1=O
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [K+]
Product: O=C(O)CCCCCCCCCCC(=O)CCCO
Yield: 93.3 %

Procedure:
0.279 g (1.00 millimole) of α-(11-cyanoundecanoyl)-γ-butyrolactone, 0.68 g (10.3 millimole) of 85 % potassium hydroxide and 5.66 g of water were charged and heated under reflux over 10 hours. After completion of the reaction, the system was cooled and made acidic by use of 5 ml of 4N-HCl, followed by extraction once from 70 ml of methylene chloride and two times from 20 ml of the same. After the methylene chloride solution was dried over sodium sulfate, concentration was conducted to dryness to obtain white solid. The obtained white solid was purified with use of a silicagel column by using n-hexane/ethyl acetate (1:1, volume ratio) as a developer to obtain 0.254 g (0.933 millimole, yield: 93 %) of a white solid.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>C1C=CC=CC=1>[Cl:3][C:1]([O:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=C(CO)OCc1ccc([N+](=O)[O-])cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: c1ccccc1
Product: O=C(Cl)OCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.8 g of phosgene are introduced into 60 cm3 of benzene then a suspension of 7.1 g 4-nitrobenzyl hydroxyacetate (Izv. Akad. Nauk. SSSR. Khim 1964 (4) 685-692, Chem. Abst 61, 4469g) in 150 cm3 of benzene. The mixture is agitated for 2 hours at ambient temperature, brought to 7°/8° C. and 5.16 cm3 of diazabicycloundecene is added. After maintaining for one hour at this temperature, the mixture is decanted and the supernatant phase is partially concentrated under reduced pressure at 30°/35° C. until about 30 cm3 is obtained and the product is used as it is for the following stage.
Reaction SMILES: [F:1][C:2]1([C:21]([OH:23])=O)[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:24][C:25]([F:34])([F:35])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([C:2]2([F:1])[CH2:3][CH2:4][N:5]([S:8]([C:11]3[C:12]([C:17]([F:18])([F:19])[F:20])=[N:13][N:14]([CH3:16])[CH:15]=3)(=[O:9])=[O:10])[CH2:6][CH2:7]2)=[O:23])=[CH:32][CH:33]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cn1cc(S(=O)(=O)N2CCC(F)(C(=O)O)CC2)c(C(F)(F)F)n1
Product: Cn1cc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)c(C(F)(F)F)n1
Yield: 15.8 %

Procedure:
This material was made in analogy to example 1 from 4-fluoro-1-(1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl)-piperidine-4-carboxylic acid (0.176 g) and 4-trifluoromethoxy-aniline (0.087 g) to give the desired 4-fluoro-1-(1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.04 g) as a white solid. MS (ESI): 519.28 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:24](Br)[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:26]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CCC(=O)N1CCC(c2oc3cc(O)ccc3c(=O)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Temperature: 55 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
A solution of 7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (1.00 g, 3.17 mmol) obtained in Example 31-2, allyl bromide (560 μL, 6.34 mmol), and potassium carbonate (613 mg, 4.44 mmol) in acetone (20 mL) was heated with stirring at a bath temperature of 55° C. for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure to obtain 947 mg of the title compound (yield: 84%).
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.[BH3-]C#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:40][C:36]2[S:35][CH:39]=[CH:38][N:37]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=Cc1nccs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3nccs3)C3CCCc4cccnc43)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.295 g, 0.643 mmol) in anhydrous methanol (6.5 mL), at room temperature, was added thiazole-2-carboxaldehyde (0.33 mL, 3.76 mmol) followed by NaBH3CN (0.131 g, 2.09 mmol) and the resultant solution was stirred at room temperature. After 2 days, an additional amount of NaBH3CN (0.134 g, 2.10 mmol) was added and the solution was stirred at room temperature for an additional 4 days. The solvent was removed under reduced pressure and CH2Cl2 (20 mL) and water (10 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (2 mm plate, 40:1 CH2Cl2-MeOH containing 1% NH4OH) afforded 0.164 g of the protected amine as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[S:29][C:28]2=[N:30][C:31]([CH3:36])=[C:32]([C:33](O)=[O:34])[N:27]2[C:26]=1[CH3:37]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:27]3[C:28]([S:29][C:25]([CH3:24])=[C:26]3[CH3:37])=[N:30][C:31]=2[CH3:36])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1nc2sc(C)c(C)n2c1C(=O)O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sc(C)c(C)n23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3,6-Trimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=520.0.
Reaction SMILES: C(N[C:9]1[CH2:17][CH2:16][CH2:15][CH2:14][C:10]=1[C:11]([NH2:13])=[O:12])C1C=CC=CC=1.[SH2:18]>C(O)(=O)C>[OH:12][C:11]1[C:10]2[CH2:14][CH2:15][CH2:16][CH2:17][C:9]=2[S:18][N:13]=1
Reactant: NC(=O)C1=C(NCc2ccccc2)CCCC1
Reactant: S
Solvent: CC(=O)O
Product: Oc1nsc2c1CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-benzylamino-3,4,5,6-tetrahydrobenzamide 21a (15 g) in glacial acetic acid (100 mL) was added excess hydrogen sulfide at 80° C. for 4 h. The reaction mixture was evaporated and ether was added to the residue which afforded crystallisation. The crystals were dissolved in ethyl acetate (30 mL) and a solution of bromine (8.3 mL) in ethyl acetate (30 mL) was dropwise added at room temperature. The mixture was stirred for 20 h at room temperature and evaporated. Column chromatography on silica gel (eluent:ethyl acetate-ethanol 1:1 containing 1% glacial acetic acid) gave the title compound (3.3 g): mp 157-158° C.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[S:12]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([OH:15])(=[O:14])=[O:13].[OH:23][O:24][O:25][O:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.[K].[CH3:52][C:53]([N:55]([CH3:57])C)=[O:54]>>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[S:12]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([OH:15])(=[O:14])=[O:13].[C:40]1(=[O:50])[N:44]([C:28]([N:55]2[C:53](=[O:54])[C:52]3=[CH:7][CH:6]=[CH:5][CH:11]=[C:10]3[C:57]2=[O:13])([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:27][O:26][O:25][O:24][OH:23])[C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12
Reactant: CC(=O)N(C)C
Reactant: CCCCCCCCCCCCOOOOO
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K]
Product: CCCCCCCCCCCC(OOOOO)(N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Temperature: 165 °C

Procedure:
A suspension of ditosylate (Step 3; 108 g), potassium phthalimide (75 g) in dimethylacetamide (700 mL) is heated at 165° C. for 2 hrs with vigorous stirring. The reaction mixture is then cooled to room temperature and the precipitate filtered. The precipitate is washed with water and acetone to afford 53 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][N:6]([CH3:14])[C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1>>[CH3:5][N:6]([CH3:14])[CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:3]([NH:2][CH3:1])=[S:4])[CH2:9][CH2:8]1
Reactant: CN=C=S
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Product: CNC(=S)NC1CCC(N(C)C)CC1
Temperature: 25 °C

Procedure:
0.90 g of Methyl-isothiocyanate are added to a solution of 1.74 g of trans-4-dimethylamino-cyclohexanamine in 50 ml of EtAc. The mixture obtained is stirred at RT, solvent is evaporated and 1-(4-dimethylaminocyclohexyl)-3-methyl-thiourea is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(N3CCN(C)CC3)cc21
Yield: 73.7 %

Procedure:
A mixture of 1-ethyl-6-bromo-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.65 g, N-methylpiperazine 2.5 g and pyridine 2 ml was refluxed for 12 hours by heating. The reaction mixture was evaporated under vacuum. The residue was dissolved in an aqueous solution of acetic acid to separate insoluble matters by filtration and neutralized with an aqueous solution of NaOH. The precipitated crystals were collected by filtration and dried. Recrystallizing the precipitates from a mixed solvent of DMF and ethanol, 1.45 g (74%) of 1-ethyl-6-bromo-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid was obtained as colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH3:29][C:30]([CH3:32])=O>>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH:30]([CH3:32])[CH3:29])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: CC(C)=O
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2NC(C)C)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from the compound of Example 32 and acetone as described for Example 58, with stirring at room temperature for 3 hours. Workup afforded the title compound as a light yellow gum.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:52]2[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]2)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2]
Reactant: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {6-ethyl-5-[5-(3-fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.13 g, 0.38 mmol) that was obtained in Example 30 (30a), carbon tetrabromide (0.25 g, 0.75 mmol), triphenylphosphine (0.20 g, 0.75 mmol), methyl 3-azetidinecarboxylate hydrochloride (78 mg, 0.51 mmol), and N,N-diisopropylethylamine (0.15 ml, 0.86 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 7:3) as the eluent to afford the title compound (0.11 g) in a yield of 69% as a pale yellow oily product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 18 h
Yield: 29.8 %

Procedure:
A solution of the compound of Example 47, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was treated with triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated with 4-morpholinecarbonyl chloride (0.365 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mL CH2Cl2 and 25 mL water and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water and brine. The organic portion was then dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 393 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=CN=CC=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].C(Cl)(Cl)Cl.CO.[CH3:35][C:36]([N:38](C)C)=O>>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][C:12]2[CH:13]=[CH:18][N:38]=[CH:36][CH:35]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)n1cnc2c(Nc3ccncc3)nc(F)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
To a stirred solution of (2-fluoro-9H-purin-6-yl)-pyridin-4-ylmethyl-amine (0.6 g, 2.46 mmol) in DMA (10 mL) under Ar, at RT, was added K2CO3 (powdered, anhydrous, 1.65 g, 11.93 mmol) followed by 2-bromopropane (2.25 mL, 23.96 mmol). The reaction mixture was stirred at RT for 48 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between H2O (200 mL) and EtOAc (100 mL), the aqueous phase was separated and extracted with more EtOAc (2×50 mL). The bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (100:0→95:5), to afford the title compound as a white solid (0.40 g, 57%). Mp 270-273° C. 1H-NMR (d6-DMSO, 250 MHz): δ 1.49 (2×s, 6H, —CH(CH3)2), 4.63 (m, 3H, —CH(CH3)2+—HNCH2-Pyr) 7.30, 8.47 (2×m, 4H, Pyr), 8.28 (s, 1H, —N═CH—N—), 8.97 (bs, 1H, —HNCH2-Pyr). FAB-MS m/z (relative intensity): 287 ([M+H)]+, 100), 245 (8), 154 (23), 136 (18). Accurate Mass (M+H): Actual: 287.1420, Measured: 287.1412. Microanalysis (Expected:Measured) C14H15N6F: C, 58.73:58.57; H, 5.28:5.21; N, 29.35:29.27.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][NH2:25])=O)=[N:18][CH:17]=1>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:25][N:24]=[C:22]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][N:18]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Reactant: NNC(=O)c1ccncn1
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccncn2)n[nH]1

Procedure:
The mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (1.5 g, 6.6 mmol) and pyrimidine-4-carbohydrazide (1.2 g, 8.7 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to yield the desired product as light green viscous oil. LCMS calculated for C1-4H19N8 (M+H): 299.2. found: 299.1.