Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CN(C)C=O.C(Cl)(Cl)(Cl)Cl>[CH2:5]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:3])=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
10 ml of CCl4, 5 ml of thionyl chloride and one drop of dimethylformamide were added to 2.0 g of 4-(5-octyl-2-pyrimidinyl)benzoic acid. The mixture was refluxed for 3 hours under stirring. The solvent was distilled off initially under normal pressure and then under reduced pressure. As a result, 2.2 g of 4-(5-octyl-2-pyrimidinyl)benzoic acid chloride was obtained in the form of a colorless plate-form crystal. 1.2 g of the thus obtained 4-(5-octyl-2-pyrimidinyl)benzoic acid chloride was dissolved in a mixed solvent composed of 20 ml of CCl4 and 5 ml of anhydrous pyridine under stirring. The thus obtained solution was added with a solution prepared by dissolving 0.7 g of (S)-4-(1-oxo-2-methylbutyl)phenol in 10 ml of CCl4, and the admixture was stirred at the room temperature for one night. The admixture was heated to reflux for 3 hours. 200 ml of water and 100 ml of ethyl ether were added to the reaction admixture, followed by stirring. The organic phase was separated, and rinsed initially with a dilute hydrochloric acid solution, then with an aqueous solution of NaHCO3 and finally with a saturated aqueous solution of NaCl. The rinsed organic phase was added with anhydrous Na2SO4 and allowed to stand for one night to dry the same. After removing the drying agent by filtration, the solvent was distilled off to obtain 1.86 g of a crude product. The crude product was refined through silica gel column chromatography while using a mixed solvent of hexane/ethyl acetate (ratio by volume: 8/2). The refined product was recrystallized from ethanol to obtain 200 mg of (S)-4-(1-oxo-2-methylbutyl)phenyl 4-(5-octyl-2-pyrimidinyl)benzoate in the form of a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1([O:12]C)[C:6]([CH2:7][CH3:8])=[C:5]([CH3:9])[CH:4]([O:10]C)O1.O1CCCC1.[Cl-].[Na+]>O>[CH3:9][C:5]1[CH:4]([OH:10])[CH2:1][C:2](=[O:12])[C:6]=1[CH2:7][CH3:8]
Reactant: CCC1=C(C)C(OC)OC1(C)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1=C(C)C(O)CC1=O
Yield: 61.4 %

Procedure:
2,4-Dimethyl-3-ethyl-2,5-dimethoxy-2,5-dihydrofuran (9.3 g) was added to a mixture of 100 ml of a buffer solution (pH 5; prepared from potassium hydrogen phthalate and sodium hydrogen carbonate) and tetrahydrofuran (50 ml), and the mixture was refluxed for 1 hour. The reaction solution was poured into water, saturated with sodium chloride and extracted three times with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was distilled to obtain 4.3 g of 2-methyl-3-ethyl-cyclopent-2-en-4-on-1-ol.
Reaction SMILES: [CH3:1]/[C:2](/[CH:8]=[N:9]/[N:10]=[C:11]([NH2:13])[NH2:12])=[N:3]\[N:4]=[C:5]([NH2:7])[NH2:6].Cl.C(O)(C)C>O>[CH3:1][C:2](=[N:3][NH:4][C:5](=[NH:6])[NH2:7])[CH:8]=[N:9][NH:10][C:11](=[NH:12])[NH2:13]
Reactant: CC(/C=N/N=C(N)N)=N\N=C(N)N
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C=NNC(=N)N)=NNC(=N)N
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A suspension of etude MGBG (460 g) in 920 g DI water was warmed to 40°-50° C. to give a clear pale yellow solution. The mixture was cooled to 30° C. and 920 mg conc. HCl was added. A pH of 0-1 was measured with litmus paper. Isopropanol (350 g, 446 mL) was added rapidly and the mixture stirred for 1 hour at 28°-32° C. The solutions were filtered to remove insoluble material. The filtrate was added to the reaction flask and acidified further with 0.5 g of conc. HCl The isopropanol (1.84 kg) was added over 10-15 minutes to the vigorously stirred solution. The mixture was cooled to 8°-12° C. and stirred for an additional hour. The solids were collected and the cake was rinsed with 2×200 mL isopropanol. After drying in a vacuum oven at 30°-40° C. for 24 hours, the recovery was about 90%. HPLC (ETI)=0.65%, nmr (dmsod6); IR (Kbr).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]([CH2:13]O)=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[CH:9][N:8]=1>>[Cl:3][CH2:13][C:12]1[C:7]([O:6][CH3:5])=[N:8][CH:9]=[N:10][C:11]=1[C:15]([F:18])([F:17])[F:16]
Reactant: COc1ncnc(C(F)(F)F)c1CO
Reactant: O=S(Cl)Cl
Product: COc1ncnc(C(F)(F)F)c1CCl
Reaction time: 3 h
Yield: 98.3 %

Procedure:
1.19 g (10.1 mmoles) of thionyl chloride was added, at room temperature, to a solution of 0.42 g (2.02 mmoles) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.45 g (yield: quantitative) of 5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCC(O)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 4-hydroxypiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.09 minutes; C21H20Cl2N4O3 (447.32); mass spectrum: (M+H)+=447.2.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][N:25]4[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]4)[CH2:17][CH2:18]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC1CCNCC1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: OC1CCN(CC2CCN(c3ccc(CN4CCCC4)cc3)CC2)CC1

Procedure:
Prepared from the product of Example 16 and 4-hydroxypiperidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:30])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[C@@H:18]([CH3:29])[CH2:17]3)[CH:10]=2)[CH:8]=1.CC(OC([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=2)[C:47]([OH:49])=O)[CH2:40][CH2:39]1)=O)(C)C>>[F:30][C:6]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:29])[CH2:17]3)[CH:10]=2)=[CH:8][C:3]([CH2:2][NH:1][C:47](=[O:49])[C:46]2[CH:50]=[CH:51][CH:52]=[C:44]([CH:41]3[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]3)[CH:45]=2)=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 18 %

Procedure:
Following the standard procedure outlined in Example 57, 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate, 50 mg, 0.121 mmol) was reacted with the commercially available 3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)benzoic acid (37 mg, 0.121 mmol) to give the title compound (11 mg, 18%). LC/MS: m/z, 501 (M+H), 1.27 min.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([NH2:21])=O.[OH-].[Na+]>O>[NH2:21][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 140 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]-quinoline (50.0 g, 0.192 mol) and formamide (125 ml, 3.136 mole, 16.3 equiv.) was heated at about 140° C. under nitrogen atmosphere for 26 hours. Then, the reaction mixture was cooled to 95° C. and water (10 ml) was added. The reaction mixture was heated at this temperature for 2 hours. Water (250 ml) and 47% aqueous sodium hydroxide solution were then added to produce a pH of about 9 and the mixture was stirred at ambient temperature for 2 hours. A solid was collected by filtration, washed with water (3×50 ml) and methanol (3×50 ml) and dried at 50° C. under reduced pressure overnight to give crude 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (Imiquimod) (39.0 g). The crude compound (39.0 g) was slurried in a mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 33.0 ml) under reflux for 6 hours. The mixture was cooled to ambient temperature and a colorless solid was collected by filtration, washed with methanol (3×20 ml), water (3×20 ml) and methanol (3×20 ml) and dried at 50° C. under reduced pressure overnight to yield 22.0 g of Imiquimod in 47.6% yield, having a purity of 98.2% (by HPLC). The product was crystallized from N,N-dimethylformamide to afford colorless Imiquimod having a purity of 99.9% (by HPLC).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)C=Cc1cccc(O)c1
Reactant: CO
Product: COC(=O)C=Cc1cccc(O)c1

Procedure:
3-(3-Hydroxy-phenyl)-acrylic acid (2 g, 12.2 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:44][C:45]([F:53])([F:52])[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:49]3[CH2:50][CH2:51][CH:46]([C:45]([F:53])([F:52])[F:44])[CH2:47][CH2:48]3)=[O:30])=[CH:26][CH:27]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.090 g, 0.2 mmol) in CH2Cl2 (10 mL) with 1,1′-carbonyldiimidazole (0.065 g, 0.4 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4-trifluoromethylpiperidine hydrochloride (0.057 g, 0.3 mmol) and diisopropylethylamine (0.039 g, 0.3 mmol) and stir for 12 hours at room temperature. Purify on silica gel column with 25% to 75% ethyl acetate in hexanes to afford 0.065 g (55%) of the title compound. MS (m/z): 582 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCCOCCBr
Reactant: COc1ccc(O)cc1F
Product: CCCOCCOc1ccc(OC)c(F)c1

Procedure:
The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]2[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([O:13][C:8]1[C:7]([C:14]2[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][C:9]=1[CH:10]=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
step 2—A mixture of 48 (737 mg, 2.59 mmol), benzyl bromide (0.625 mL, 5.26 mmol) and K2CO3 (734 mg, 5.31 mmol) in DMF (10 mL) was stirred overnight at RT then partitioned between EtOAc and water. The organic layer was thrice washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 10% EtOAc) to afford 812 mg (84%) of 2-benzyloxy-5-tert-butyl-3-(2-methoxy-pyridin-3-yl)-benzaldehyde (50) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:29]3[N:30]=[CH:31][C:32]([C:35]([OH:44])([C:36]([F:37])([F:38])[F:39])[C:40]([F:42])([F:43])[F:41])=[CH:33][N:34]=3)[C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1)S(C)(=O)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 17.2 %

Procedure:
A 5-mL vial was charged with N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.170 g, 0.386 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.124 g, 0.442 mmol, Intermediate D), DIPEA (0.202 mL, 1.16 mmol), and 1,4-dioxane (2 mL). The vial was sealed and stirred at 100° C. for 21 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 40 to 100% EtOAc in hexanes followed by 0-10% (2M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.0454 g) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Br[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:36][CH:37]=2)[CH:8]=1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)cc1)C2
Yield: 72.4 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (150 mg) and 1-[2-(4-bromophenoxy)ethyl]piperidine (150 mg) according to an analogous synthetic method to Example 116, the title compound (186 mg) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: NCCCO
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(NCCCO)c1ccc2c(c1)OCO2
Yield: 65 %

Procedure:
1,3-Benzodioxole -5-carboxylic acid (2.0 g, 12.0 mmol) and 3-amino-1propanol (0.8 ml, 15.6 mmol) were coupled according to the procedure of Example 17 to 1.74 g (65% yield) of a white solid. MP 112-113° C.; 1H NMR (DMSO-d6): δ1.65 (m, CH2), 3.27 (m, CH2), 3.42 (m, CH2), 4.45 (t, NH), 6.0 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1 Ar H), 7.4 (d—d, 1 Ar H), 8.28 (t, NH) Electrospray Mass Spec: m/z 224.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[Cl:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>O1CCCC1.O>[Cl:41][C:42]1[CH:43]=[C:44]([S:48]([N:7]2[C:8]([C:9]3[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=3)=[C:4]([F:3])[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cncc(Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cncc(Cl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 78.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 52 mg) in tetrahydrofuran (3 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (286 mg) and a solution of 5-chloropyridine-3-sulfonyl chloride (318 mg) in tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred for 20 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:117:3) to give the title compound as a colorless oil (yield 391 mg, 78%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>CCOCC>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCc1[nH]n(C2CCCC2)c2nc(Nc3ccccc3)nc(=O)c1-2
Temperature: 185 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo[3,4-d]pyrimidin-4-one (2.3 g, 7.4 mmol) and aniline (1.2 g, 13 mmol) was heated at 180-190° C. for 3 hours. The reaction mixture was cooled to room temperature and allowed to stand at room temperature overnight. Ether was added to the reaction mixture and the product was collected by filtration, washed with ether and dried at 80-85° C. in a vacuum oven to afford crude product. The crude product was treated with saturated NaHCO3 (25 mL) and the insoluble material was collected by filtration, dissolved in hot isopropanol, treated with charcoal and concentrated in vacuo. The residue was crystallized from ether and dried at 80-85° C. in a vacuum oven to afford 0.58 g (25%) of 1-cyclopentyl-3-ethyl-6-(phenylamino)pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:20]4[O:19][C:18]([F:22])([F:21])[O:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[N:7]([CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])[C:6]=2[C:5]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:20]4[O:19][C:18]([F:22])([F:21])[O:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:6]=2[C:5]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cccc3c2OC(F)(F)O3)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cccc4c3OC(F)(F)O4)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(2,2-difluoro-1,3-benzodioxol-4-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (900 mg, 1.77 mmol) in tetrahydrofuran (8.0 mL) was added lithium tetrahydroborate (193 mg, 8.86 mmol) at 0° C. The mixture was stirred at room temperature for 19 hr. and the reaction was quenched by methanol. The mixture was neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (630 mg, 1.35 mmol, 76%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CCOCC>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:21])=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)c1ccccn1
Yield: 66.2 %

Procedure:
An anhydrous solution of 1,1'-carbonyldiimidazole (13.13 g, 81 mmol) in dimethylformamide (80 mL) was treated with picolinic acid (10.0 g, 81 mmol), and after 1 hour 4-fluoroaniline (8.46 mL, 89 mmol) was introduced. After 27 hours the reaction mixture was poured into saturated sodium bicarbonate solution (900 mL) and ether (400 mL). The aqueous layer was extracted again with ether (3×400 mL) and the ethereal layers were dried and concentrated. The crude solid residue was recrystallized from a mixture of ether and petroleum ether to yield N-(4-fluorophenyl)-2-pyridinecarboxamide (11.6 g, 66%) as beige crystals, m.p. 100°-103° C.