Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(OC(=O)[NH:50][C@H:51]([CH2:59][NH2:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(C)(C)C>CN(C=O)C>[NH2:50][C@@H:51]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:59][NH:60][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)Cc1ccccc1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c(C(=O)NC[C@@H](N)Cc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (0.225 g, 1.2 mmol) and HATU (0.46 g, 1.2 mmol) in DMF (10 mL) is added N-methylmorpholine (0.53 mL, 4.8 mmol) and ((S)-1-aminomethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.3 g, 1.2 mmol) and the resulting yellow solution is stirred at RT for 18 h. The solvent is removed in vacuo and the residue is diluted with water (10 mL). The precipitate which forms is collected by filtration and dissolved in DCM (5 mL). TFA (1 mL) is added and the solution stirred at RT for 1 h. The solvent is removed in vacuo, and the residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield the title compound. [M+H]+ 321
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:24][CH3:23])=[CH:17][N+:18]([O-:20])=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCCCSc1cccc(CN(C)C)n1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCCSc1cccc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[3-(6-Dimethylaminomethyl-2-pyridylthio) propylamino]-1-methylthio-2-nitroethene (1.25 g, 0.0037 mol) is added to ethanol (15 ml) saturated with monomethylamine gas at ice bath temperature and is allowed to stir at ambient temperature for 18 hours. The reaction solvent is removed and the residue is chromatographed on silica gel (50 g) eluting with 5-20% methanol/chloroform to 1.1 g of a glassy product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[C:12](=[O:22])[O:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12](=[O:22])[C:11]=1[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: CCC(c1cccc(N)c1)c1c(O)c2ccccc2oc1=O
Reactant: O=S(=O)(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cccc(C(CC)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 14.7 mg of 3-[1-(3-aminophenyl)propyl]4 hydroxy-coumarin is added 1 ml of methylene chloride and 8.1 microliters of pyridine. 5.71 microliters of chloroethylsulfonyl chloride is added at room temperature and protection from moisture. The reaction mixture is allowed to stir at room temperature for 3 hours. 5 ml of methylene chloride is added and the solution is washed twice with 5 ml of water. The organic solution is dried over anhydrous sodium sulfate, filtered and dried to give crude title product. Chromatography over 15 g of silica gel using 5% methanol in chloroform and collecting material with Rf =0.3 gives 6.3 mg of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 44.4 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and isopropylamine (0.035 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (43 mg, 0.12 mmol, yield 44%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>>[O:15]=[C:13]([CH3:14])[CH2:12][S:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(S)c1
Reactant: CC(=O)CCl
Product: CC(=O)CSc1cccc(B(O)O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 3-mercaptophenylboronic acid and chloroacetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:28](O)(=[O:32])[C:29]#[C:30][CH3:31]>>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](=[O:32])[C:29]#[C:30][CH3:31])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CC#CC(=O)O
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Product: CC#CC(=O)N1CC[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)C1

Procedure:
In accordance with Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) and 2-butynoic acid were used, the title compound was obtained as a colorless, amorphous substance. Table 1 shows the physical properties thereof.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.283 g), cuprous iodide (0.115 g) and diisopropylamine (0.57 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.600 g) and trimethylsilylacetylene (0.57 ml) in ethyl acetate (10 ml) cooled to −20° C. under a nitrogen atmosphere. The mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite and the crude product in solution was then absorbed onto silica and purified by column chromatography using 20% dichloromethane in isohexane as eluent. There was thus obtained the title compound as an oil (0.560 g). NMR Spectrum: (CDCl3) 0.24 (s 9H), 4.03 (s, 2H), 6.02 (s, 2H), 6.91 (s, 1H); Mass Spectrum: M+H+ 268 and 270.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:11])[CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:19](=[O:20])[CH2:18][Br:17])[CH:3]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cc(F)ccc1C(=O)O
Temperature: -5 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A solution of 4-fluoro-2-aminobenzoic acid (5.0 g, 32.2 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask which was equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.44 g, 2.8 mL, 32.2 mmol) was added dropwise while keeping the internal temperature between -5° and 0° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to room temperature and stirred overnight. To this solution was slowly added 150 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 8.13 g (91.4%) of the title compound as a white solid, mp 166°-168° C.: 1H NMR (DMSO-d6) δ13.92 (bs, 1H), 11.83 (s, 1H), 8.32 (dd, J=12, J=2.4, 1H), 8.09 (dd, J=9.2, J=6.8, 1H), 7.06 (ddd, J=8.8, J=9.2, J=2.4, 1H), 4.29 (s, 2H); 13C NMR (DMSO-d6) δ168.55, 165.60, 164.80 (d, J=248), 142.29 (d, J=12.9), 133.93 (d, J=10.6), 113.19, 110.42 (d, J=22), 106.43 (d, J=28), 30.54; MS (EI, m/z) 275 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].[N-:17]=[C:18]=[O:19].[Na+]>C(O)(=O)C.O>[NH2:17][C:18]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:19]
Reactant: [N-]=C=O
Reactant: Cc1c(-c2ccccc2)sc(N)c1C(N)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)sc(NC(N)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.1 %

Procedure:
To a mixture of 2-amino-4-methyl-5-phenyl-3-thiophencarboxamide (0.18 g) in glacial acetic acid (5 mL) and water (0.5 mL) was added sodium isocyanate (101 mg). The resulting solution was stirred at room temperature for 4 h and then poured into water. The precipitate was filtered off and washed with more water. The product was chromatographed on silica gel eluting with dichloromethane/methanol mixtures to give the title product as a solid (30 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:12][CH2:11][CH2:10][C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]1=2)=O.[Cl:13][C:14]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:17]([NH2:18])=[C:16]([F:25])[CH:15]=1.O>C1(C)C=CC=CC=1.CN(C1C=CC=CN=1)C>[Cl:13][C:14]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:17]([N:18]2[C:8](=[O:9])[C:3]3[CH:2]([CH3:1])[CH2:12][CH2:11][CH2:10][C:4]=3[C:5]2=[O:7])=[C:16]([F:25])[CH:15]=1
Reactant: CC1CCCC2=C1C(=O)OC2=O
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(C2=O)C(C)CCC3)c(F)cc1Cl
Reaction time: 2 h
Yield: 81.9 %

Procedure:
15.4 g (0.093 mol) of 3-methyl-3,4,5,6-tetrahydrophthalic acid anhydride are dissolved in 90 ml of toluene. 18.4 g (0.093 mol) of 4-chloro-2-fluoro-5-isopropoxyaniline and 0.6 g of dimethylaminopyridine are added and the mixture is heated until the solvent and the water that has formed distil off. After approximately 2 hours at a bath temperature of 145° C. the reaction is complete. The residue is chromatographed over a column of silica gel with hexane/ethyl acetate 9:1. As main fraction there are obtained 26.8 g (82.0%) of the title compound (Compound No. 1.030) of the formula ##STR9## in the form of an oil, nD22 =1.5458.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH:17]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18]([OH:20])=[O:19])[N:9]=1.[CH2:30](Br)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([O:7][CH3:6])[N:9]=[C:10]([O:16][CH:17]([CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])[C:18]([O:20][CH2:30][CH3:31])=[O:19])[N:11]=1
Reactant: CCBr
Reactant: COc1cc(OC)nc(OC(Cc2c(Cl)cccc2Cl)C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)Oc1nc(OC)cc(OC)n1

Procedure:
50 ml of a N,N-dimethylformamide solution of 1.65 g of 2 (4,6-dimethoxypyrimidin-2-yl)oxy-3-(2,6-dichlorophenyl)propionic acid, 0.5 g of ethyl bromide 0.6 g of potassium carbonate was stirred at 80° C. for 2 hours under heating. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed and dried. Then, the solvent was distilled off to obtain colorless crystals.
Reaction SMILES: [N:1]([C@H:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].O.O.Cl[Sn]Cl>CO>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C@H:4]([NH2:1])[CH2:5][CH2:6]2
Reactant: [N-]=[N+]=N[C@@H]1CCc2cc(Br)ccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: N[C@@H]1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A solution of (R)-1-azido-5-bromo-indane (14.0 g, 58.8 mmol) was dissolved in methanol (150 mL) and was treated with SnCl2.2H2O (23.0 g, 106 mmol). The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (300 mL) and was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with 1N HCl followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (2×300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 10.0 g (80%) of (1R)-5-bromoindan-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C.O>[N+:17]([C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2ccc3cccc4ccc1c2c34

Procedure:
A solution was prepared by dissolving 101 g of pyrene in 800 ml of glacial acetic acid. While heating this solution at 50° C. in water bath with stirring, a mixed solution of 42 ml of nitric acid (D=1.4) and 50 ml of glacial acetic acid was slowly added thereto dropwise. At the end of 30 minutes, the reacted mixture was filtered with suction. The precipitate was washed with a small quantity of glacial acetic acid and then thoroughly washed with water to obtain 115 g of yellow crystals (melting point: 150° C.). By recrystallizing these crystals in glacial acetic acid, crystals having a melting point in the range of 153°~154° C. were obtained. The result of elemental analysis of this product was as shown in the following table:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([C:14]#[N:15])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:23](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[NH2:24]>>[C:14]([C:7]1[C:8]([CH3:13])([CH3:12])[O:9][C:10]2[C:5]([C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[CH:4][CH:3]=[C:2]([NH:24][C:23](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:11]=2)#[N:15]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C#N
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C#N)=C2c1ccc(F)cc1

Procedure:
The compound obtained in (2) described above (340 mg) and tert-butyl carbamate (380 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (427 mg) as a pale yellow powder.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C1CCN2C(=NCCC2)CC1.[CH2:22]([N:26]1[C:31]2=[N:32][N:33]([CH2:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[C:30]2[C:29](=[O:52])[NH:28][C:27]1=[O:53])[CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:22]([N:26]1[C:31]2=[N:32][N:33]([CH2:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:34]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)=[C:30]2[C:29](=[O:52])[N:28]([CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:27]1=[O:53])[CH:23]([CH3:25])[CH3:24]
Reactant: ClCCN1CCOCC1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(CCN2CCOCC2)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 80 °C
Yield: 91.1 %

Procedure:
4-(2-chloroethyl)morpholine hydrochloride (0.0435 g) followed by DBU (0.094 g) were added to a solution of 7-isobutyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.0668 g) in dimethylformamide (1 ml). The mixture was heated at 80° C. for 18 hours then cooled to room temperature. The crude reaction was purified on preparative HPLC to give the title compound (0.077 g). Mass: 538.90 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 8639.2 %

Procedure:
The product from Example 247a (0.89 g, 2.63 mmol) was mixed with cesium carbonate (0.85 g, 2.63 mmol) and 4-benzyloxyphenol (0.53 g, 2.63 mmol) in DMF (10 mL) and stirred at room temperature a total of sixty hours. The reaction mixture was diluted with ethyl acetate (100 ml) and treated with 2N HCl (20 ml). The organic layer was separated and washed with 2N NaOH, 2, 10% sodium chloride and dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was evaporated under vacuum leaving the title compound as a yellow solid (118 g, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([N:27]([CH3:26])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[O:9])[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cc(C(=O)Nc2ccc(O)cc2)ncn1)C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (75.0 mg; 0.30 mmol) in THF (4 mL) was treated with triethylamine (42 μl; 0.30 mmol) and N-methylcyclohexylamine (Aldrich, 43 μl; 0.33 mmol). The reaction mixture was stirred for 24 h. The solvents were removed in vacuo, then the crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][CH:34]([CH3:39])[CH:35]=[CH:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:37][CH:36]=[CH:35][CH:34]([CH3:39])[CH3:33])[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)C=CC=O
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CC=CC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (60 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL) was added 4-methyl-pent-2-enal (15 mg, 0.15 mmol) and sodiumtriacetoxyborohydride (37 mg, 0.17 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 4-methyl-2-{5-[1-(4-methyl-pent-2-enyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.30 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 531.24 (ethyl ester).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.B1([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:33][CH:32]=2)OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:32]=[N:33][C:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)c1Cl
Yield: 52 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-morpholino)pyridine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a beige foam (52% yield). M.p. (foam), LCMS: m/z=458.04 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28-3.34 (m, 2H), 3.51-3.59 (m, 6H), 3.81-3.88 (m, 4H), 4.54 (s, 2H), 5.30 (s, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.00-7.08 (m, 2H), 7.11-7.18 (m, 1H), 7.53 (s, 1H), 7.61 (dd, J=8.8 Hz, 2.5 Hz, 1H), 8.33 (s, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+]>C(C(C)=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCCCBr)c(Cl)c1
Yield: 94.8 %

Procedure:
A mixture of 4.16 g of 2,6-dichloro-4-nitrophenol, 40.4 g of 1,3-dibromopropane, 2.76 g of potassium carbonate and 2.46 g of potassium t-butoxide was heated under reflux for 4 hours in 50 ml of methyl ethyl ketone. The reaction mixture was allowed to cool down and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform. The thus-prepared chloroform solution was washed with water, and the chloroform was then distilled off. The residue was purified by chromatography on a silica gel column (eluent: chloroform/hexane=4/1, by volume) to obtain 6.24 g of 1-bromo-3-(2,6-dichloro-4-nitrophenyloxy)propane. This compound was employed in the next reaction without any further purification.