Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][OH:21])=[CH:14][C:13]=1[F:22])C1C=CC=CC=1.O1CCCC1>CO>[CH2:27]([C:25]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][OH:21])=[CH:14][C:13]=2[F:22])=[C:9]([OH:8])[CH:26]=1)[CH3:28]
Reactant: CCc1ccc(Oc2ccc(NCCO)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccc(NCCO)cc2F)c(O)c1
Yield: 78.4 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for N-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-aminoethanol (350 mg, 0.92 mmol) and tetrahydrofurane for methanol (25 mL), the title compound (210 mg; 78%) was obtained as a yellow solid, after purification on silica gel (ethylacetate and petroleum ether: 5/5)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]([OH:17])=[CH:5][CH:4]=1.[C:18](Cl)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:18]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:11]([CH3:13])([CH3:14])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]=1[OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(O)c2c1C(C)(C)CCC2(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(Cc2ccccc2)c(O)c2c1C(C)(C)CCC2(C)C

Procedure:
To a solution cooled to +5° C. of 23.44 g (0.1 mole) of 4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol, obtained in Example I, in 400 cm3 of anhydrous 1,2-dichloroethane and 11.7 cm3 (14.06 g=0.1 mole) of benzoyl chloride, there are added, by portions, 16 g (0.12 mole) of anhydrous aluminum chloride over a period of about 30 minutes.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=1.C[Si](Cl)(C)C>C(Cl)Cl.CCOCC>[CH3:11][C:12]1([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH2:15][C:14](=[O:18])[CH2:13]1
Reactant: CC1=CC(=O)CCC1
Reactant: C=CCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(CCCCc2ccccc2)C=CCC(=O)C1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
Cp2ZrHCl (103 mg, 0.40 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 4-phenyl-1-butene (0.08 mL, 0.5 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for about 20 min, the resulting clear yellow solution was transferred via syringe over about 1 min to a clear colourless stirred solution of CuOTf-ligand complex (15.0 mg, 0.020 mmol, 0.10 eq.) in Et2O (2.0 mL) under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before 3-methyl-2-cyclohexenone (0.023 mL, 0.20 mmol, 1.0 eq.) and then TMSCl (0.13 mL, 1.0 mmol, 5.0 eq.) were added dropwise via syringe. The reaction was stirred until complete (TLC control (EtOAc/Petrol 1:9)). The reaction was quenched by the addition of Et2O (ca 3 mL) and then NH4Cl (1 M. aq., ca 1.5 mL). The mixture was partitioned between water and Et2O and the aqueous phase extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (aq. sat., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the residue (EtOAc/petrol; SiO2) gave (−)-3-methyl-3-(4-phenylbutyl)cyclohexenone (21.9 mg, 0.09 mmol, 45%) as a yellow oil. HPLC analysis indicated an enantiomeric excess of 60% [Chiralpak® IA; flow 1 ml/min; hexane/i-PrOH: 99:1; λ=210 nm; minor enantiomer (+)-3-methyl-3-(4-phenylbutyl)cyclohexenone, tR=14.90 min; major enantiomer (−)-3-methyl-3-(4-phenylbutyl)cyclohexenone, tR=15.70 min].
Reaction SMILES: C(OC([N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:9]1[CH:23]=[CH:22][C:12]([CH:13]=[CH:14][C:15](N2C=CN=C2)=[O:16])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)(Cl)Cl>[CH2:24]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45])=[O:16])=[CH:22][CH:23]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCCCCCCN(C(=O)OC(C)(C)C)c1ccc(C=CC(=O)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCNc1ccc(C=CC(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-[N-(t-butyloxycarbonyl)-4-(pentadecylamino)cinnamoyl] imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[O:16]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:24][CH:25]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(Oc4ccccc4)nc3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (20 mg, 0.10 mmol), 6-phenoxynicotinic acid 56-1 (21.5 mg, 0.10 mmol), and HATU (40 mg, 0.105 mmol) were added N,N-diisopropylethylamine (DIEA, 26 μL, 0.15 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected to reverse phase preparative HPLC separation to yield N-((2′-methyl-[2,4′-bipyridin]-5-yl)methyl)-6-phenoxynicotinamide 94 as a solid. MS m/z 397.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.O=S(Cl)[Cl:12]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COCCOCC(=O)O
Product: COCCOCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To 2-methoxyethoxyacetic acid (670 mg.; 4.00 mmoles) was added at 0°-2° under N2 atmosphere, SOCl2 (5ml.). The mixture was stirred at room temperature under N2 for 2 hours. Excess SOCl2 was evaporated and the residue was diluted with dry benzene (15 ml.), evaporated again, and dried over NaOH (in vacuo) to yield 2-methoxyethoxyacetyl chloride (705 mg.; 4.62 mmoles; yield 92.5%) as a colorless liquid. nmr (CDCl3): δppm 3.40 (3H, s, -OCH3), 3.4-3.9 (4H, m, -CH2CH2 -), 4.56 (2H, s, ClOCH2O-); ir (neat): 1810 cm-1 (νc=o, acid chloride).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].S(OC)(O[CH3:22])(=O)=O>C(=O)(O)[O-].[Na+]>[CH3:22][N:7]1[C:6](=[S:11])[N:5]2[C:4]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:3][C:2]([CH3:1])=[C:10]2[CH:9]=[N:8]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)n2c(=S)n(C)ncc12
Reaction time: 15.5 h
Yield: 7 %

Procedure:
8-Methyl-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-thione (3.76 g, 0.014 mole) is dissolved in aqueous sodium bicarbonate (125 ml. 6.7%). Dimethyl sulfate (1.85 g, 0.0147 mole) is added at room temperature and the reaction mixture stirred overnight (appr. 15-16 hours). The precipitated solid is collected by filtration and washed thoroughly with water. The dried solid (3.84 g) is extracted with benzene. The benzene solution is evaporated to dryness, and the residual red solid obtained is extracted with hexane. Evaporation of the hexane solution yields a tan solid (0.25 g). Recrystallization of this tan solid from methanol yields pale yellow crystals, m.p. 194°-195° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:24]I>CN(C=O)C.FC(F)(F)C([O-])=O.[Ag+]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)[C:5]([I:24])=[CH:4][N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(=O)O
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2I)cc1C(=O)O
Temperature: -40 °C
Reaction time: 7 h
Yield: 81.6 %

Procedure:
5-(2-Amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxylic acid (0.70 g, 2.13 mmol) and Iodine (1.134 g, 4.47 mmol) in dry DMF (5 mL), under a nitrogen atmosphere, were stirred at −40° C. (internal temperature) and treated drop wise with silver trifluoroacetate (0.987 g, 4.47 mmol) in DMF (5 mL). The mixture was stirred at −40° C. for 7 h and then filtered over a short plug of celite. The panel was washed with DMF (5 mL) and the filtrate was collected in a flask containing 10% Na2S2O3 (50 mL). Precipitation of a pale yellow solid occurred. Dilution with water (50 mL) and filtration of the solid afforded 0.79 g of crude product, which was reacted in the next step with no further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]#[N:23])[CH:11]=3.S(=O)(=O)(O)[OH:26].N>>[CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]([NH2:23])=[O:26])[CH:11]=3
Reactant: CC1(C)C(=O)Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c21
Reactant: O=S(=O)(O)O
Agent: N
Product: CC1(C)C(=O)Oc2ccc3cc(C(N)=O)c(Cn4cncn4)cc3c21

Procedure:
A solution of 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonitrile, (0.35 g) and concentrated sulphuric acid (2 ml) was kept at room temperature for 18 h. The mixture was treated with crushed ice and neutralised with concentrated aqueous ammonia, and the mixture was extracted twice with ethyl acetate. The combined extracts were dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography using methanol:dichloromethane, 1:14 v/v, as eluant, to give 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carboxamide, m.p. 231°-232° after recrystallisation from a mixture of methanol and ethyl acetate.
Reaction SMILES: [O:1]1[C:7]2[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]2[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cccc2c1OCCCC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Cl)cc2c1OCCCC2
Reaction time: 8 h

Procedure:
To a solution of 1.7 g (8.9 mmol) of 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 5 ml of DMF is added 1.41 g(10.6 mmol) of N-chlorosuccinimide (NCS) in one portion at room temperature. The solution is stirred overnight and then diluted with ethyl acetate and washed with water. The organic layer is then dried (MgSO4), filtered and concentrated to obtain 7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3].[H-].[Na+].[CH2:48](Br)[C:49]#[CH:50]>CN(C=O)C>[CH2:50]([N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:12]/[CH:11]=[CH:10]/[CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:49]=[CH2:48]
Reactant: C#CCBr
Reactant: C=CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CCCN(C/C=C/CN(CCCN(CC=C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.6 g (0.936 mmol) of (E)-1-allyl-1,5, 10, 14-tetra-BOC- 1,5,10,14-tetraazatetradec-7-ene (see Example 2a) in 8 ml of DMF there are added, with stirring, 0.075 g (1.875 mmol) of sodium hydride dispersion (approx. 60%) and, after 5 min., 0.141 ml (1.872 mmol) of propargyl bromide. The reaction mixture is stirred for 15 h at room temperature; a further 0.0375 g (0.937 mmol) of sodium hydride dispersion (approx. 60%) and 0.071 ml (0.94 mmol) of propargyl bromide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the title compound, Rf value=0.44 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17].C(O)(C)C>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:9]([C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([CH3:8])[NH:22][C:21]=1[NH2:23])=[O:24])[CH3:17]
Reactant: CCOC(=O)C(=Cc1ccco1)C(C)=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccco1
Yield: 78 %

Procedure:
Upon boiling a solution of 10.4 g of 2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 183°C (isopropanol) is obtained. Yield: 78% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(NC(C)C)(C)C.[Li].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2cnccc2c1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc2cnccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A 2.0-mL vial equipped with a stirrer bar was charged with 6-aminoisoquinoline (100 mg, 0.7 mmol) in THF (1.0 mL) and cooled to −78° C. Lithium diisopropylamine (40 μL, 0.35 mmol) was added to the reaction at −78° C. followed by dropwise addition of chloroacetylchloride (62 μL, 0.7 mmol). The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was concentrated in vacuo then the solid was triturated with cold methanol. The solid was collected by filtration to afford 2-chloro-N-isoquinolin-6-yl-acetamide (58 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.14 (s, 2H) 8.01 (dd, J=9.08, 1.66 Hz, 1H) 8.45 (d, J=8.98 Hz, 2H) 8.66 (d, J=1.56 Hz, 1H) 11.46 (s, 1H); LCMS: 221 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10]N(CC)CC)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.[CH2:22]([N:24]([CH2:29]C)[CH2:25][CH2:26]CCl)[CH3:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:29][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCN(CC)CCCCl
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Agent: Cl
Product: CCCC(=O)c1ccc(OCCCN(CC)CC)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of 3-diethylaminopropyl chloride hydrochloride. The product is obtained as a colorless oil upon distillation in vacuo (0.2 mm.).
Reaction SMILES: [F:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([O:25][CH3:26])=[C:6]([NH:8][C:9](=[O:24])[O:10][CH:11]([CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH3:12])[CH:7]=1.Br[C:37]1[N:38]=[C:39]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[N:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[C:41]=12>>[F:1][C:2]1[C:3]([C:37]2[N:38]=[C:39]([CH:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:40]3[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[C:41]=23)=[CH:4][C:5]([O:25][CH3:26])=[C:6]([NH:8][C:9](=[O:24])[O:10][CH:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH3:12])[CH:7]=1
Reactant: Cc1nccn2c(C3CCOCC3)nc(Br)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)OC(C)CCCO[Si](C)(C)C(C)(C)C
Product: COc1cc(-c2nc(C3CCOCC3)n3ccnc(C)c23)c(F)cc1NC(=O)OC(C)CCCO

Procedure:
Reaction of 5-(tert-butyldimethylsilyloxy)pentan-2-yl 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (prepared according to the procedures described in example 44, 82 mg) and 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (47.5 mg) according to the procedure described in example 4 step 4c and purification using prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) gave 5-hydroxypentan-2-yl 5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2h-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate (14 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(NC(=O)OC(C)(C)C)cn1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Temperature: 85 °C

Procedure:
A solution of tert-butyl 5-methylpyrazin-2-ylcarbamate (2.79 g, 13.33 mmol), NBS (2.61 g, 14.67 mmol) and AlBN (0.219 g, 1.33 mmol) in CCl4 (45 mL) was purged with Argon, then the solution was heated with 85° C. oil bath for 4 h. The reaction mixture was cooled to room temperature, concentrated and the residue was redissolved in EtOAc (˜50 mL), washed with dilute aqueous NaOH twice (10 mL 1 N NaOH diluted in 20 mL H2O), brine (30 mL), dried (Na2SO4) and concentrated. The residue was further purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-30%) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate was obtained in off-white solid. LCMS (m/z): 288.1/290.1 (MH+), 0.82 min; 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (s, 1H), 8.32 (d, J=1.2 Hz, 1H), 7.62 (br. s., 1H), 4.56 (s, 2H), 1.56 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[C:5]2[N:16]([CH:19]3[CH2:21][CH2:20]3)[CH:17]=[N:18][C:4]=2[CH:3]=1.[O:22]1[CH2:25][CH:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[CH:19]1([N:16]2[C:5]3[C:6]([O:8][CH2:9][C@H:10]4[CH2:14][NH:13][C:12](=[O:15])[CH2:11]4)=[N:7][C:2]([C:35]4[CH:36]=[CH:37][C:32]([N:29]5[CH2:30][CH2:31][N:26]([CH:24]6[CH2:25][O:22][CH2:23]6)[CH2:27][CH2:28]5)=[CH:33][CH:34]=4)=[CH:3][C:4]=3[N:18]=[CH:17]2)[CH2:21][CH2:20]1
Reactant: O=C1C[C@@H](COc2nc(Br)cc3ncn(C4CC4)c23)CN1
Reactant: CC1(C)OB(c2ccc(N3CCN(C4COC4)CC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1C[C@@H](COc2nc(-c3ccc(N4CCN(C5COC5)CC4)cc3)cc3ncn(C4CC4)c23)CN1

Procedure:
(R)-4-(((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)methyl)pyrrolidin-2-one (50 mg, 0.14 mmol), 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (63.28 mg, 0.18 mmol), Cesium Carbonate (137.18 mg, 0.42 mmol), & PEPPSI″-IPr catalyst (20 mg, 0.03 mmol) were taken up in dioxane (4 ml) and water (1 mL) and heated in a sealed tube at 100° C. for 45 minutes. Reaction was then chromatographed in silica gel 0-30% DCM/MeOH providing 94 mg of (R)-4-(((3-cyclopropyl-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)methyl)pyrrolidin-2-one. (68 mg, 84%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.01-7.91 (m, 2H), 7.71-7.57 (m, 2H), 7.05-6.95 (m, 2H), 5.82-5.64 (m, 2H), 4.63-4.34 (m, 6H), 3.69 (td, J=7.0, 3.5 Hz, 1H), 3.55-3.34 (m, 2H), 3.37-3.12 (m, 9H), 2.98 (p, J=7.9 Hz, 1H), 2.50-2.32 (m, 6H), 2.20 (dd, J=16.7, 7.0 Hz, 1H), 1.27-0.97 (m, 6H). ESI MS m/z 489 [M+H]+; HPLC, 1.24 min, 97.5% (AUC).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>C(#N)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 49.6 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol), valeryl chloride (0.16 mL, 1.4 mmol), and pyridine (0.30 mL, 3.7 mmol) in acetonitrile (15 mL) provided N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)pentanamide (0.17 g). MS (ESI) m/z 286([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8][C:7]=1[C:17]1[C:18]([CH3:23])=[N:19][NH:20][C:21]=1[NH2:22].[OH:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>C(O)(C(F)(F)F)=O>[CH3:23][C:18]1[C:17]2[C:7]3[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=3[C:29]([C:28]3[CH:31]=[CH:32][C:25]([OH:24])=[CH:26][CH:27]=3)=[N:22][C:21]=2[NH:20][N:19]=1
Reactant: COCCOc1cccc(-c2c(C)n[nH]c2N)c1OCCOC
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCCOC
Yield: 37.6 %

Procedure:
A solution of 4-(2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine (70 mg, 0.22 mmol), and 4-hydroxybenzaldehyde (40 mg, 0.33 mmol) in TFA (2 mL) was stirred in a sealed pressure vessel at 90° C. for 14 h. The reaction mixture was concentrated and purified by HPLC to give 4-(1-methyl-8,9-bis{[2-(methyloxy)ethyl]-oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol (35 mg, 38% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ9.90 (br. s, 1H), 7.79 (d, 1H), 7.46 (m, 2H), 7.38 (d, 1H), 6.93 (m, 2H), 4.32 (m, 2H), 4.27 (m, 2H), 3.76 (m, 2H), 3.69 (m, 2H), 3.34 (s, 3H), 3.23 (s, 3H), 2.82 (s, 3H); MS (EI) for C23H25N3O5: 424 (MH+).