Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1([NH2:6])[CH2:14][CH2:13]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccccc1C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 214.2 %

Procedure:
To a cold solution of 2-(trifluoromethyl)benzonitrile (1.0 g, 0.58 mmol) in diethyl ether (20 mL) was added titanium isopropoxide (2.0 g, 0.70 mmol) at −70° C. and ethyl magnesium bromide (4.30 mL, 12.86 mmol). The reaction mass was stirred at RT for 2-3 h. Followed by addition of boron trifluoride solution (1.5 mL) and continued stirring for 2 h at RT. The reaction mass was quenched in 1N HCl and basified with NaOH solution. The obtained crude product was further purified by column chromatography on silica gel eluting with 1% EtOAC:DCM eluent to afford 0.250 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.82-0.84 (s, 2H), 0.91-0.93 (br s, 2H), 2.24 (br s, 2H), 7.41 (t, J=6.6 Hz, 1H), 7.58-7.67 (m, 3H).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:11]=[C:10]([F:12])[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1>CO.O>[F:12][C:10]1[CH:11]=[C:4]([CH2:3][CH:2]=[O:1])[CH:5]=[C:6]([F:13])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)cc(CC(O)CO)cc1F
Solvent: CO
Solvent: O
Product: N#Cc1c(F)cc(CC=O)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,3-dihydroxypropyl)-2,6-difluorobenzonitrile (500 mg, 2.4 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0° C. by ice bath, then NaIO4 (754 mg, 3.5 mmol) was added and the mixture was stirred at 0° C. for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 2,6-difluoro-4-(2-oxoethyl)benzonitrile. MS m/z: 182 (M+1)+.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]3[CH:18]=[CH:19][N:20]([CH3:21])[C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:24]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:24][C:18]1[C:15]2[CH:16]=[N:17][C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:22]=[CH:23][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[CH:13][C:14]=2[N:20]([CH3:21])[CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cnc(NC(=O)c3ccc(C(C)(C)O)cc3)cc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc(C(C)(C)O)cc3)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
In a 125 ml round bottom flask, 4-(2-hydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (2.8 g, 9.05 mmol) was dissolved in DMF (25 ml). To this was added N-chlorosuccinimide (1.5 g, 11 mmol) and the mixture was stirred at 50° C. for 3 hours. The mixture was then poured into 50 ml water and then extracted with ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by preparatory HPLC (RFA-mode: eluting with 25-55% ACN in water). Fractions containing the desired mono chlorinated product were combined and concentrated. To the residue was added saturated NaHCO3 and the aqueous mixture was extracted with ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the title compound (840 mg, 27% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.26 (m, 1H) 1.46 (s, 139H) 3.66-3.86 (m, 3H) 5.17 (s, 1H) 7.40-7.69 (m, 3H) 8.01 (d, J=8.59 Hz, 2H) 8.34 (s, 1H) 8.59 (s, 1H) 10.68 (s, 1H)
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:33])[CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:16][N:14]1[N:13]=[N:12][C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:29]4[CH:28]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:37])([F:38])[F:39])=[O:33])[CH:26]=[CH:25][CH:30]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)=[N:15]1
Reactant: Cn1nnc(-c2ccn3c(I)cnc3c2)n1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cn1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
A mixture of 3-iodo-7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (170 mg, 0.52 mmol), 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (16, 225 mg, 0.65 mmol) and Cs2CO3 (340 mg, 1.04 mmol) in dry DME (2.5 ml) was deoxygenated by evacuate/fill N2 (×2). PdCl2dppf (38 mg, 0.05 mmol) was added, and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. for 16 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined EtOAc extracts were dried (Na2SO4) and filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (60 mg) as a solid.
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.C([O:26]C)(C)(C)C.ClCCl>O>[OH:26][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Reactant: COC(C)(C)C
Agent: Br
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1

Procedure:
first isolating the compound (VI) as a solid by stirring the reaction solution into a suitable organic solvent, methyl tert-butyl ether, dichloromethane etc., and subsequently reacting the resulting product with water and by stirring at 50°-100° C., preferably at 60°-80° C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII)
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1([CH3:24])[O:12][CH:11]([CH2:13][O:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][O:9]1.[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CC(O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:16]([C:15](=[CH:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:26]=1[Cl:25])[O:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:24])[O:12]1)=[O:23])[CH3:22]
Reactant: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)CC(=O)C(=Cc1cccc(Cl)c1Cl)OCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
Piperidine (1.0 g) was added dropwise over 5 minutes to a stirred, ice-cooled solution of ethyl 4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy }acetoacetate (26.0 g) (see Preparation 5) and 2,3-dichlorobenzaldehyde (17.5 g) in 2-propanol (200 ml) and the mixture was stirred with ice-cooling for 2 hours and at room temperature for 14 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on silica (150 g) using toluene plus 0-40% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give essentially pure ethyl -(2,3-dichlorobenzylidene)-4-{(2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}acetoacetate (17.3 g) as an oil. A solution of this oil in 2-propanol (150 ml) was treated with methyl 3-amino-crotonate (5.0 g) and the mixture stirred at room temperature for 24 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (110 g) using toluene plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (2.75 g), m.p. 135°-137° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cc1ccccc1)c1c(O)c2ccncc2n(-c2ccccc2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2ccncc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-phenylacetyl-1,7-naphthyridin-2(1H)-one (100 mg, 0.28 mmol) produced in Synthesis Example 26 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 68 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-4(5H)-one (78 mg, 79%).
Reaction SMILES: Cl.Cl.[NH2:3]N.C[N:6](/[CH:8]=[N:9]/[C:10]([C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[C:35](=[O:36])[NH:34][C:33]([CH3:37])=[N:32]4)=[CH:27][CH:26]=3)[CH:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=O)C.C(O)(=O)C.CO>[OH-].[Na+].O1CCOCC1.C(OCC)(=O)C>[CH3:37][C:33]1[NH:34][C:35](=[O:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([S:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:12]4([C:10]5[NH:9][CH:8]=[N:6][N:3]=5)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[CH:19]=3)=[CH:26][CH:27]=2)[N:32]=1
Reactant: NN
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)/N=C/N(C)C)CCOCC4)c3)cc2)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nn(-c2ccc(Sc3cccc(C4(c5nnc[nH]5)CCOCC4)c3)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrazine dihydrochloride (1.13 g, 10.75 mmol) in sodium hydroxide solution (5N, 3 mL) was added to a solution of N-[(1E)-(dimethylamino)methylene]-4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxamide (3.0 g, 2.15 mmol) (example 11) in 1,4-dioxane. Glacial acetic acid (30 mL, 70%) was added and the reaction mixture was stirred at room temperature for about 30 minutes and then at 90° C. for about 5 hours. The solvent was evaporated under vacuum and a saturated mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated under vacuum to afford a thick oily residue, which upon column chromatography over silica gel using methanol and ethyl acetate (1:19) afforded the title compound as white crystalline solid. Yield: 1.10 g
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].Cl.[C:17]([O-])(O)=O.[Na+].O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C=Cc1cc([N+](=O)[O-])ccc1Cl

Procedure:
A solution of 34.1 g (150 millimoles) of the product from Example 1 in 300 ml of methanol was saturated with HCl gas, after which further HCl gas was passed in during the reaction time of 5 hours. The solid obtained on cooling was stirred thoroughly with NaHCO3 /water and taken up in methylene chloride. The CH2Cl2 solution was washed with water and dried over MgSO4, and the abovementioned product was obtained by evaporating down the solution and triturating the residue with diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cn1
Reaction time: 24 h
Yield: 80 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min benzylbromide (1.1 eq.) is added and the reaction solution is stirred 24 hours. The reaction solution is pored into water and extracted with methyltert.-butyl ether. The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. 5-Benzyloxy-2-bromo-pyridine is obtained after column chromatography as brown oil in a yield of 80%. HPLC (method C): 2.01 min; LC-MS (method A): 1.97 min, 264.00 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (100 mg) in dry N,N-dimethylformamide (1 ml) at room temperature and under nitrogen was added potassium carbonate (158 mg) in one go. The reaction was stirred at 60° C. for 1.5 hours and then cooled to 50° C. A solution of 3-(bromomethyl)tetrahydro-2H-pyran (56 mg) in dry N,N-dimethylformamide (0.3 ml) was added in one go and the reaction heated at 50° C. for 16 hours. The reaction was diluted with ethyl acetate (15 ml) and washed with water (5 ml). The organic layer was separated, dried over magnesium sulphate, filtered, and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a yellow oil (45 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH2:12][C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-]>CO.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Part A. Methyl 4-(cyano)-beta-[3-(cyano)phenyl]benzene pentanoate (0.250 gm, 0.786 mmol) was dissolved in methanol and LiOH (0.056 gm, 2.3 mmol) in 1 mL of water was added. The solution was stirred at room temperature for 2 hrs. and extracted with ethyl acetate. The resultant aqueous layer was made acidic with 1 N HCl and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated to give 4-(cyano)-beta-[3-(cyano)phenyl]benzene pentanoic acid as an oil 0.138 gm (58%). 1H NMR (DMSO-d6): 1.95 (m, 2H), 2.3 (m, 3H), 2.70 (dd, 1H), 3.05 (m, 1H), 7.3 (d, 2H), 7.5 (t, 1H), 7.60 (d, 1H), 7.7 (m, 3H), 12.10 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[N:7](C)[C:8](=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[NH3:18]>O1CCCC1>[CH3:17][O:16][C:15]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:10]([NH2:18])=[O:9])=[C:6]([NH:7][CH3:8])[CH:14]=1
Reactant: N
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Solvent: C1CCOC1
Product: CNc1cc(OC)c(OC)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.40 g (10.1 mmol) 6,7-Dimethoxy-1-methyl-1H-benzo(d)(1,3)oxazine-2,4-dione were dissolved in 30 ml tetrahydrofuran and 15.0 ml ammonia (25%) added at 0° C. The solution was stirred for 30 min at 0° C. and for 30 min at room temperature. THF was distilled under vacuum and the remaining suspension was neutralized with diluted hydrogen chloride acid. The product was isolated by filtration.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].[C:22]([C:28]([O:30]C)=[O:29])#[C:23][C:24]([O:26]C)=[O:25].[OH-].[Na+].Cl>O1CCOCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:23](=[CH:22][C:28]([OH:30])=[O:29])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C=C(Oc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 90 °C
Yield: 52.8 %

Procedure:
Benzyltrimethylammonium hydroxide (1.5 mL of a 40% weight aqueous solution, 1.2%) was added to a solution of 3,4-dichlorophenol (20.0 g, 123 mmol), dimethyl acetylenedicarboxylate (16.6 mL, 135 mmol), and dioxane (230 mL) The dark, homogeneous mixture was heated at 90° C. for 1.5 h before the solution was cooled to ambient temperature, combined with 20% aqueous NaOH (100 mL), and warmed to 90° C. After an hour, the mixture was cooled to ambient temperature and combined with 2N aqueous HCl until the pH of the solution was neutral. White sediment was removed by filtration. The filtrate was combined with 2N aqueous HCl until acidic (pH=2). The resulting precipitate was collected by filtration, washed with copious water, and air-dried to provide the product (18.0 g, 53%) as a yellow solid. MS (APCI) m/z 275 [M−H]+; 1H NMR (300 MHz, DMSO-D6) δ ppm 6.64 (s, 1H) 6.95 (dd, J=8.82, 2.71 Hz, 1H) 7.25 (d, J=3.05 Hz, 1H) 7.57 (d, J=8.82 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:25]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1)=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([CH2:51][C:52](Br)([CH3:56])[C:53]([O-:55])=[O:54])(C)(C)C>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:25]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1)=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:52]([C:53]([OH:55])=[O:54])([CH3:56])[CH3:51])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1
Reactant: CC(C)(C)CC(C)(Br)C(=O)[O-]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1cn(C)c2ccc(OC(C)(C)C(=O)O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound of example 114 (0.097 g, 0.18 mmol) was dissolved in acetone (1.5 mL). Cesium carbonate (0.175 g, 0.54 mmol) and tert-butylbromoisobutyrate (0.080 g, 0.36 mmol) were added and the mixture stirred at 60° C. overnight in a sealed tube. The reaction mixture was then diluted with water (10 mL) and the product extracted with EtOAc (50 mL). The organic phase was dried (MgSO4), concentrated and the residue purified by flash chromatography using 60-80% EtOAc in hexane as eluent. The purified diester was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. After stirring at room temperature for 1.5 h, volatiles were removed under a stream of nitrogen and the residue purified by preparative C18 reversed-phase HPLC to give the title compound of example 115.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[N:3][C:4]([C:12]([F:15])([F:14])[F:13])=[N:5]4)[CH3:11])[C:26]=3[CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.051 g, 0.23 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.23 mmol) in DMF (1 mL) were added Hunig's base (0.059 g, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (0.096 g, 0.25 mmol). The mixture was stirred at room temperature for 1 hour and then partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (0.029 g, 0.069 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.44 (ddd, J=10.4, 5.2, 2.8 Hz, 2H), 7.21-7.10 (m, 2H), 5.61 (q, J=7.1 Hz, 1H); 3.77 (ddd, J=12.6, 7.5, 3.0 Hz, 1H), 3.52 (ddd, J=12.5, 8.4, 3.0 Hz, 1H), 2.82 (td, J=6.4, 2.4 Hz, 2H), 2.52 (s, 3H), 2.10-1.80 (m, 5H); MS: (ES) m/z calculated for C19H18ClF3N6O [M+H]+ 423.1, found 422.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][CH:17]([CH:31]([CH3:33])[CH3:32])[CH2:18][CH:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]1[CH2:22][O:21]1)[CH:12]=[CH:11]2.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(O)(C)C>[OH:21][CH:20]([CH:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18][CH:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[CH:8][CH:9]=2)[CH:14]=1)[CH:31]([CH3:32])[CH3:33])[CH2:22][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNCC1
Reactant: COCCOc1cccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Solvent: CC(C)O
Product: COCCOc1cccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN3CCCCC3)C(C)C)cc12

Procedure:
A solution of 0.23 g of tert-butyl {3-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate in 4 ml of isopropanol and 0.99 ml of piperidine is stirred at 70° C. On completion of reaction (TLC monitoring), the reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9]Cl)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClCCN1CCOCC1.[CH3:20][C:21]1[CH:37]=[C:24]2[NH:25][C:26](=[O:36])[C:27]3[CH:32]=[N:31][C:30]4[NH:33][N:34]=[CH:35][C:29]=4[C:28]=3[N:23]2[N:22]=1>>[CH3:20][C:21]1[CH:37]=[C:24]2[N:25]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:26](=[O:36])[C:27]3[CH:32]=[N:31][C:30]4[NH:33][N:34]=[CH:35][C:29]=4[C:28]=3[N:23]2[N:22]=1
Reactant: ClCCCN1CCNCC1
Reactant: Cc1cc2[nH]c(=O)c3cnc4[nH]ncc4c3n2n1
Agent: ClCCN1CCOCC1
Product: Cc1cc2n(CCCN3CCNCC3)c(=O)c3cnc4[nH]ncc4c3n2n1

Procedure:
By substituting 3-piperazinopropyl chloride for the 1-chloro-2-morpholinoethane in the procedure of Example 5 and utilizing the 2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one product of Example 8, 2-methyl-4-(3-piperazino)propyl-4H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.