Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:24])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH2:20][CH2:21][OH:22])=[CH:13][C:12]=3[F:23])[C:3]=12.[OH-].[K+].[CH3:27]I>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:24])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH2:20][CH2:21][O:22][CH3:27])=[CH:13][C:12]=3[F:23])[C:3]=12
Reactant: CI
Reactant: Cn1cc(-c2cc3c(cc2F)CCN3CCO)c2c(Br)ccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCN1CCc2cc(F)c(-c3cn(C)c4nccc(Br)c34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of 2-(6-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoroindolin-1-yl)ethanol (D41) (150 mg, 0.384 mmol) in DMSO (3 mL) was added potassium hydroxide (64.7 mg, 1.153 mmol) followed by methyl iodide (0.036 mL, 0.577 mmol). The reaction mixture was stirred at RT for 1 hour, after which an additional 0.5 eq of methyl iodide (0.012 mL) was added. The reaction mixture was stirred for an additional hour. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution (20 mL). The aqueous layer was extracted with DCM (3×40 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated. The crude was purified by column chromatography on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford title compound (106 mg). LCMS (A): m/z (M+H)+ 404/406, C19H19BrFN3O requires 403/405 (acidic).
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:8]1([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCOc2ccccc21
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCCOc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 119.5 %

Procedure:
A solution [sic], maintained under an inert atmosphere, of 33.5 ml (0.1 mol) of 3M methylmagnesium chloride in solution in tetrahydrofuran is heated to 50° C. 11.3 g (0.069 mol) of 3,4-dihydro-2H-benzoxepin-5-one, dissolved in 150 ml of tetrahydrofuran, are added fairly quickly. This solution is brought to reflux for 4 hours and is then left stirring overnight at room temperature. The reaction mixture is subsequently gently hydrolysed with water under cold conditions. An ammonium chloride solution (120 g per litre) is then poured into the reaction mixture. The latter is extracted with ethyl acetate and then the organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. 14.7 g of a yellow oil are obtained, which oil is purified by crystallization from isoctane. 11.9 g of the title compound are thus obtained, the melting point of which is 92° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[CH2:20]([OH:23])[CH2:21][OH:22]>C(Cl)Cl>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([O:22][CH2:21][CH2:20][OH:23])=[O:3])=[CH:5][C:6]1=2
Reactant: OCCO
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: ClCCl
Product: O=C(OCCO)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1.0 gm of 2-chlorocarbonyl-6,11-dihydro-11-oxo-dibenz[b,e]oxepin in 50 cc of methylene chloride, add 3 gm of ethylene glycol and stir the mixture for 18 hours at room temperature. Distill off the solvent and excess ethylene glycol under high vacuum (0.1 mm). Chromatograph the residue on a silica gel column (100 gm), eluting with 10% ethyl acetate in benzene to obtain the title product.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13](=[CH2:16])[C:14]#[N:15]>C(OCC)C>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[CH2:16][CH:13]([Cl:12])[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cl)C#N
Reactant: OCCNCc1ccccc1
Solvent: CCOCC
Product: N#CC(Cl)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
2-(benzylamino)ethanol 2a (5 g, 0.03 mol) and 2-chloro-propenenitrile (3 g, 0.03 mol) were dissolved in 50 mL of anhydrous ethyl ether in an ice-water bath, heated to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 3-(benzyl(2-hydroxyethyl)amino)-2-chloro-propanenitrile 2b (7 g) as a red oil liquid, which was used in the next step without further furification.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH:35]=[CH:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1.Cl>O1CCCC1.ClCCl.O>[Cl:7][CH:8]=[C:29]1[CH:35]=[CH:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C=CC(=O)CO2
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
1.3 equivalents of n-butyllithium are added to a suspension of 122 mg (0.35 mmol) of chloromethyltriphenylphosphonium chloride in tetrahydrofuran cooled to 0° C. After stirring for one hour, the ylide is added at 0° C., via a hollow tube, to 55 mg (0.25 mmol) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 31. Immediately afterwards, water, 1N hydrochloric acid and dichloromethane are added. The phases are separated and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are then dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 5/95) to provide 61 mg (96%) of methyl 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a yellow-white solid comprising two Z/E isomers as a mixture in an 85/15 ratio; M.p.=72–77° C.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:7]=1[CH:8]=[O:9].O>C(Cl)Cl>[F:5][C:6]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(F)c(C=O)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(O)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
BBr3 (4 mL, 4 mmol, 1.0 M in heptane) was added dropwise to a solution of 2-fluoro-5-(methyloxy)benzaldehyde in CH2Cl2 at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, slowly warmed to 0° C. and stirred for 2 hours. The reaction mixture was poured into water, extracted with EtOAc (3×10 mL). The extracts were combined, washed with water, brine, and dried (Na2SO4). The solvent was evaporated, and the residue was purified on silica gel, using 0-20% EtOAc-Hexane to give the desired product (142 mg, 25%) as a white solid. MS m/z 141 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH2:10][CH3:11].FC(F)(F)C(O)=O.[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH2:10][CH3:11])[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1
Reactant: CCOc1c(N)ncnc1Cl
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A reaction mixture of 6-Chloro-5-ethoxy-pyrimidin-4-ylamine (30.00 mg; 0.17 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (107.92 mg; 0.17 mmol; 1.00 eq.), and Cs2CO3 (225.22 mg; 0.69 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for overnight. Purified the product by prep HPLC, collected title compound 27 mg, yield 24%. LC-MS: (M+1=534, obsd.=534).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:17][C:9](=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Yield: 62.3 %

Procedure:
278 g of benzyl bromide were added to a stirred solution of 215 g of D-leucic acid and 246 g of triethylamine in 2.5 l of ethy acetate. The mixture was then heated under reflux for 5 hours, cooled and filtered to remove triethylamine hydrobromide. The filtrate was washed twice with 2M hydrochloric acid, water, saturated sodium bicarbonate solution and then saturated sodium chloride solution. The organic extract was dried over magnesium sulfate and evaporated to give 225 g of D-leucic acid benzyl ester as a yellow liquid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ccc(CO)o2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.52 g, 19.11 mmol) in dry CH2Cl2 (35.2 mL) was treated at 0° C. with Et3N (3.20 mL, 22.93 mmol) followed by DMAP (233 mg, 1.91 mmol) and Ms-Cl (1.63 mL, 21.02 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (35 mL), extracted with CH2Cl2 (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 3.65 g of crude 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane as an orange oil. The crude material in acetone (20 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (1.57 g, 13.91 mmol) in acetone (20 mL). K2CO3 (7.69 g, 55.66 mmol) followed by TBA iodide (1.03 g, 2.73 mmol) were added and the reaction mixture was stirred at rt overnight. Water (100 mL) and EA (100 mL) were added. The aq. layer was extracted with EA (100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as an orange oil. TLC: rf (60:40 hept-EA)=0.31. LC-MS-conditions 02: tR=0.91 min. 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 3.99 (dd, J=4.5, 2.5 Hz, 2H), 4.06 (dd, J=4.4, 2.5 Hz, 2H), 5.31 (s, 2H), 6.35 (d, J=3.3 Hz, 1H), 6.42 (d, J=3.3 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](=O)([O-])[O-].[K+].[K+].CO.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[N:1]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([O:5][CH3:9])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)N1CCC[C@@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a stirred suspension of D-proline ((R)-29, 13.955 g, 120.0 mmol) and potassium carbonate (K2CO3, 33.17 g, 240.0 mmol, 2.0 equiv) in anhydrous methanol (MeOH, 240 mL, 5925 mmol) at 0° C. was added ethyl chloroformate (28.4 mL, 288 mmol, 2.4 equiv) at room temperature. The resulting reaction mixture was then stirred at room temperature for 18 h. When LCMS showed the reaction was deemed complete, the solvent was removed under reduced pressure. The resulting residue was then treated with water (80 mL) and saturated aqueous NaHCO3 (80 mL) before being extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure to give the pure (2R)-1-ethyl 2-methyl pyrrolidine-1,2-dicarboxylate ((R)-30, 18.792 g, 24.14 g theoretical, 77.8% yield) as a colorless volatile oil. For (R)-30: 1H NMR (CDCl3, 400 MHz) δ ppm 4.35 (dd, 0.5H, J=8.7, 3.5 Hz), 4.28 (dd, 0.5H, J=8.7, 3.7 Hz), 4.13 (m, 2H), 3.72 (s, 1.5H), 3.70 (s, 1.5H), 3.59-3.41 (m, 2H), 2.20 (m, 1H), 2.01-1.86 (m, 3H), 1.25 (t, 1.5H, J=7.1 Hz), 1.18 (t, 1.5H, J=7.1 Hz); C9H15NO4(MW, 201.22), LCMS (EI) m/e 201.9 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][N:30]=1>C(Cl)Cl>[CH3:28][C:29]1[N:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][CH:6]3[N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]2)=[CH:33][CH:34]=1
Reactant: COC(=O)N1CCN(C2CCc3c(N)cccc32)CC1
Reactant: Cc1ccc(N=C=O)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(C2CCc3c(NC(=O)Nc4ccc(C)nc4)cccc32)CC1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a room temperature solution of Methyl 4-(4-amino-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate (175 mg, 0.635 mmol, 1.0 equiv) and triethylamine (90 μL, 0.635 mmol, 1.0 equiv) in dry DCM (1.7 mL) was added freshly filtered 2-methyl-5-isocyanatopyridine (94 mg, 0.699 mmol, 1.1 equiv) in dry DCM (1.7 mL) dropwise via cannula. After 1 h, the reaction was diluted with DCM and washed with water and with brine. The resulting solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was dissolved in a minimal volume of DMF and water was added to precipitate the product. The resulting solid was filtered, washed three times with water and twice with hexane to provide the title compound as a light brown solid (133 mg, 51%). LCMS [M+H]+=410.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)C3CC3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was added cyclopropane carboxylic acid chloride (0.16 mL, 1.7 mmol) and N,N-diisopropyl ethylamine (0.59 mL, 3.6 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as an off-white solid (310 mg, 54% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.50 min (98.6%); mp, decomposed at 298° C.; 1HNMR (DMSO-d6) 0.67-0.70 (m, 4H, cyclo-CH2CH2), 1.65-1.73 (m, 1H, cyclo-CH), 2.11-2.20 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.77-4.87 (m, 2H, CH2NH), 5.23 (dd, J=6, 12 Hz, 1H, CH), 7.31-7.78 (m, 3H, Ar), 8.44 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.28, 13.57, 20.76, 23.28, 30.58, 41.53, 56.47, 117.65, 124.50, 125.44, 133.89, 141.14, 148.44, 154.77, 160.94, 169.53, 172.60, 172.73. LCMS MH=369; Anal Calcd For C19H20N4O4+0.1H2O: C, 61.65; H, 5.50; N, 15.13. Found: C, 61.48; H, 5.47; N, 14.97.
Reaction SMILES: ClC1N=C(C2C(C3C=C(NC(=O)C4C(F)=CC=CC=4F)C=CC=3)=[N:10][N:11]3C=CC=CC=23)C=CN=1.[F:34][C:35]([F:50])([F:49])[C:36]([N:38]1CCC2[C:40](=[CH:41][C:42]([NH2:48])=[CH:43]C=2)[CH2:39]1)=[O:37]>CC(O)C>[NH:10]1[C:41]2[CH:40]=[CH:39][N:38]=[N:48][C:42]=2[CH:43]=[N:11]1.[F:34][C:35]([F:50])([F:49])[C:36]([NH2:38])=[O:37]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Solvent: CC(C)O
Product: NC(=O)C(F)(F)F
Product: c1cc2[nH]ncc2nn1
Temperature: 160 °C
Yield: 349.1 %

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (200 mg, 0.43 mmol) and 2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinamine (211 mg, 0.86 mmol) in a few mL i-PrOH was heated in a microwave apparatus at 160° C. until the reaction was complete. The by partitioning the reaction mixture between saturated aqueous NaHCO3 and CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue that was purified by silica gel chromatography to afford the intermediate trifluoroacetamide pyrazolopyridazine (350 mg). A portion of this material (250 mg) was subjected to similar conditions as described in Example 62, step F to afford the title compound (198 mg) as a tan powder. LC-MS (AP)+=574.07. 1H NMR (400 MHz, DMSO-d6) δ 2.59 (t, 2H, J=5.5), 2.89 (t, 2H, J=5.5), 3.74 (s, 2H), 6.46 (d, 1H, J=5.1), 6.90 (d, 1H, J=8.2), 7.10 (t, 1H, J=6.7), 7.22 (d, 1H, J=8.0), 7.24 (d, 1H, J=7.9), 7.32 (s, 1H, 7.34 (s, 1H), 7.44-7.48 (m, 3H), 7.53-7.60 (m, 1H), 7.80 (d, 1H, J=8.0), 7.97 (s, 1H), 8.21 (d, 1H, J=5.3), 8.46 (d, 1H, J=9.1), 8.82 (d, 1H, J=6.7), 9.37 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([CH3:23])=[N:9][C:10]2[N:11]([N:20]=[CH:21][CH:22]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:7]([O:1][CH:2]([C:7]1[C:8]([CH3:23])=[N:9][C:10]2[N:11]([N:20]=[CH:21][CH:22]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:8])([CH3:12])[CH3:2]
Reactant: COC(=O)C(O)c1c(C)nc2ccnn2c1-c1ccc(C)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2ccnn2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
To a suspension of methyl 2-hydroxy-2-(5-methyl-7-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.128 mmol) in tert-butyl acetate (1 mL) at room temperature was added perchloric acid (0.015 mL, 0.257 mmol). The reaction mixture was stirred for 2 h at room temperature before being quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (26 mg, 55.1%). 1H-NMR (500 MHz, CDCl3) δ ppm 0.96 (9H, m), 2.46 (3H, s), 2.66 (3H, s), 3.78 (3H, s), 5.10 (1H, s), 6.59 (1H, d, J=2.4 Hz), 7.37-7.40 (2H, m), 7.43-7.55 (2H, m), 7.99 (1H, d, J=2.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].CI.[CH3:14]N(C)C=O.[OH-].[Na+]>[Ag]=O.C(O)C>[CH3:14][O:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CN(C)C=O
Reactant: Cc1cccc(C(=O)O)c1O
Agent: O=[Ag]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: COc1c(C)cccc1C(=O)O

Procedure:
A mixture of 7.1 g. (0.05 mole) of 3-methylsalicylic acid, 23.1 g. (0.1 mole) of silver oxide and 25 ml. of methyl iodide in 150 ml. of N,N-dimethylformamide was stirred at 25° C. for 16 hours, then filtered. The filtrate was evaporated to provide a residue which was hydrolyzed by heating at 50° C. in an equivolume mixture of ethanol and 6N sodium hydroxide solution. The resulting mixture was acidified and filtered. The filtrate was evaporated, and the residue dissolved in base and treated with decolorizing charcoal. Acidification provided white solid 2-methoxy-3-methylbenzoic acid, m.p. 70°-75° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][C@H:16]([CH3:18])[NH:15][CH2:14][C@@H:13]2[CH3:19])=[N:4][N:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[C@@H:13]([CH3:19])[CH2:14][N:15]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[C@@H:16]([CH3:18])[CH2:17]2)=[N:4][N:3]=1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-chloro-4-((2S,5S)-2,5-dimethylpiperazin-1-yl)phthalazine (496 mg, 1.79 mmol) was dissolved in DMF (5 mL) and N,N-diisopropylethylamine (0.5 mL). Benzoyl chloride (0.23 mL, 2.02 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave off-white foam. MS (M+H)+=381.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25](Cl)(=O)[C:26](Cl)=O.[N:31]1[CH:36]=CC=C[CH:32]=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:25][CH2:26][N:31]([CH3:36])[CH3:32])=[O:13])(=[O:6])=[O:7]
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CN(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 50.2 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 3.1 mmol) dissolved in 30 mL of anhydrous dichloromethane (DCM) was reacted with 1.8 mL (3.6 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of (2-dimethylamino)ethanol (0.55 g, 6.2 mmol) and 0.50 mL of pyridine (0.49 g, 6.2 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and methanol (MeOH) as eluent (EtOAc/MeOH=9:1) to provide 0.7 g (50% yield) of the title compound (28a) as a colorless oil. Rf=0.23 (EtOAc/MeOH=9:1). 1H NMR (400 MHz, CDCl3): δ=1.08 (s, 3H), 1.09 (s, 3H), 2.28-2.30 (m, 8H), 2.57-2.60 (m, 2H), 3.22-3.26 (m, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.88 (s, 1H), 4.02 (d, J=9.2 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.27-4.32 (m, 1H), 4.32 (d, J=11.2 Hz, 1H), 4.65 (d, J=11.6 Hz, 1H), 7.30-7.35 (m, 5H) ppm. MS (ESI) m/z 450.04 (M+H)+. The analytical data is consistent with the proposed structure.