Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5]N=C[C:2]=1[C:7](N)=[O:8].[C:10]1([CH2:16][C@H:17]([NH:21][C:22]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:23])[C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C[C@]12[C@H]3C[C@H](C3(C)C)C[C@H]1[O:34][B:35]([C@@H:37]([NH2:42])[CH2:38][CH:39]([CH3:41])[CH3:40])O2.C(N(CC)C(C)C)(C)C>CN(C)C=O>[O:8]1[CH2:7][CH2:2][NH:1][CH2:6][CH2:5][O:34][B:35]1[C@@H:37]([NH:42][C:18](=[O:20])[C@@H:17]([NH:21][C:22]([C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:23])[CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:38][CH:39]([CH3:41])[CH3:40]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reactant: NC(=O)c1cnccn1
Reactant: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OCCNCCO1
Temperature: -25.5 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Preparation of N-[(1S)-1[[[(1R)-1-[3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-benzyl]2-pyrazine carboxamide. A 500 ml three neck round bottomed flask equipped with a stir bar, addition funnel, thermocouple, nitrogen inlet/outlet and cooling bath is charged with 11 g (99.9 mmol) of (S)-3-phenyl-2-[(pyrazine-2-carbonyl)-amino]-propionic acid, 15.5.0 g (40.6 mmol) of 0-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU), 12.2 g (40.6 mmol) of (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride salt (87:13 mixture of isobutyl diastereomers (R:S)) and 165 mL of N,N-dimethylformamide (DMF). The pale yellow reaction solution is cooled to −35° C. where 12.6 g (17 mL, 97.3 mmol) of N,N-di-isopropyl ethyl amine is added dropwise over six minutes at −34° C. to −35° C. The resulting solution is then stirred overnight at −40 to −11° C. The reaction mixture is quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture. After transferring into a reparatory funnel the layers are separated. The organic phase is then washed successively with 10% aqueous sodium hydrogen phosphate (1×200 mL), 8% aqueous sodium bicarbonate (2×200 mL) and saturated sodium chloride (1×200 mL). The product solution is dried over magnesium sulfate then filtered. The filtrate is evaporated to dryness in vacuo to give 19.57 g (37.7 mmol, 93%) of the title compound as a light brown foam with an HPLC purity of 92 A %. 1H NMR (d6-DMSO, 400 MHz) δ 9.15 (d, 1H, J=1.44 Hz), 8.87 (d, 1H, J=2.48 Hz), 8.7 (m, 3H), 7.25 (m, 4H), 7.18 (m, 1H), 4.89 (q, 1H, J=6.88, 15.4 Hz), 4.13 (dd, 1H, J=1.8, 8.56 Hz), 3.15 (d, 2H, J=6.88 Hz), 2.7 (m, b, 1H), 2.22 (m, b, 1H), 2.05 (m, b, 1H), 1.87 (t, 1H, J=5.40 Hz), 1.81 (s, b, 1H), 1.67 (d, b, 1H), 1.52 (m, b, 1H), 1.13-1.33 (m, 9H), 0.83 (dd, 6H, J=2.48, 6.56 Hz), 0.80 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:24][CH2:23][CH2:22][Cl:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g, 40 mmol), K2CO3 (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol) and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford 6.5 g of an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol-water to yield 2.2 g (51%) of a solid, m.p.=124-126° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][OH:15])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N1C(=O)CC[C@H]1C(O)=O>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]=[O:15])[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CO)OC1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (37.5 g, 162.13 mmol) in DCM (310 mL) cooled to −10° C. was added DIPEA (84.75 mL, 495.06 mmol). Then a solution of Pyr.SO3 complex (50%, 69.47 g, 218.25 mmol) in DMSO (225 mL) was slowly added. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was partitioned between water (150 mL) and DCM (220 mL). The two layers were separated and the aq. layer was extracted twice with DCM (2×150 mL). The combined org. layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was co-evaporated 3 times with toluene and purified over a short pad of silica gel (EA-Hept. 2-1) to afford the title aldehyde as a white solid (33.58 g, 90% yield).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>CO>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: NN
Reactant: Clc1nncc2ccccc12
Solvent: CO
Solvent: O
Product: NNc1nncc2ccccc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A 2 L, 3-necked, round-bottomed flask fitted with a temperature probe and condenser, and was charged 375 mL of hydrazine hydrate; the solution was then cooled to 0 to 5° C. About 75 g of 1-chlorophthalazine salt was added in portions at a rate to maintain the solution temperature at 0 to 5° C. After addition, the solution was stirred at 20 to 25° C. for about 24 hrs. The reaction mixture was then cooled to 0 to 5° C. and 150 mL of methanol was added, the solution stirred for 3 hrs, and the resulting solid material was filtered, washed with 150 mL of cold methanol, and dried under vacuum at 35° C. Yield 99%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:10])=O.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([OH:20])[CH:19]=1)[CH2:15][OH:16].[CH2:21](Cl)[C:22]#[CH:23]>ClCCl>[CH2:7]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:23][C:22]#[CH:21])[CH:19]=1)[CH2:15][OH:16])[C:8]#[CH:10]
Reactant: C#CCCl
Reactant: CC(C)=O
Reactant: OCc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#CCOc1cc(CO)cc(OCC#C)c1
Yield: 97 %

Procedure:
Finely powdered K2CO3, 14 grams (0.10 moles), and Kl, 17 grams (0.10 moles) were placed in a 500 mL round flask, and 200 mL acetone was added. Under a nitrogen atmosphere, 3,5-dihydroxybenzylalcohol, 4.2 grams (0.03 moles), and propargyl chloride, 5.3 grams (0.07 moles) were then added. The resulting mixture was refluxed overnight. The results from thin layer chromatography showed no starting material (3,5-dihydroxybenzylalcohol) as well as the presence of a new compound. The solution was filtered, and the filtered solid washed with acetone. The acetone of the resulting filtrate was removed by rotary evaporation, leaving an organic residue. Dichloromethane (50 mL) was added to dissolve the organic residue, and this was washed with water (30 mL×2), and then dried over anhydrous sodium sulfate. After filtering the organic phase, the solvents were removed by rotary evaporation leaving a yellow oil, which solidified upon standing. 6.3 g of product was obtained, which corresponds to a 97% yield.
Reaction SMILES: C([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14]C)=[O:13])(=O)C1C=CC=CC=1.[ClH:19]>>[ClH:19].[NH2:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Agent: Cl
Product: C[C@@H](O)[C@H](CN)C(=O)O
Temperature: 25 °C
Yield: 93 %

Procedure:
10.65 g (42.43 mmol) of methyl (2S,3R)-2-(N-bezoylaminomethy)-3-hydroxybutyrate was added to the 70 ml of 10% aqueous HCl solution at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature. Precipitated benzoic acid was filtered out, the filtrate was washed twice with 100 ml toluene, and the aqueous layer was taken and concentrated under reduced pressure to obtain 6.67 g of the title compound (yield: 93%).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:11][C:10](=O)[CH2:9]1>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]([S:5]([N:7]=[C:10]1[CH2:11][O:8][CH2:9]1)=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1COC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2-Methylpropane-2-sulfinamide (3.36 g, 27.77 mmol, 1 eq) and Ti(OEt)4 (12 ml, 55.54 mmol, 2 eq) were added to a solution of oxetan-3-one (2 g, 27.77 mmol, 1 eq) in THF at 22° C. The reaction mixture was stirred at 50° C. for 5 h. It was cooled to room temperature and poured into saturated brine solution, and then the suspension was filtered through a pad of Cellite. The filtrate was extracted with ethyl acetate, and the organic layer washed with saturated brine solution, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120 mesh) columatography using 30% EtOAc/Petroleum ether. Yield: 0.55 g (45.4%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl.[NH:19]1[CH2:22][CH:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20]1>CN(C)C=O.O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:19]1[CH2:22][CH:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc3ccccc3n2)C1
Temperature: 120 °C
Yield: 80 %

Procedure:
Cesium carbonate (4.68 g, 14.4 mmol), 2-chloroquinoline (0.782 g, 4.8 mmol) and tert-butyl azetidin-3-yl-carbamate hydrochloride (1.0 g, 4.8 mmol) were dissolved in dry dimethylformamide (15 mL) and the resulting mixture was heated at 120° C. overnight. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), then dried over sodium sulfate. The organic was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% ethyl acetate in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)-carbamate (1.14 g, 3.84 mmol, 80% yield) as white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 896.8 %

Procedure:
To a solution of 2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL) cooled to 0° C. was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol) followed by p-TSA.H2O (100 mg) was added. Reaction mixture was stirred at 0° C. for 5.0 h. The reaction mixture was washed with aq NaHCO3 and brine, dried over Na2SO4 and evaporated to give the product 25 (75.0 g, 90%). This crude product was taken to next step without purification.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C(O)C>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:11]([CH:8]1[CH2:10][CH2:9]1)[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)CCN(CCC(=O)OCC)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
A mixture of ethyl acrylate (30.0 g, 300 mmol, 2.0 eq.) and cyclopropyl amine (8.5 mL, 149 mmol, 1.0 eq.) in absolute ethanol (45 mL) was stirred 24 h at room temperature. The crude mixture was purified by fractionated distillation in vacuo (20 mbar). One fraction was collected (boiling point: 135° C. at 20 mbar), yielding to 20.58 g (54%) of the desired product as a colorless oil. MS (m/e): 274.3 (MH+, 100%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[OH-].[Cs+:10]>O>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[Cs+:10]
Reactant: CC(=O)CCC(=O)O
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCC(=O)[O-]
Temperature: 65 °C

Procedure:
46.9 gr. of 99% pure levulinic acid is slurried in 100 cc. distilled water. 97.3 g. of a 4.22 molar, pure cesium hydroxide solution is added and the temperature is raised to 65° C. to obtain complete solution. The solution is filtered through No. 40 filter paper to remove dust, etc. The solution is then evaporated on a hot plate to 200 g., which gives a 2 molar concentration, and it is then bottled.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21](I)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(COC)OC>[Br:18][C:19]1[CH:24]=[C:23]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Reaction time: 4 h
Yield: 73.9 %

Procedure:
In argon atmosphere, a mixture of 31.4 g (141 mmol) of 9-phenanthreneboronic acid, 40.0 g (141 mmol) of 3-bromoiodobenzene, 3.30 g (2.83 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 50 ml of dimethoxyethane and 212 ml of a 2 M sodium carbonate aqueous solution, and the mixture was refluxed under stirring for 4 h. After the reaction, the reaction mixture was added with toluene and washed with water. The organic phase was dried over sodium sulfate, and then toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 34.7 g (yield: 74%) of 9-(3-bromophenyl)phenanthrene.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12)(=O)C.[OH-].[Na+].C(O)(=O)C.O>CO>[OH:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 98.2 %

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine-7,7-dioxide (6.6 g) in methanol (200 ml), kept under a nitrogen atmosphere was added 2N aqueous sodium hydroxide solution (132 ml). The mixture was stirred at room temperature for 7 minutes, then there was added 10% acetic acid (200 ml) and water (300 ml). After 10 minutes of stirring the mixture was filtered to afford the title compound (5.68 g) as a pink solid. The solid was recrystallized from THF, m.p. 334° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:23](O)[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:23][CH3:24])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g of conc. H2SO4 in 470 ml of ethanol was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, stirred with 6 g of solid K2CO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (200 ml), washed with 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil. PMR (CDCl3) δ 1.25 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J=7.0 Hz), 7.16 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[CH:5]=1)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Product: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A 30.0 g portion of 3-acetamidoacetophenone was heated with 50 ml of dimethylformamide dimethylacetal on a steam bath under inert atmosphere for 8 hours. After cooling, the precipitated material was collected by filtration to yield the desired material as orange crystals (37.20 g, mp 184°-185° C.).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].S1(CCCC1)(=O)=O>>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 140 °C
Yield: 16 %

Procedure:
A mixture of potassium fluoride (61.5 g; 1.06 mole), 2-chloronitrobenzene (157.5 g; 1.0 mole) and sulpholane (88.8 g; 0.74 mole) was heated to 140° C. for 28 hours. 2-Fluoronitrobenzene was obtained in 16% yield together with 61% recovered 2-chloronitrobenzene.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.O>CN(C=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:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccccc1-c1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Temperature: 100 °C
Yield: 51.7 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (21.0 mg, 0.08 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg, 0.007 mmol), 2-chlorophenyl boronic acid (15 mg, 0.096 mmol), and Na2-CO3 (21.0 mg in 0.5 mL water). The reaction mixture was heated at an oil bath temperature of 100° C. for about 12 hours. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (30% EtOAc/hexanes) to give the title compound as a brown solid (15 mg, 55%). 1H-NMR (300 MHz, CDCl3) δ 9.14 (d, 1H, J=9.2 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 2H), 7.46-7.42 (m, 2H), 5.61 (bs, 1H), 2.88 (m, 1H), 0.89 (m, 2H), 0.66 (m, 2H); MS (ESI) (M+H)+ 363.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cl)nc1

Procedure:
A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g (0.03 mol) dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 hours. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the title compound as a low-melting white solid. PMR (CDCl3): δ 1.44 (3H, t, J~6.2 Hz) 4.44 (2H, q, J~6.2 Hz), 7.44 (1H, d, J~8.1 Hz), 8.27 (1H, dd, J~8.1 Hz, 3 Hz), 9.02 (1H, d, J3 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O>[CH3:19][O:18][C:16]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: OCC1CCNCC1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
4-Hydroxymethylpiperidine (1.0 g, 8.6 mmol) was dissolved in water (15 mL) and cooled to 0° C. To this solution was added dropwise a solution of potassium carbonate (4.8 g, 34.7 mmol) in water (10 mL), followed by methyl chloroformate (2.68 mL, 34.7 mmol). The mixture was stirred vigorously and allowed to warm to room temperature over 2 h. After stirring overnight (16 h), the reaction mixture was acidified with 6M aqueous hydrochloric acid and extracted with dichloromethane (3×60 mL). The extracts were combined, dried over sodium sulfate and filtered. The filtrate was evaporated to yield the title intermediate (1.4 g, 8.1 mmol, 93%) as a colorless oil. (m/z): C8H15NO3 calcd. 173.11; found 156.2 [M−H2O+H]+. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 0.98 (m, 2H), 1.52 (m, 1H), 1.63 (br d, 2H), 2.72 (br m, 2H), 3.23 (d, 2H), 3.56 (s, 3H), 3.95 (br d, 2H), 4.48 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:19]([CH3:20])[CH3:18])=[O:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
5-Bromopyridine-2-carboxylic acid (20 g, 100 mmol, Frontier Scientific catalog# B1704) was stirred in methylene chloride (30 mL) and cooled to 0° C. 2.0 M oxalyl chloride in methylene chloride (100 mL) was added slowly, followed by N,N-dimethylformamide (0.8 mL). The mixture was stirred for 30 minutes at 0° C. and then room temperature overnight. The mixture was evaporated, redissolved in methylene chloride (130 mL) and was added slowly to a mixture of dimethylamine hydrochloride (9.8 g, 120 mmol) and triethylamine (56.1 mL, 400 mmol) in methylene chloride (130 mL) cooled to 0° C. The reaction mixture was stirred at room temperature for 2 hrs. This mixture was diluted with methylene chloride (200 mL) and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. The product was purified by FCC on silica gel using ethyl acetate in hexanes (0-60%) gradient to give 5-bromo-N,N-dimethylpyridine-2-carboxamide, (22.0 g, 100%). LCMS calculated for C8H10BrN2O (M+H)+: m/z=229.0, 231.0; found: 228.9, 230.9.