Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[CH:7][CH:6]=1.Br[CH2:25][C:26]#[N:27]>CN(C)C=O>[O:21]=[C:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:22])[F:23])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]1[CH2:25][C:26]#[N:27]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 0.5 h

Procedure:
To a mixture of 95% dry sodium hydride (48 mg, 2.00 mmol) in anhydrous N,N-dimethylformamide (10 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg, 1.00 mmol). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of 2-bromoacetonitrile (480 mg, 4.00 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (as checked by LCMS), then quenched by addition of methanol (10 mL). The mixture was concentrated under reduced pressure, and the residue was subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (compound No. 90) (307 mg, 0.93 mmol, 93%). LCMS mz 331.0 (M+H), 353.0 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; CDCl3) δ 7.69 (m, 4H); 7.57 (dd, J=8.4 and 2.1 Hz, 1H); 7.47 (d, J=3.0 Hz, 1H); 7.16 (d, J=8.2 Hz, 1H); 6.90 (s, 2H); 3.05 (m, 2H); 2.79 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[F:18])[O:8][N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([F:18])=[C:11]([C:9]2[O:8][N:7]=[C:6]([CH:4]=[O:3])[CH:10]=2)[CH:16]=1
Reactant: CCOC(=O)c1cc(-c2cc(Cl)ccc2F)on1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc(-c2cc(Cl)ccc2F)on1
Temperature: -78 °C
Yield: 84.4 %

Procedure:
In a 50 ml round bottom flask equipped with stir bar and drying tube added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (0.78 g, 2.89 mmol) and dichloromethane (10 ml). Cooled the solution down to −78° C. and to this stirred solution added diisobutylaluminum hydride (1M hexanes, 5.3 ml, 5.3 mmol). The resulting mixture was left stirring at −78° C. for 3 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stirred at 63° C. for 15 min after which it was filtered through a celite pad. The filterate was concentrated in-vacuo to isolate an off-white solid, which was triturated with hexanes to isolate the title compound as a white solid (0.55 g, 84%). 1H-NMR (CDCl3), d (ppm): 10.2 (s, 1H), 7.99 (m, 1H), 7.44 (m, 1H), 7.20 (m, 1H), 7.10 (d, 1H). Step 2: 1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol: In a 50 ml round bottom flask equipped with stir bar added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carbaldehyde (0.55 g, 2.42 mmol) and tetrahydrofuran (6 ml). Cooled the mixture down to 0° C. and to it added methyl magnesium iodide (3M in diethyl ether, 3.23 ml, 9.67 mmol). The resulting mixture was left stirring at 0° C. for 3 h. Reaction mixture was quenched with hydrochloric acid (1N, aqueous, 10 ml), extracted with diethyl ether (3×50 ml). Combined organic phase was washed with water (50 ml), brine (50 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 10% ethyl acetate in hexanes to isolate the desired compound as clear oil (179 mg, 31%).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)\[CH2:5][CH3:6].[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1([CH2:5][CH3:6])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
To a solution of 1-[(E)-3-chloro-1-ethyl-1-propenyl]-3-nitrobenzene (Preparation 15, 50 g, 0.22 mol) in dichloromethane (40 ml) was added rhodium (II) acetate dimer (2.0 g, 4.6 mmol). To the mixture was added dropwise at room temperature over 6 hours a solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture stirred at room temperature for 16 hours. To the mixture was added dropwise at room temperature over 7 hours a solution of ethyl diazoacetate (20 ml, 21.70 g, 0.190 mol) in dichloromethane (20 ml), then the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue purified by silica column (1 kg) chromatography, eluting with 1:1 hexane/dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale orange oil (10.5 g, 15%).
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)C(O)c1ccccc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a cooled (0° C.) solution of 0.425 g (2.19 mmol) of the product of Step B dissolved in 10 mL of dichloromethane was added 0.717 g (2.74 mmol) of triphenylphosphine followed by 0.908 g (2.74 mmol) of carbon tetrabromide. After 30 minutes the reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.373 g (66%) of the title compound.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.[CH3:11][NH:12][NH2:13]>>[I:10][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:12]([CH3:11])[N:13]=[CH:8][C:7]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: CNN
Product: Cn1ncc2c(I)ccnc21

Procedure:
227 mg of 2-fluoro-4-iodo-pyridine-3-carbaldehyde (0.9 mmol, 1 eq.; prepared as described in J. Org. Chem. 1993, 58, 7832) were dissolved in 3.6 mL 1-PrOH, treated with 72 μL methyl hydrazine (1.36 mmol, 1.5 eq.) and heated to 100° C. for 30 min (Biotage Initiator 60®). The reaction mixture was concentrated in vacuo, the residue was partioned between water and ethyl acetate, the aq. layer was extracted with ethyl acetate, the combined organic layers were dried and concentrated in vacuo to provide the crude target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[S:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[S:17][CH:18]=[C:14]([CH3:13])[CH:15]=2)=[N:3][N:4]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,4-Dichlorophthalazine (1.40 g, 7.03 mmol), 4-methylthiophen-2-ylboronic acid (999 mg, 7.03 mmol), and PdCl2(DPPF) (721 mg, 985 μmol) were added into a sealed tube. The tube was purged with Argon. Then sodium carbonate (2.0 M in water) (7.74 ml, 15.5 mmol) and 1,4-dioxane (35.2 ml, 7.03 mmol) were added. The tube was sealed, stirred at rt for 5 min, and placed in a preheated oil bath at 110° C. After 1 h, LC-MS showed product and byproduct (double coupling), and SM dichlorophthalazine. The reaction was cooled to rt, filtered through a pad of celite with an aid of EtOAc, concentrated, and loaded onto column. The product was purified by column chromatography using Hex to remove the top spot, then 80:20 Hex:EtOAc to collect the product. The product, 1-chloro-4-(4-methylthiophen-2-yl)phthalazine was obtained as yellow solid. LC-MS showed that the product was contaminated with a small amount of SM dichlorophthalazine and biscoupling byproduct. MS m/z=261 [M+1]+. Calcd for C13H9ClN2S: 260.12.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O>>[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: O=C(O)c1cccc(F)c1F
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc(F)c2F)o1
Yield: 35 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,3-difluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 108 mg, 35%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12](=[O:23])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12](=[O:23])[CH2:11][CH2:10]1
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCC(=O)N(Cc2ccc(F)cc2)C1
Reaction time: 5 h
Yield: 76.1 %

Procedure:
0.5 g (S)-5-dibenzylamino-1-(4-fluorobenzyl)-piperidin-2-one are placed in 20 ml of methanol and hydrogenated with 0.150 g Pd/C 10% at a pressure of 3 bar and a temperature of 60° C. After 5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 0.21 g of the product are obtained as an oil. Analytical HPLC-MS (method A): RT=0.68 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][N:9]1[CH2:14][N:13]([CH2:15][CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:12][C:11]([NH2:24])([CH3:23])[CH2:10]1)[CH2:6][CH3:7].[C:25]([OH:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>C1C=CC=CC=1>[CH3:22][CH2:21][CH2:20][CH2:19][CH:16]([CH2:15][N:13]1[CH2:14][N:9]([CH2:8][CH:5]([CH2:4][CH2:3][CH2:2][CH3:1])[CH2:6][CH3:7])[CH2:10][C:11]([NH2:24])([CH3:23])[CH2:12]1)[CH2:17][CH3:18].[C:25]([O-:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: O=C(O)c1cccnc1
Agent: CCCCC(CC)CN1CN(CC(CC)CCCC)CC(C)(N)C1
Solvent: c1ccccc1
Product: O=C([O-])c1cccnc1

Procedure:
Hexetidine (0.1 mole) was dissolved in benzene at 40°C and nicotinic acid was added dropwise. The solution was reacted for 2 hours and cooled under stirring to yield crystals of hexetidine nicotinate which were filtered and dried.
Reaction SMILES: [BH4-].[Na+].[Li+].[Br-].C([O:7][C:8](=O)[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)C>C1COCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][CH2:9][CH2:8][OH:7])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CNCc1cccc(OC)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CNCCO)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 135 %

Procedure:
Next, NaBH4 (3.8 g, 100 mmol) and LiBr (8.7 g, 100 mmol) were added to THF (100 ml), and the mixture was stirred at 80° C. for 1 hour. To this mixture, [(3-methoxyphenyl)methylamino]acetic acid ethyl ester (7.4 g, 33.1 mmol) dissolved in THF (20 ml) was added dropwise at room temperature. The mixture was stirred at 80° C. for 5 hours and further at room temperature for 16 hours. After the reaction solvent was evaporated to about half, KH2PO4 (1 M, 200 ml) was slowly added dropwise thereto. The organic layer was extracted with dichloromethane (50 ml) times and dried over Na2SO4 to give crude 2-[(3-methoxyphenyl)methylamino]ethanol (yield: 8.1 g).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][O:7]1)C>C1COCC1.CO.[OH-].[Na+]>[CH:6]1([CH2:5][C:4]([OH:16])=[O:3])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][O:7]1
Reactant: CCOC(=O)CC1OCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-isochroman-1-yl-acetic acid ethyl ester (1.90 g, 8.63 mmol, 1 eq.) in THF (40 mL) and MeOH (10 mL), 1M aq. NaOH soln. (17.3 mL, 17.3 mmol, 2 eq.) was added. The pale yellow solution was stirred at r.t. for 2 hours, then the organic solvents were removed in vacuo. The aq. layer was washed with AcOEt (1×10 mL). The aq. layer was acidified with 1N aq. HCl (pH=1). The resulting emulsion was extracted with DCM (3×25 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil that solidifies upon standing. The product was used without further purification.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>C([O-])(=O)C>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Ten g of maltose was suspended in 8.5 ml of 50 mM acetate buffer (pH 6.0), and 900 units of pullulanase derived from microorganisms of the genus Klebsiella (produced by Amano Pharmaceutical Co., Japan) were added thereto and reacted for 48 hours at 60° C. Regarding the enzyme activity of pullulanase, one unit thereof indicates an amount producing a reducing sugar corresponding to 1 μmol of glucose in one minute when reacted with a pullulan at a pH of 6.0 and a temperature of 40° C.
Reaction SMILES: [C:1]1([NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:14][C:13]1([CH3:18])[NH:11][C:9]2[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=2)=[CH:4][CH:3]=[CH:2][C:1]=3[NH:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccc2cccc(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)Nc2cccc3cccc(c23)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29096.4 %

Procedure:
A solution of 1,8-naphthalene diamine (3.5 g, 22 mmol), distilled as in Example 1, acetone (25 ml) and p-toluene sulfonic acid (10 mg) was prepared and stirred at room temperature for 0.5 hour under a nitrogen atmosphere. The mixture was basified with concentrated sodium carbonate (2 ml) and concentrated to about 5 ml volume. The mixture was diluted with ether (150 ml), washed with water and brine, and dried over potassium carbonate. Concentration gave 3.35 g (77%) 2,3-dihydro-2,2-dimethyl perimidine as a pale pink solid. Recrystallization from hexane-ether gave crystals: mp 114°-115° C.; NMR (CDCl3) 7.07(m, 4H), 6.33(m, 2H), 4.06(bs, 2H), 1.42(s, 6H); IR (KBr) 3364, 3290, 1618, 1595 cm-1.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O:7][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[NH:32][C:31]([CH3:33])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:34])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=O)C>CS(C)=O>[OH:2][CH2:1][CH2:3][NH:4][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[NH:32][C:31]([CH3:33])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:34])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=[O:7]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)[nH]4)ccc3C)csc12
Solvent: CS(C)=O
Product: Cc1nnc(-c2ccc(C)c(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)[nH]1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
Ethanolamine (1.5 mL; 24.9 mmol) (Aldrich) was added to a suspension of 4-amino-3-[2-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (68.4 mg; 0.162 mmol) (from Example 62 supra) in dimethylsulfoxide (0.5 mL). The mixture was heated in a microwave reactor at 135° C. for 90 minutes and then for 1 hour at 140° C. The crude reaction mixture was concentrated under high vacuum with heat to remove most of the ethanolamine and DMSO. The residue was diluted with water, causing a milky precipitate to drop out of solution. The solid was collected by filtration, washed with water and dried. The material was then triturated with hot methanol to give 4-amino-3-[2-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as an off-white solid. (Yield 48 mg, 67.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][NH:15][CH3:16].[I-].[Na+]>C(#N)C.O1CCCC1.C(OCC)(=O)C>[CH3:14][N:15]([CH3:16])[CH2:2][CH2:3][O:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CNC
Reactant: Fc1ccc(CNOCCCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCONCc1ccc(F)cc1
Temperature: 55 °C
Yield: 91 %

Procedure:
A solution of O-(2-chloroethyl)-N-(4-fluorobenzyl)-hydroxylamine (0.327 g, 1.6 mmol) in acetonitrile (2 ml) was treated with a solution of dimethylamine (16 mmol, 8 ml of a 2 M solution in tetrahydrofuran). Sodium iodide (0.06 g) was then added and the resulting mixture was sealed and heated at 55° C. for 16 h. The cooled mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure yielded 0.310 g (91% yield) of the crude title hydroxylamine as a light brown oil which was used as such for the next step. 1HNMR 400 MHz (C6D6) δ (ppm): 2.19 (6H, s, NCH3), 2.47 (2H, t, J=6.1 Hz, CH2), 3.82 (2H, s, NCH2), 3.84 (2H, t, J=6.1 Hz, CH2), 6.9 (2H, m, aromatics), 7.11 (2H, m, aromatics).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18](O)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CCN(S(F)(F)[F:34])CC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([F:34])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)CC(CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (1.97 g, 5.0 mmol) in dichloromethane was added DAST (4.03 g, 25 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by chromatography to give the title compound. MS (m/z): 396 (M+H)+.
Reaction SMILES: C[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/C)C)C)[CH3:3].CC([CH2:25][CH2:26][CH2:27][C@H:28]([C@@H:30]1[C@:48]2(C)[C@H:33]([C@H:34]3[C@H:45]([CH2:46][CH2:47]2)[C@]2(C)[C:37]([CH2:38][C@H:39](CC2)[OH:40])=[CH:36][CH2:35]3)[CH2:32][CH2:31]1)C)C>O>[C:39]([O:21][CH2:20][CH2:19][CH2:17][CH2:16][CH2:15][CH2:14][CH2:12][CH2:11][CH2:10][CH2:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:2][CH3:3])(=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:45][CH2:46][CH2:47][CH2:48][CH2:33][CH2:32][CH2:31][CH2:30][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC

Procedure:
Examples of encapsulants include polymers and waxes. Waxes are water insoluble, organic materials that are solid or semi-solid at room temperature, usually of lower density than water, and typically can be melted above room temperature to form a liquid. Preferred waxes include any naturally occurring and synthetic waxes, wax esters, and greases that generally have a melting temperature of 30° C. or more, with a melting range of less than 10° C., and that are usually non-reactive with the reagents or solvents to which they are exposed. Examples of waxes include esters of various long-chain (fatty) alcohols and long-chain acids, preferably where at least one member of the ester has 10 or more carbon atoms, including various unsaturated and branched chain types and also those esters of glycerols and sterols. Also, certain free alcohols or acids have wax-like properties of melting temperature and inertness. Examples of saturated fatty acids that may be encapsulants include capric, lauric, myristic, palmitic, margaric, stearic, arachidic, behenic, tetracosanic, lignoceric, cerotic, and melissic. Examples of unsaturated fatty acids that may be encapsulants include tiglic, hypogaeic, gaidic, physetoleic, elaidic, oleic, isooleic, erudic, brassidic, and isoerudic. Examples of fatty alcohols that may be encapsulants include octadecyl, carnaubyl, ceryl, melissyl, and phytol. Also included are various esters of these and other fatty acids with any suitable fatty alcohols, or sterols such as cholesterol, or glycerols. Other examples include natural or suitably modified or derivatized waxes such as various plant derived waxes, greases and oils including carnauba wax, cranberry wax, ouricuri wax, candelilla wax, raphia wax, apple, cotton and cactus waxes; waxes (including greases) produced by bacteria (e.g. cetyl stearate); fungi, protozoa and algae; various invertebrate waxes and greases including insect waxes such as beeswaxes (e.g. triacontyl palmitate, palmatyl palmitate), and Coccus sp. derived waxes (e.g. lac, cochineal and Chinese insect); other animal fats (e.g. triglycerides) and waxes including spermaceti (e.g. cetyl palmitate), lanolin and wool grease.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1ccccc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.8 g, 2.70 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-2-chlorobenzene (0.666 g, 3.24 mmol) and potassium carbonate (1.120 g, 8.10 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as solid (0.96 g, 84%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (s, 3H) 2.89-3.18 (m, 4H) 3.66-3.91 (m, 4H) 5.34 (s, 2H) 6.35-6.50 (m, 1H) 6.57 (d, J=2.27 Hz, 1H) 7.00-7.21 (m, 2H) 7.21-7.33 (m, 1H) 7.47 (dd, J=7.82 1.11 Hz, 1H); MS (ES+) m/e 420.0 [M+H]+.