Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:22]([C:26]#[N:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1>CO.O.Cl>[CH2:28]([C:21]1[C:22]([C:26]#[N:27])=[CH:23][CH:24]=[C:25]2[C:20]=1[CH2:19][CH2:18][C@H:17]2[O:16][C:14]1[CH:13]=[CH:12][C:11]2[C@H:7]([CH2:6][C:5]([OH:35])=[O:4])[CH2:8][O:9][C:10]=2[CH:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccccc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1Cc1ccccc1)CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1 M aqueous NaOH solution (0.60 mL) is added to a solution of {(S)-6-[(R)-4-benzyl-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g) in methanol (3 mL) at room temperature. The mixture is stirred at 40° C. for 1 h. The mixture is diluted with water and neutralized with 1 M aqueous HCl solution. The resulting mixture is extracted with ethyl acetate, and the combined extract is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. In case the product is insufficiently pure after this procedure the product is submitted to HPLC on reversed phase (MeCN/water). LC (method 4): tR=1.14 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[ClH:13].[N:14]1([C:19](=N)[NH2:20])C=CC=N1>CC#N>[ClH:13].[N:1]1([C:19](=[NH:14])[NH2:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N=C(N)N1CCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of pyrrolidine (5.8 mL, 70.30 mmol) in CH3CN (30 mL). Triethylamine (9.8 mL, 70.17 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (10.2 g, 69.59 mmol) was added to the reaction. The reaction mixture was stirred overnight at 60° C. The product was collected by filtration to yield 7.5 g (71%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:8])=[CH:5][CH2:6]Br.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>>[CH3:3][C:4]([CH3:8])=[CH:5][CH2:6][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CC(C)=CCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.4 %

Procedure:
Sodium hydride (1.37 g 60% dispersion in oil, 0.82 g; 34.2 mmol) was weighed out in a 100 mL round bottom flask, and washed with hexane (3×15 mL) to remove the mineral oils. DMF (anhydrous, 15 mL) was added to the sodium hydride and the whole was stirred at room temperature for a couple of minutes under N2. 3,3-Dimethylallyl bromide (1.05 g, 7.02 mmol) was added to the reaction mixture, followed by slow addition of imidazole (2.28 g, 33.5 mmol) while cooling in an ice bath. The mixture was a milky cream colour initially, turning into a homogeneous brown solution. Stirring was continued at room temperature for 20 h. When the TLC showed complete consumption of the dimethylallyl bromide, the DMF was distilled off at 120° C. under high vacuum (Kugelrohr), leaving a viscous yellow heterogeneous mixture. This was triturated with chloroform to give a brown organic layer after removing the precipitated solids by filtration. The organic layer was washed with brine (3×20 mL), dried (Na2SO4) and the solvent was removed under reduced pressure and then under high vacuum. This gave the product as a dark brown oil (0.52 g, 54%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][C:12]2[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:3]=1[Cl:10]
Reactant: Oc1cc(Cl)cc(Br)c1Cl
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(Cl)c1Oc1cc(Cl)cc(Br)c1Cl
Reaction time: 7 h

Procedure:
3-bromo-2,5-dichlorophenol (8.0 g, 33 mmol) and 2,3-dichloronitrobenzene (6.4 g, 33 mmol) were dissolved in NMP (30 mL), followed by the addition of potassium carbonate (5.5 g, 40 mmol). The resulting suspension was placed in an oil bath at 120° C. for 7 hours, after which the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2×00 mL). The combined organic fractions were washed with water (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (330 g) eluting with 0-20% CH2Cl2/hexanes to afford the title compound. 1H NMR (CDCl3) δ 7.98 (dd, J=8.2 Hz, J=1.6 Hz, 1H), 7.79 (dd, J=8.2 Hz, J=1.6 Hz, 1H), 7.44 (dd, J=8.2 Hz, J=8.2 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 6.54 (d, J=2.2 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[O:21]1[CH:22]=[CH:23][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:24])[CH:13]=2)=[CH:20]1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CBr)cc1
Solvent: ClCCl
Product: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (85% purity, 0.33 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(furan-3-ylmethoxy)-1H-pyridin-2-one (example 5.1b) in 1.5 mL DCM is added 108 μL (1.31 mmol) pyrrolidine at RT. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=1)[C:12]2=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([Mg]Br)[CH3:35].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][CH:20]=1)[C:12]2([CH2:34][CH3:35])[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2C(=O)N1c1ccc(OCc2ccccc2)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(O)c2cc(OCc3ccccc3)ccc2C(=O)N1c1ccc(OCc2ccccc2)cc1
Temperature: 3 °C
Reaction time: 0.25 h

Procedure:
To a cooled (3° C.) solution containing 5-benzyloxy-2-(4-benzyloxyphenyl)-isoindoline-1,3-dione (870 mg) in THF (25 mL) under nitrogen atmosphere was added ethylmagnesium bromide (4 mL, 3M solution in THF) dropwise. The mixture was stirred at 3° C. for 15 min then allowed to warm to room temperature for 2 h. The mixture was cooled, poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine. Evaporation of the solvent yielded the title compound (900 mg) as a tan solid. MS: 466 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][C:11]#[CH:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH2:1])[C:11]#[CH:12]
Reactant: C#CCOCCOCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CCOCCOCCN
Temperature: 25 °C
Reaction time: 10 h
Yield: 79.8 %

Procedure:
3-(2-(2-azidoethoxy)ethoxy)prop-1-yne (s-4) (2 g, 11.82 mmol, 1.0 equiv) was dissolved in THF (30.5 mL). Triphenylphosphine (3.72 g, 14.20 mmol, 1.2 equiv.) and water (0.21 mL, 11.83 mol, 1.0 equiv.) were added to the solution and the reaction was allowed to stir at room temperature for 10 hours. The reaction was concentrated under reduced pressure and chromatographed (5% CH3OH in CHCl3, then 5% CH3OH in CHCl3+5% Et3N) to yield 2-(2-(prop-2-ynyloxy)ethoxy)ethanamine (s-5) as a pale green oil (1.35 g, 80%). IR (thin film) 3250 (m), 2863 (m), 2112 (w), 1589 (w), 1443 (w), 1349 (m), 1291 (w), 1093 (s), 1037 (m), 918 (w), 840 (w), 673 (m); 1H NMR (500 MHz, CDCl3) δ 4.21 (d, J=2.3 Hz, 2H), 3.73-3.68 (m, 2H), 3.68-3.62 (m, 2H), 3.51 (t, J=5.2 Hz, 2H), 2.87 (t, J=5.2 Hz, 2H), 2.43 (dd, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 79.7, 74.7, 73.7, 70.3, 69.2, 58.6, 41.9. HRMS (ES+) calc'd for C7H13NO2 (M+H) m/z 144.0980 Found 144.1019.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCBr
Reaction time: 48 h

Procedure:
For protecting thiol groups, take 2-thioethylamine hydrochloride and triphenylmethanol as reactants and boron trifluoride-diethyl ether complex is used as a catalyst to get 2-[(triphenylmethyl)thio]ethylamine. The reaction temperature is 72 degrees Celsius and the reaction time is 4 hours. Step (2): Use 2-[(Triphenylmethyl)thio]ethylamine and chloroacetyl chloride to carry out the amidation reaction in trichloromethane solution so as to produce N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide. Step (3): Take 2-[(Triphenylmethyl)thio]ethylamine, N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide and use triethylamine used as a reagent to carry out the substitution reaction in dichloromethane solution. Thus an amine-amide-thiol ligand is produced. The reaction temperature of the substitution reaction is 55° C. and the reaction time is 48 hours. Step (4): Dissolve 6-bromohexanoic acid and thionyl chloride in absolute methanol solution to carry out the esterification reaction and get methyl 6-bromohexanoate. The reaction temperature of the esterification reaction is 25° C. and the reaction time is 24 hours. Step (5): Take the amine-amide-thiol ligand and methyl 6-bromohexanoate and use sodium hydroxide (NaOH) as a reagent to carry out the substitution reaction in acetonitrile solution and get methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate. The reaction temperature of the substitution reaction is 85° C. and the reaction time is 24 hours. Step (6): Hydrolyze methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate in alkaline methanol solution to get 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenyl-methyl)thio]dodecanoic acid.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([O:22][C:23]2[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=2[Cl:37])[C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:27])=[CH:6][C:7]([NH:10][C:11]2[S:15][N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]=2)=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:47](Cl)(=[O:49])[CH3:48]>CN(C=O)C>[C:47]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[N:12]=[C:11]([NH:10][C:7]3[CH:6]=[C:5]([O:22][C:23]4[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=4[Cl:37])[C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:27])[C:4]([Br:3])=[CH:9][N:8]=3)[S:15][N:14]=2)[CH2:17][CH2:18]1)(=[O:49])[CH3:48]
Reactant: CN(C)CCNC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(C4CCNCC4)ns3)ncc2Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2nsc(Nc3cc(Oc4cc(C(=O)NCCN(C)C)ccc4Cl)c(Br)cn3)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
3-(5-bromo-2-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-4-yloxy)-4-chloro-N-(2-(dimethylamino)ethyl)benzamide dihydrochloride (0.12 g, 0.18 mmol) was dissolved in DMF (2 mL) and the solution was cooled to 0° C. DIEA (0.13 ml, 0.73 mmol) was added followed by acetyl chloride (0.017 mL, 0.24 mmol). The solution was warmed to RT. After 15 minutes, the solution was quenched with water, extracted with EtOAc, dried, and concentrated. HPLC purification gave 3-(2-(3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-bromopyridin-4-yloxy)-4-chloro-N-(2-(dimethylamino)ethyl)benzamide (0.0066 g, 6%) as a white solid. 1H NMR (400 MHz, CDCl3) 01.69-1.76 (m, 1H), 1.81-1.88 (m, 1H), 1.86-2.12 (m, 2H), 2.04 (s, 3H), 2.26 (s, 6H) 2.60 (t, 2H), 2.78-2.85 (m, 1H), 2.95-3.04 (m, 1H), 3.13-3.21 (m, 1H), 3.54-3.60 (m, 2H), 3.78-3.84 (m, 1H), 4.41-4.46 (m, 1H), 6.15 (s, 1H), 7.40 (s, 1H), 7.53 (d, 1H), 7.59-7.64 (m, 3H), 8.49 (s, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1([C:10]2[N:15]=[C:14]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][CH2:6][C:5](=O)[NH:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[F:1][CH2:2][C:3]1([C:10]2[N:15]=[C:14]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][CH2:6][C:5](=[S:35])[NH:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(CF)(c2cccc(NC(=O)c3ccc(Cl)cn3)n2)N1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C2(CF)COCC(=S)N2)n1)c1ccc(Cl)cn1

Procedure:
To a solution of 5-chloro-pyridine-2-carboxylic acid [6-(3-fluoromethyl-5-oxo-morpholin-3-yl)-pyridin-2-yl]-amide (0.24 g, 0.658 mmol) in THF (10.0 ml), Lawesson's reagent (0.798 g, 1.974 mmol) was added at rt and heated at reflux temperature for 24 h. Reaction mass was concentrated under reduced pressure. The crude compound was directly purified by column chromatography using 23% ethyl acetate in hexane to furnish title compound as off-white solid. Yield=0.19 g (72% [2 steps]). TLC (50% ethyl acetate in hexane) Rf=0.71; LCMS: RtH8=1.578, [M+1]+=381.1 and 382.9.
Reaction SMILES: [Cl:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH:9]=[CH2:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:10][CH:9]=[CH2:8])=[O:4]
Reactant: O=C(O)C(F)(F)Cl
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)C(F)(F)Cl

Procedure:
In a 1.5 liter sulfonation flask with a water separator, 294.0 g (2.25 mol) of chlorodifluoroacetic acid (pure, from Fluka AG) and 228.0 g (3.93 mol) of allyl alcohol are dissolved in 1 liter of chloroform and kept under reflux for 17 hours in the presence of 11.25 g of p-toluenesulfonic acid (0.06 mol), 41 ml of H2O separating out. The yellow reaction solution is washed twice with H2O and 3 times with saturated aqueous NaHCO3 solution, dried over MgSO4 and distilled under normal pressure through a Vigreux column. Yield: 306.0 g (80%) of a colourless oil of boiling point 98°-100° C./988 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[ClH:19]>O1CCOCC1>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1cccc(F)c1)N1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1cccc(F)c1)N1CCCCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
Methyl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (224 mg, 0.89 mmol) and 37% HCl (813 μl, 26.7 mmol) were dissolved in dioxane (3 ml) and stirred under microwave irradiation at 100° C. for 6 hours. The solvents were evaporated and the residue was triturated with Et2O and sonicated. The solid was collected by suction filtration, washed with Et2O and dried under vacuum overnight to collect 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (230 mg, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[N:37][C:36]=1[C:41](O)=[O:42].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:14]([NH:13][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([NH:1][C:41]([C:36]3[N:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:16])[CH3:15]
Reactant: O=C(O)c1ncccn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ncccn3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Ethyl 1-[5-[7-amino-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (159 mg, 0.27 mmol), pyrimidine-2-carboxylic acid (64.2 mg, 0.52 mmol) and diisopropylethylamine (271 mg, 2.1 mmol) were dissolved in DMF (5 mL). The reaction was purged with N2 then HATU (197 mg, 0.5 2 mmol) was added and the reaction stirred at rt for 18 h. The DMF was removed under reduced pressure and the resulting residue diluted with water and extracted with EtOAc. During the work up a solid precipitated which was collected by filtration and dried in the vacuum oven to provide the crude product (100 mg, 66% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.[H][H]>[Pd].CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCNc3ncccn3)cc2)S1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1

Procedure:
A mixture of 5-[4-(2-(2-pyrimidinylamino)ethoxy) benzylidene]-2,4-thiazolidinedione (3 g) and 10% palladium on charcoal (9 g) in DMF (70 ml) was stirred under a pressure of 200 psi of hydrogen until hydrogen uptake ceased. The mixture was filtered through diatomaceous earth, and the filter pad washed exhaustively with DMF. The combined filtrates were evaporated to dryness and the title compound (m.p. 173° C.) obtained following recrystallization from methanol.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10](Cl)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.O1CCCC1.[NH3:19].[OH-].[NH4+]>O>[N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10]([NH2:19])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cccc2nonc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3.0 g of 2,1,3-benzoxadiazole-4-sulfonyl chloride and 200 mL of tetrahydrofuran at -30° C. was added 10 mL of ammonia under an inert atmosphere. The resulting suspension was stirred at ambient temperature for 3 hours. Concentrated ammonium hydroxide (20 mL) and water (20 mL) were added. The reaction was extracted with ethyl acetate and the organic extracts were combined, dried over magnesium sulfate, filtered, and stripped to give a crude solid. Recrystallization from chlorobutaneethanol afforded 1.82 g of the title compound as an orange-tan solid, m.p. 157°-159° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[C@@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1>CCCCCCC.CCO>[O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[C@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Solvent: CCO
Solvent: CCCCCCC
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1ccccc1
Yield: 32.3 %

Procedure:
Racemic trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (772 mg, 2.55 mmol) was subjected to chiral preparative HPLC (Column: Chiralpak AD (250×20), 5 μm particle size, mobile phase: Heptane/EtOH 75/25, flow rate 15 mL/min) to yield (2S,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (249 mg, 32%). Optical rotation [α]D20=+23.0 (acetonitrile, c=1), Chiral purity 99.7% ee.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
Diethyl malonate (9.8 g, 1.1 eq) was added to a stirred suspension of sodium hydride (60% in mineral oil, 2.09 g) in DMF (88 mL) over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL) and brine (100 mL), dried (MgSO4) and filtered. Evaporation of the volatiles under reduced pressure gave 10.0 g of crude product which was purified by chromatography over silica gel (hexane/EtOAc) gave of diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (7.0 g). 1H-NMR (CDCl3, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cnc(Br)c(N)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To Fe power (2.18 g, 39.0 mmol), AcOH (10 mL) was added drop wise and heated to 80° C. To it, a solution of 2-bromo-5-methyl-3-nitro-pyridine (1.96 g, 9.07 mmol) in AcOH (10 mL) was added slowly. After 30 min, reaction mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL), filtered through a pad of celite. The filter cake was washed with EtOAc (25 mL) and filterate was concentrated. The residual liquid was slowly treated with saturated aqueous NaHCO3 solution (70 mL), followed by small portions of solid NaHCO3 to neutralize the AcOH, extracted with EtOAc (2×50 mL) and the extracts were dried (anhydrous Na2SO4) and concentrated under reduced pressure to get 2-bromo-5-methyl-pyridin-3-ylamine (1.45 g) as a brown solid in 86.3% yield. ESMS m/z (relative intensity): 187 (M+H)+ (100).
Reaction SMILES: ClC[NH:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[CH3:9][C@@H:10](N)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[K+]>[C:11]1([CH:10]([C@H:4]([NH2:3])[Si:5]([CH3:8])([CH3:7])[CH3:6])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C[Si](C)(C)CNCCl
Agent: [K+]
Agent: [OH-]
Product: CC(c1ccccc1)[C@H](N)[Si](C)(C)C

Procedure:
Chloromethyl(trimethylsilyl)methylamine (25 g, 0.166 mol) was treated under reflux with (R)-(+)-α-methylbenzylamine (78.5 mL, 0.61 mol) for 6 h. After cooling 100 mL of 15% KOH was added. The resulting solution was stirred before extracting twice with diethyl ether. The organics were combined and washed with brine and dried (K2CO3). The solvent was removed in vacuo and the residue was distilled at 0.001 mm Hg to give the title compound as a clear oil between 38°-45° C.