Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24]C1C(=O)C=COC=1C)C1C=CC=CC=1.C(N1C=CC(=O)C(O)=C1C)(=O)C.[NH2:45][CH2:46][C:47]([OH:49])=[O:48].OCCN>>[CH2:1]([O:8][C:9]1([OH:24])[C:14](=[O:15])[CH:13]=[CH:12][N:45]([CH2:46][C:47]([OH:49])=[O:48])[CH:10]1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCC(=O)O
Agent: CC(=O)n1ccc(=O)c(O)c1C
Solvent: NCCO
Product: CC1N(CC(=O)O)C=CC(=O)C1(O)OCc1ccccc1

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with glycine under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one, which is deprotected using the procedure described under (I) to give 1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one as white crystals, m.p. >230° C.; δmax (nujol) 1625, 1645 cm-1 ; δ(d6DMSO) 1.9 (s, 3H), 4.3 (s. 2H), 5.9 (d, 1H), 7.35 (d, 1H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=O)=[O:6])C>CN(C=O)C.[Pd]>[Cl:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][C:11]=1[Cl:15])[N:16]([OH:18])[C:4](=[O:3])[C:5](=[O:6])[NH:7]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n(O)c1=O
Reaction time: 1.5 h
Yield: 87 %

Procedure:
This compound was prepared using an adaptation of the method of Loev, et al., supra. A mixture of ethyl-N-(4,5-dichloro-2-nitro-phenyl)oxamate (0.307 g, 1 mmol) and 0.04 g of 5% Pd-C in 5 mL of DMF was hydrogenated at 45 psi for 1.5 h. The reaction mixture was filtered and the liquid was added to water (18 mL). A white precipitation formed. The mixture was vacuum filtered. The solid was rinsed with water (5×2 mL), and air dried for 1 h to yield 215.14 mg (0.87 mmol)of 6,7-dichloro-N-hydroxy-1,4-dihydroquinoxaline-2,3-dione as a pale yellow solid (87%). The pale yellow solid (215 mg, 0.87 mmol) was dissolved in 4 mL of DMSO with heating. Water (0.8 mL) was added until precipitation appeared. The mixture was heated again to redissolve the precipitate. The yellow solution was cooled down. Pale yellow crystals came out which were collected by vacuum filtration and rinsed with water (5×2 mL) and dried in vacuum to yield 173 mg (0.70 mmol) of 6,7-dichloro-N-hydroxy-1,4-dihydroquinoxaline-2,3-dione as pale yellow crystals. Mp >300° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ12.244 (br s, 1H, NH), 11.953 (br s, 1H, N-OH), 7.562 (s, 1H, H-8), 7.318 (s, 1H, H-5). HRMS calcd. for C8H4Cl2N2O3, 245.9599; found, 245.9600.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([F:25])=[C:22]([CH:24]=1)[NH2:23]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([F:25])=[C:22]([NH:23][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cc(Cl)ccc1F
Product: O=c1[nH]c2nccc(Nc3cc(Cl)ccc3F)c2c2ccccc12
Yield: 47.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 5-chloro-2-fluoroaniline (82 mg, 0.56 mmol) to provide 205 (70 mg, 48% yield) as a white solid. LC-MS (M+H=340, obsd.=340).
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@H:25]([N:28]5[CH2:32][CH2:31][CH2:30][C@@H:29]5[CH3:33])[CH2:24]4)=[CH:19][C:18]=3[CH3:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:34][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][CH2:26][C@H:25]([N:28]3[CH2:32][CH2:31][CH2:30][C@@H:29]3[CH3:33])[CH2:24]2)[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][C:11]2([CH2:10][CH2:9][NH:8][CH2:36][CH2:35]2)[C:15]1=[O:16]
Reactant: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCNCC2)C1=O
Reaction time: 1 h

Procedure:
2-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (150 mg) was treated with 1 mL (excess) of 4M HCl in dioxane at 0° C. The stirring was continued at rt for 1 h. The solvent was evaporated and the solid was further dried under high vacuum at rt for 2 h to obtain the title compound as a tan solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:11][C:10]([CH2:9][CH2:8][O:7][C:6]1[CH:13]=[CH:14][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCOc1ccc(CO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCOc1ccc(CO)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[4-(hydroxymethyl)phenoxy]propionic acid (0.98 g) and potassium carbonate (0.9 g) in N,N-dimethylformamide (5 mL) was added benzyl bromide (0.65 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (1.1 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6](O)[C:7]#[CH:8].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])#[N:11].C(O)(=O)C>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4].ClCCl>[C:10](/[C:12](=[CH:6]\[CH:7]=[CH:8]\[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])/[C:13]([O:15][CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])#[N:11]
Reactant: CCCCC(CC)COC(=O)CC#N
Reactant: C#CCO
Reactant: CCNCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)/C(C#N)=C/C=C/N(CC)CC
Temperature: 90 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
Diethylamine (30 g, 0.41 mol) and propargyl alcohol (18.4 g, 0.328 mol) are dissolved in 250 ml of toluene. 72.6 g of manganese dioxide (activated, <5 μm; 2.5 equiv.) are added portionwise while controlling the strong exotherm (temperature <50° C.) and the mixture is left stirring at 90° C. for 5 hours. The reaction mixture is filtered. The yellow filtrate is poured into a reactor surmounted by a Dean and Stark apparatus. 2-Ethylhexyl cyanoacetate (61.5 g, 0.312 mol) and catalyst (0.1 equiv., 1.77 ml of acetic acid and 3.2 ml of N,N-diethylamine) are added with stirring and the reaction mixture is brought to reflux. It is left at reflux for 5 hours 30 minutes. After cooling, 500 ml of dichloromethane are added and washing is carried out once with a saturated sodium bicarbonate solution and then twice with water. The organic phase is dried and then purified on a silica bed. The first fractions are recovered and concentrated under vacuum. 21.9 g (yield: 23%) of the pure fractions of the derivative of Example 5 are thus obtained in the form of an orange-coloured gum which crystallizes; recrystallization from heptane gave the derivative of Example 5 in the form of a yellow powder
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6][C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([N+:24]([O-:26])=[O:25])[CH:13]=2)=[CH:6][C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dimethyl-6-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.4 g) in acetic acid (22 ml) were added conc.sulfuric acid (9 ml) and conc. nitric acid (18 ml) under ice-cooling. The mixture was stirred at 5°-10° C. for 1.5 hours and at ambient temperature further for 2 hours. The mixture was poured into ice-water, and stirred. After the aqueous mixture was neutralized with aqueous sodium hydroxide, the resultant precipitates were filtered. The precipitates were washed with water and dried in air to give 1,3-dimethyl-6-(4-methoxy-3-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.67 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:8][C:9]#[N:10].[K+].[CH3:12][C:13]([CH3:15])=O>CN(C=O)C>[CH2:9]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8]([CH2:12][C:13]1[CH:15]=[CH:7][C:1]([CH:6]=[CH2:5])=[CH:2][CH:3]=1)[C:9]#[N:10]
Reactant: CC(C)=O
Reactant: N#C[S-]
Reactant: Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(CSC#N)cc1
Product: C=Cc1ccccc1
Temperature: 25 °C

Procedure:
The desired terpolymer of styrene, 4-thiocyanatomethylstyrene, and vinyl benzyl polyethylene glycol was synthesized from the terpolymer of Step II as follows: 1.5 g of the terpolymer formed in Step II was mixed with 350 mL of toluene taken in a 500 mL flask and the contents stirred. To this mixture was added 1.2 g of potassium thiocyanate dissolved in 115 mL of a solvent mixture of DMF and acetone (100/15, v/v). The entire contents of the flask was then heated and allowed to reflux for about 30 hours. The contents were then allowed to cool to room temperature at which time slightly turbid mixture became homogeneous. The solvents were evaporated under vacuo and the residual solids were precipitated from water. The precipitate was washed with methanol and dried to yield a white powder of the terpolymer (0.9 g). The structure of the produced terpolymer was verified by 1H and 13C NMR, and IR spectroscopy.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([CH2:8][NH2:9])[CH2:6][CH:5]([O:10][CH3:11])[O:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:9][CH2:8][CH:7]1[CH2:6][CH:5]([O:10][CH3:11])[O:4][CH:3]1[O:2][CH3:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1CC(CN)C(OC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CC(CNC(=O)c2ccccc2)C(OC)O1
Reaction time: 1 h
Yield: 73 %

Procedure:
2 g (12.4 mmol) of 2,5-dimethoxy-3-aminomethyltetrahydrofuran and 3.4 ml (24.8 mmol) of triethylamine were dissolved in 50 ml of anhydrous tetrahydrofuran. At 0° C., 1.7 g (12.4 mmol) of benzoyl chloride dissolved in 20 ml of anhydrous tetrahydrofuran were added dropwise. The mixture was stirred for 1 h and then filtered, and the filtrate was concentrated under reduced pressure. The residue was reprecipitated from ether/petroleum ether to yield 2.4 g of impure product which was used in the next step.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:25]([O:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]3[C:17](=[N:16][CH:15]=2)[NH:8][CH2:9][CH2:10][CH2:11]3)[CH:19]=[N:20][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Yield: 87.9 %

Procedure:
A solution of 6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (790 mg, 1.9 mmol) in 20% TFA in DCM (21 mL) is stirred at room temperature for 16 h. The solvent is removed under vacuum to afford 6-(5-benzyloxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (530 mg).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[NH2:2].C(O)C.[F:16][C:17]([F:31])([F:30])[C:18](=O)[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=O>>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:1]([C:3]3[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:5][CH:4]=3)[N:2]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)O)cc2)cc1
Yield: 82.2 %

Procedure:
To a stirred suspension of p-hydrazino-benzenesulfonic acid (42 g, 0.223 mol) in ethanol (450 ml) 6N hydrochloric acid (74 ml, 0.446 mol) was added at room temperature, followed by addition of 4,4,4-trifluoro-1-(4-methyl-phenyl)-butane-1,3-dione (51.45 g, 0.223 mol). The obtained suspension was refluxed for 8 h, then concentrated in vacuo. The residue was dissolved in water (300 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with water (1×100 ml) and brine (1×100 ml), dried over MgSO4, decolorized, filtered and concentrated in vacuo. The obtained crystalline product was recrystallized from diisopropyl ether (300 ml) to yield 70.12 g (82%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])=[O:33])([O-:22])=[O:21]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
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: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 2-phenylpropan-2-amine (5.5 g, 40.4 mmol), diisopropylethylamine (18.8 mL, 108 mmol), 3-(3-nitropyridin-4-yl)benzoic acid (8.8 g, 27.0 mmol) and DMF (180 mL) was added HATU (15.4 g, 40.4 mmol) in one portion. The solution was maintained at room temperature for 1 h then concentrated. Purification on silica gel (50-100% ethyl acetate/hexanes, 60 min. gradient) afforded 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a dark yellow, fluffy solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.21 (s, 1H), 8.93 (d, J=5.02 Hz, 1H), 8.51 (s, 1H), 7.97 (dt, J=7.03, 1.76 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J=5.02 Hz, 1H), 7.52-7.61 (m, 2 H), 7.34-7.41 (m, 2H), 7.27 (t, J=7.65 Hz, 2H), 7.16 (t, J=7.28 Hz, 1H), 1.64-1.72 (m, 6H). LCMS: retention time: 2.060 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 362 (MH+).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].I[CH2:13][CH2:14][CH3:15].O>CN(C=O)C>[CH2:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:14][CH3:15]
Reactant: O=Cc1ccccc1O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1C=O
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of salicylaldehyde (12.21 g, 0.1 mol) in DMF (65 ml) was cooled in an ice/water bath under argon and 60% sodium hydride in mineral oil (4.0 g, 0.1 mol) was added in several portions. The mixture was stirred for one hour and then iodopropane (16.99 g, 0.1 mol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, poured into water (800 ml) and stirred. The mixture was extracted with chloroform (3×), the chloroform layer was concentrated in vacuo and the dark oil thus obtained was distilled under vacuum (92°-94° C. at 1.15 mm Hg) to afford 12.68 g (77%) of 2-propoxybenzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)O.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](Cl)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:39].[OH-].[Na+]>O1CCCC1.C1C=CC=CC=1>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30]1[S:39][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=2)[CH2:2][N:1]=1
Reactant: CCCCCCCCOc1ccc(C(O)CN)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(Cl)c1c(F)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C2CN=C(c3c(F)cccc3Cl)S2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2.65 g (10 millimoles) of 2-amino-1-(4-n-octyloxyphenyl)ethanol, 1.01 g (10 millimoles) of triethylamine and 30 ml of tetrahydrofuran contained in a 100 ml eggplant-shaped (spheroidal) flask, a solution of 1.93 g (10 millimoles) of 2-chloro-6-fluorobenzoyl chloride dissolved in 10 ml of tetrahydrofuran was added over 30 minutes with stirring at ice-bath temperature. After further continuation of stirring for 3 hours at room temperature, the produced triethylamine hydrochloride was removed by filtration using a glass filter and the filtrate was concentrated under reduced pressure. To this concentrate and 30 ml of toluene contained in a 100 ml eggplant-shaped flask, 4.44 g (20 millimoles) of phosphorus pentasulfide was added at once and refluxed for 4 hours on an oil bath with stirring. After cooling to room temperature, the reaction mixture was added with 40 ml of a 30% aqueous sodium hydroxide solution and stirred for 1 hour at room temperature. The reaction liquid was added with 100 ml of benzene and washed with a saturated aqueous sodium chloride solution followed by desiccation over anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was purified by silica-gel column chromatography using a 8/2 solvent mixture of n-hexane/ethyl acetate as a movable phase to obtain 2-(2-chloro-6-fluorophenyl)-5-(4-n-octyloxyphenyl)-2-thiazoline (Compound Number 91).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)C(C)C)(C)C.Br[C:26]1[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=1.[NH4+].[Cl-]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:26]2[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1nnc(Br)s1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (15.16 g, 52.5 mmol) in 1,4-dioxane (80 mL) was added N,N-diisopropylethylamine (Hünig's base or DIPEA) (20 mL, 115 mmol) followed by 5-bromo-1,3,4-thiadiazole-2-carbonitrile (10.02 g, 52.7 mmol). The mixture was stirred 1 h at room temperature. The reaction mixture was then poured into saturated aqueous NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with 10-40% EtOAc/hexanes) to afford the desired product as a colorless oil.
Reaction SMILES: C(Cl)(=O)C.CO.[NH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][C:21]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:45])[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:20]4)=[CH:13][C:11]=2[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:37][C:34]([CH3:36])([CH3:35])[C:33]([N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:22]=[N:23][C:24]3[C:19]([CH:20]=2)=[N:18][C:17]([C:14]2[CH:15]=[CH:16][C:10]4[O:9][C:8]([NH2:7])=[N:12][C:11]=4[CH:13]=2)=[CH:26][CH:25]=3)[CH2:28][CH2:29]1)=[O:45]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(C)(N)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Acetyl chloride (4.3 mL, 60.5 mmol) was added to MeOH (11 mL) at 0° C., the resulting solution was stirred at 0° C. for 30 min. To this solution, tert-butyl (1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-21) (85 mg, 0.16 mmol, 1.0 eq) was added, and the mixture was stirred at RT for 2 h. The reaction was complete based on TLC analysis. The mixture was diluted with water (20 mL), neutralized with solid Na2CO3 (about 3.5 g) to adjust pH value to 8-9, and extracted with CH2Cl2 (6×30 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (11% MeOH/CH2Cl2) to afford the desired product, 2-amino-1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methylpropan-1-one (43) (43 mg, 62.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.96 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.12-8.09 (m, 2H), 7.92 (d, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.60-7.47 (m, 3H), 4.01 (m, 4H), 3.42 (m, 4H), 1.347 (s, 6H); ESI-MS m/z: 432.21[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:11]1([CH3:14])[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)CC1(C)CCN(c2ccc(N)cn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1(C)CCN(c2ccc(NC(=O)C(=O)OC)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of methyl [1-(5-aminopyridin-2-yl)-4-methylpiperidin-4-yl]acetate (3.29 g, 13.20 mmol) in DCM (100 mL) was added triethylamine (2.2 mL, 15.84 mmol) followed by methyl chlorooxoacetate (1.6 mL, 17.15 mmol) and the reaction mixture was allowed to stir at ambient temperature for 1.5 hrs. The reaction mixture was washed brine (2×100 mL), the aqueous layer was re extracted with DCM (50 mL) the organic washings were combined, dried and concentrated to leave the title compound as a brown gum (4.4 g, 13.2 mmol, 100%). 1H NMR δ 1.06 (s, 3H), 1.40-1.46 (m, 2H), 1.53-1.57 (m, 2H), 2.36 (s, 3H), 3.46-3.52 (m, 2H), 3.59 (s, 3H), 3.67-3.73 (m, 2H), 3.78 (s, 3H), 6.90 (d, 1H), 7.56 (d, 1H), 8.06 (s, 1H); MS m/e MH+ 350.