Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH3:10])[CH2:6][CH2:5]1
Reactant: C=C1CC(=O)O1
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 32.5 g (0.25 mol) 1-(2-hydroxyethyl)piperazine in 100 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 36.10 g (0.17 mol, 71% yield) of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:23])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL), a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) was added dropwise over 1.5 hours. The resultant solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resultant suspension was filtered, and the solid was washed with water and dried under vacuum. The solid was suspended in dichloromethane and methanol (1:1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with dichloromethane and air-dried to afford the title compound (18.0 g, 73%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:18])=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(/C=C\c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (Z)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[C:15](=O)([O:18]C)[O:16][CH3:17]>C1COCC1>[CH3:17][O:16][C:15](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccncc1N
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Nc1cnccc1C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of potassium tert-butoxide (32.8 g, 277 mmol) in THF (250 mL) at 0° C. was treated with 3-amino-4-methylpyridine (10.0 g, 92.5 mmol) and the resulting mixture stirred for 30 minutes before dimethyl carbonate (11.7 mL, 139 mmol) was added. The mixture was stirred for 30 minutes then quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine then dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (DCM) then triturated with diethyl ether to afford 9.42 g (62%) of (4-methyl-pyridin-3-yl)-carbamic acid methyl ester. LCMS (Method B, ESI): RT=0.40 min, m+H=167.4; 1H NMR (400 MHz, CDCl3) δ: 8.86 (s, 1H), 8.28 (d, 1H), 7.12-7.12 (m, 1H), 6.45 (s, 1H), 3.80 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[C:29]([O:33][C:34](=[O:49])[NH:35][C:36]([CH3:48])([CH3:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:35][C:36]([CH3:48])([CH3:47])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:43][CH:44]=1)=[O:49])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Yield: 91.8 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (58 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (222 mg) according to an analogous synthetic method to Example 212, the title compound (92 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([O:6][CH2:7]Cl)=[CH:4][CH:3]=1.[F:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1.[OH-].[Na+].O>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([O:6][CH2:7][O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][F:11])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: OCc1ccc(OCCF)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FCCOc1ccc(COCOc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
A mixture composed of 1.0 g of 4-chlorophenoxychloromethane, 1.0 g of 4-(2-fluoroethoxy)benzyl alcohol, 0.3 g of triethylbenzylammonium bromide and 20 g of a 50% aqueous solution of sodium hydroxide was stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and poured into water. Toluene was added, and the mixture was fully stirred. The toluene layer was separated, washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated. The resulting crude ether was recrystallized from benzene to give 1.18 g of the desired 4-(2-fluoroethoxy)benzyl 4-chlorophenoxymethyl ether.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH:17](=[O:22])/[CH:18]=[CH:19]/[CH2:20][CH3:21]>CCO>[C:2]([N:5]1[CH:17]([OH:22])[CH2:18][CH:19]([CH2:20][CH3:21])[C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC/C=C/C=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)C(CC)CC(O)N1C(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH (1.4 L) at ambient temperature under argon. The reaction mixture was cooled to 0° C., and trans-2-pentenal (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5° C. After the addition, the reaction was allowed to warm to room temperature, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3 solution (2×300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 mL, then heated to reflux and treated with hexane (1 L). On cooling, the title compound precipitated and was collected, mp 106°-109° C. 1H NMR (CD3OD) δ 5.65 (d, 1H, J=5 Hz), 4.1-4.25 (m, 4H), 2.7-2.8 (m, 1H), 2.21 (s, 3H), 2.10 (dd, 1H, J=6, 13, Hz),1.86-1.97 (m, 2H), 1.27 (t, 3H, J=7 Hz), 1.23 (t, 3H, J=7 Hz), 1.1-1.25 (m, 1H), 0.97 (t, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Cl:9])=[N:4][CH:3]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:8][C:6]1[N:7]=[C:2]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH:3]=[N:4][C:5]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: Nc1nc(Br)cnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c(N)n3)cn2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
Into a 2 L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of compound 90e (42.8 g, 206 mmol) in 1,4-dioxane (1 L), compound 90b (80.0 g, 206 mmol), Pd(dppf)Cl2 (7.53 g, 10.3 mmol) and Cs2CO3 (167 g, 514 mmol). The reaction mixture was stirred overnight at 90° C. Upon cooling, the reaction was quenched with water (100 mL). The resulting mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel (DCM/MeOH (100:3 v/v)) to obtain compound 90f as a yellow solid (23.0 g, 29% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C18H23ClN6O2: 391.2 (M+H). found 391.1.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>C(Cl)(Cl)Cl>[N:1]1([CH2:6][CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:31](=[O:32])[CH2:30][C:25]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1nc2c([nH]1)CCNC2CN1CCCC1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCc2[nH]cnc2C1CN1CCCC1

Procedure:
Prepared as Example No. 12, from 900 mg (4.37 mmoles) of 4-(pyrrolidin-1-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine, 950 mg (6.88 mmoles) of anhydrous potassium carbonate and 1.30 g (5.80 mmoles) of 3,4-dichlorophenylacetyl chloride in 35 ml of dry chloroform.
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[C:8]([O:26][C@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[O:33][CH3:34])[CH:7]=1.O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42]>CN(C=O)C.CCOC(C)=O>[O:42]=[C:37]1[CH2:38][CH2:39][C:40](=[O:41])[N:36]1[O:24][C:23]([C:20]1[S:19][C:15]2[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=3[O:26][C@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[O:33][CH3:34])[C:14]=2[C:21]=1[CH3:22])=[O:25]
Reactant: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)ON3C(=O)CCC3=O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (53 mg, 0.28 mmol) was added to a mixture of 0.100 g 4-[4-fluoro-2-((1S,2S)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd.42.2) and 0.040 g N-hydroxysuccinimide in 1 ml DMF. And stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was passed through a hydrophobic frit and concentrated.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:25]3[CH:24]([CH2:23][C:21]([OH:22])=[O:20])[CH2:29][CH2:28][CH2:27][C:26]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(phenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22]O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2cccnc2)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccnc2)on1
Yield: 66 %

Procedure:
3-Hydroxy-5-(3-pyridyl)isoxazole (0.41 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.50 g, 65%) as colorless crystals.
Reaction SMILES: CS(O[CH2:6][CH:7]([OH:43])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]2[C:23]([F:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:28][CH:27]=3)[N:19]=2)[CH:12]=1)=[O:9])(=O)=O.[H-].[Na+].C(Cl)(Cl)Cl.CO.O>C1COCC1>[Si:36]([O:35][CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:20]2[N:19]=[C:18]([NH:17][C:13]3[CH:12]=[C:11]([NH:10][C:8]([CH:7]4[CH2:6][O:43]4)=[O:9])[CH:16]=[CH:15][CH:14]=3)[C:23]([F:24])=[CH:22][N:21]=2)=[CH:31][CH:30]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)COS(C)(=O)=O)c3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C4CO4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 3-((3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)amino)-2-hydroxy-3-oxopropyl methanesulfonate (0.240 g) in THF was added NaH (0.018 g) and the reaction mixture was stirred at room temperature for 30 min. The reaction was monitored on TLC using CHCl3:methanol (9:1) as mobile phase. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by Combiflash, and the product eluted with 1.6% methanol in CHCl3 to give 0.16 g of N-(3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)oxirane-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(N)ccc1F
Reactant: BrCCOCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(N2CCOCC2)ccc1F
Yield: 73.3 %

Procedure:
A mixture of 1-(5-amino-2-fluoro-phenyl)-ethanone (3.5 g), bromoethyl ether (5.929 g), and i-Pr2NEt (7.121 g) in toluene (20 mL) was refluxed for 16 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (25% ethyl acetate in hexane) to give 3.74 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([OH:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1)(=[O:18])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([OH:15])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5].[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[C:1]([O:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([O:28][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[C:22]([CH3:30])([CH3:29])[CH2:21]1)(=[O:18])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([O:15][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Product: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) succinate and octadecane following a procedure similar to that of Example 4.
Reaction SMILES: N1CCOCC1.C(OC([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25]([O:27][CH3:28])=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])=[CH:31][CH:30]=3)[C:23]2=[O:48])=[CH:18][CH:17]=1)=[NH:15])=O)C=C>O1CCCC1>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:26][C:25]([O:27][CH3:28])=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:44])([CH3:45])[CH3:46])=[O:38])=[CH:31][CH:30]=3)[C:23]2=[O:48])=[CH:20][CH:21]=1)(=[NH:13])[NH2:15]
Reactant: C=CCOC(=O)NC(=N)c1ccc(N2CC(OC)=C(c3ccc(CCC(=O)OCOC(=O)C(C)(C)C)cc3)C2=O)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC1=C(c2ccc(CCC(=O)OCOC(=O)C(C)(C)C)cc2)C(=O)N(c2ccc(C(=N)N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared by dropwise addition of 1 equivalent of morpholine to 1-[4-(allyloxycarbonyl-amidino)-phenyl]-4-methoxy-3-[4-[2-[(pivaloyloxymethyl)-oxycarbonyl]ethyl]-phenyl]-3-pyrrolin-2-one and 0.1 equivalents of tetrakis-(triphenyl-phosphine)-palladium(O) in tetrahydrofuran under inert gas followed by 1 hours' stirring at ambient temperature.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:8][C:7]1[C:2]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nccnc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A mixture of 3.73 g of 2,3-dichloropyrazine, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 8 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 3.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 2.69 g of diethyl (3-chloro-2-pyrazinyl)malonate.
Reaction SMILES: FC1C=CC([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=CC=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1N=C=O>>[F:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccccc4F)cc3)ccc2C1=O

Procedure:
The compound of example 226 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 2-fluoro phenyl isocyanate. The compound of example 226 was used directly without isolation for the preparation of compound of example 227.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2[nH]ccc(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nccc(Cl)c2n1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To the intermediate 6-methoxy-1,5-naphthyridin-4(1H)-one (15.0 g, 0.085 mol) was added POCl3(300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110° C. with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2×100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pH of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4×100 mL). The combined organic extracts were washed with water (2×100 mL), saturated NaCl solution (100 mL), dried (Na2SO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][CH:2]([C:6]([CH3:8])=O)[C:3]([NH2:5])=[O:4].CC(C(C)=O)C(OCC)=O.[OH-].[NH4+].[C:21]([CH2:23][C:24]([O:26]CC)=O)#[N:22]>>[NH4+:5].[OH:26][C:24]1[C:23]([C:21]#[N:22])=[C:6]([CH3:8])[C:2]([CH3:1])=[C:3]([OH:4])[N:5]=1
Reactant: CC(=O)C(C)C(N)=O
Reactant: CCOC(=O)CC#N
Agent: CCOC(=O)C(C)C(C)=O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c(O)nc(O)c(C#N)c1C
Yield: 90 %

Procedure:
2-methylacetoacetamide 2, made from ethyl 2-methylacetoacetate 1 by reaction with ammonium hydroxide for six days (at about 60% yield), is reacted with ethyl cyanoacetate 4 over four days to produce 2,6-dihydroxy-4,5-dimethyl-3-pyridinecarbonitrile, ammonium salt 5 (90% yield). The ammonium salt is hydrolyzed with hydrobromic acid and decarboxylated. The excess hydrobromic acid is evaporated to dryness followed by filtration of ammonium bromide after taking up the 2,6-dihydroxy-3,4-dimethylpyridine hydrobromide salt 6 in absolute ethyl alcohol. The ethyl alcohol is evaporated to dryness and the residue is heated with water and potassium hydroxide to isolate 2,6-dihydroxy-3,4-dimethylpyridine (70% yield).