Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=O.[C:12](=[S:15])([NH2:14])[CH3:13]>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:12]([CH3:13])[S:15][CH:2]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cn1
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc(-c2ccc(Br)cn2)cs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
2-bromo-1-(5-bromopyridin-2-yl)ethanone (3.77 g, 13.5 mmol) was dissolved in ethanol (32 mL) and ethanethioamide (1.12 g, 14.8 mmol) was added and the reaction stirred for 18 h at 75° C. The mixture was concentrated; the residual solid was dispersed in ethyl acetate (100 mL), and treated with saturated sodium bicarbonate solution (100 mL) until no further gas evolution was noted. The combined organics were washed with water (50 mL) and brine (50 mL). The aqueous washes were back-extracted with ethyl acetate (100 mL) and the combined organic layers were dried over magnesium sulfate, treated with Darco, filtered through a paper filter, and concentrated to give a yellow solid. The crude product was purified by flash chromatography (90 g silica gel, 1-5% methanol in ethyl acetate). The major product was further purified by flash chromatography (40 g silica gel, 10% ethyl acetate in hexane) to give the title compound (1.94 g) as a colorless crystalline solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].C(N(C(C)C)CC)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39].C(OCC)(=O)C>O1CCCC1>[Br:36][CH2:37][C:38]([NH:1][C@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:39]
Reactant: COc1ccccc1CCC(=O)NC[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)NC[C@@H](Cc1c[nH]c2ccccc12)NC(=O)CBr
Reaction time: 2 h

Procedure:
To a stirring solution of (R)-2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0° C. were added diisopropylethylamine (4.1 ml, 23.537 mmol) and bromoacetyl bromide (2.05 ml, 23.530 mmol). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2×), saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.Br[C:13]1[C:22]([CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1.COC([SiH3])=C(OC)OC.C(N(CC)CC)C>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:13]1[C:22]([CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1)=[CH2:2]
Reactant: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC([SiH3])=C(OC)OC
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C=Cc1cc2c(cc1Cn1cccn1)C(C)(C)CCC2(C)C
Temperature: 90 °C
Reaction time: 17 h
Yield: 21.2 %

Procedure:
To a suspension of 2.076 g (3.99 mmol) 2-bromo-5,5,8,8,-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalene p-toluenesulfonate, 0.045 g (0.20 mmol) of palladium acetate, 0.122 g (0.40 mmol) of tri-o-tolulylphosphine) and 1.22 ml (7.97 mmol) trimethoxyvinylsilane in 8 ml N-methylpyrrolidinone was added 1.80 ml (12.90 mmol) triethylamine. The reaction vessel was evacuated and filled with nitrogen three times then heated to 90° C. for 1.5 hours. The reaction was cooled and stirred for 17 hours at room temperature. The resulting suspension was quenched with 1M hydrochloric acid and extracted with ethyl ether. The organic layer was washed with 1M HCl, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution with 20% ethyl acetate/hexane) to yield 0.249 g (21%) of 2-vinyl-5,5,8,8,-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalene (M+1=295).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].C(N(C(C)C)CC)(C)C.Cl[CH2:17][C:18](Cl)=[O:19].C(OC([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=O)(C)(C)C>C(Cl)Cl.Cl.CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:18](=[O:19])[CH2:17][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Reactant: COCC(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC(C)NC(=O)CN1CCNCC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
2-Methoxy-1-methyl-ethylamine (15 mmol) and diisopropylethylamine (17 mmol) were diluted with methylene chloride to give a total volume of 8 mL. The amine solution was added in a portion-wise fashion via a syringe to a solution of chloroacetylchloride (13 mmol) in methylene chloride (10 mL) cooled to approximately 40° C. in a sealed 40 mL vial. The reaction mixture was stirred for 1 h at reduced temperature. The solution was then made acidic with 1N hydrochloric acid and then diluted with 10 mL of methylene chloride. The vial was agitated and centrifuged. The organic layer was transferred to 40 mL vials and concentrated in vacuo. The residue (1.69 g, 10.21 mmol) was diluted with 10 mL of dimethylformamide. Piperazine-1-carboxylic acid tert-butyl ester (8.67 mmol) and diisopropylethylamine (13.27 mmol) were added. The reaction mixture was shaken at 65° C. overnight and concentrated in vacuo. The crude residue was dissolved in 10 mL of dioxane and 10 mL of 4 M hydrochloric acid in dioxane. The solution was shaken overnight at room temperature then centrifuged. The supernatant was removed, and the remaining solids were shaken with hexanes then centrifuged. The supernatant was removed, and the solids was collected and dried in vacuo to give N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide. LR-MS: 216.4 [(M+H)+].
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][C:6]1[CH:7]=[C:8]([N:13]2[C:17](=[O:18])[C:16](=[N:19][NH:20][C:21]3[C:22]([OH:36])=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[C:15]([CH3:37])=[N:14]2)[CH:9]=[CH:10][C:11]=1[CH3:12]>C(O)C.O1CCCC1>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]([N:13]2[N:14]=[C:15]([CH3:37])/[C:16](=[N:19]/[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[C:22]=3[OH:36])/[C:17]2=[O:18])=[CH:7][C:6]=1[CH3:5].[CH2:3]([NH2:4])[CH2:1][OH:2]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: C1CCOC1
Solvent: CCO
Solvent: NCCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 3 h

Procedure:
To a solution of ethanolamine (0.9 g) in ethanol (100 mL) was added a solution of 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (3 g), prepared as in Example 4, in tetrahydrofuran (40 mL) at about room temperature over about 30 to 40 minutes and stirred for about 3 hours at about room temperature. The mixture was filtered, washed with ethanol (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours. Yield: 3.7 g
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]=1[CH3:23])(=O)=O>CN(C=O)C.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:1]#[N:2])=[C:11]([CH3:23])[CH:12]=1
Reactant: [C-]#N
Reactant: Cc1cc(-c2ccccc2Cl)ccc1COS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2Cl)ccc1CC#N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
KCN (1.1 eq.) was added to a stirred solution of (2′-chloro-3-methylbiphenyl-4-yl)methyl methanesulfonate (1 eq.) from step 2 in DMF (0.13M). The suspension was stirred 12 h. at 80° C. The final mixture was cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water (2×), brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) to afforded the desired compound as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:23]([C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1)[CH2:24][CH2:25][CH3:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][C:30]2[N:29]=[N:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:37][CH:38]=3)[CH:31]=2)([F:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a stirred solution of 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 mmol, 0.116. g) in THF (2 mL) at room temperature was added potassium tert-butoxide (0.5 mmol, 0.5 mL, 1M solution in THF) and continued stirring for 30 min. 3-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.5 mmol, 0.172 g) was taken THF (1 mL) and added to the reaction and stirred for 10 h at room temperature. The reaction was quenched with slow addition of water (2 mL) and the product was extracted with ethyl acetate (2×5 mL), Organic layer was washed with water (5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (90 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:19][CH:20]=1)[CH:7]=[CH:8][CH:9]=O)[CH3:2].[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1.C(O)(=O)C>O1CCCC1.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][CH2:9][CH:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:19][CH:20]=1)[CH3:2]
Reactant: CCOc1cc(C=CC=O)ccc1OCc1coc(-c2ccccc2)n1
Reactant: O=C1COC(=O)N1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of 3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (3.0 g), 2,4-oxazolidinedione (1.7 g), piperidine (0.73 g) and acetic acid (50 ml) was stirred for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure, and resulting crystalline precipitate was collected by filtration. The filtrate was dissolved in ethyl acetate. The solution was successively washed with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N HCl and water, followed by drying (MgSO4). The ethyl acetate layer was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), further crystals were collected, which were combined with the crystalline product obtained above and dissolved in tetrahydrofuran (THF) (100 ml). To the solution was added palladium-carbon (5%, 1.0 g), which was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), 5-[3-[3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione was obtained, which was recrystallized from chloroform-ether to give colorless prisms, m.p.119-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[OH:22]OS([O-])=O.[K+].[OH2:28]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)(=[O:22])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2F)CC1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
A solution of tert-butyl 4-((2-fluorophenyl)thio)piperidine-1-carboxylate (1.98 g, 6.36 mmol) in THF (54.5 mL) and MeOH (18.2 mL) at 0° C. was treated with a cold solution of Oxone® (9.77 g, 15.9 mmol) in water (54.5 mL). The reaction mixture was stirred for 5 h, gradually warming to room temperature. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were washed with water and then saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient of 10% to 50% EtOAc with 0.1% triethylamine in heptanes gave tert-butyl 4-((2-fluorophenyl)sulfonyl)piperidine-1-carboxylate as a pale yellow oil (1.31 g, 60%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:22])[N:3]=1.[C:23]([O-:26])([O-])=[O:24].[Na+].[Na+].[CH3:29][C:30]#[N:31]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:31][C@@H:30]([CH2:29][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:22])[N:3]=2)=[CH:16][CH:15]=1)[C:23]([OH:26])=[O:24]
Reactant: Nc1nc(Cl)cc(OC(c2ccc(F)c(F)c2)C(F)(F)F)n1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Nc1nc(OC(c2ccc(F)c(F)c2)C(F)(F)F)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1

Procedure:
4-Chloro-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-amine (0.14 g, 0.421 mmol), L-p-boronophenylalanine (110 mg, 0.505 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), Na2CO3 (98 mg, 0.926 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 150° C. for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 74 mg of the title compound. M+1=469; 1H NMR (CD3OD) δ 7.83 (d, 2H), 7.47 (m, 1H), 7.38 (m, 4H), 7.28 (m, 1H), 4.21 (t, 1H), 3.29 (m, 1H), 3.15 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:16][C:17]#N)[S:14][CH:15]=1)(C(C)(C)C)(C)C.[OH-:19].[K+].[OH2:21]>C(O)C>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:16][C:17]([OH:21])=[O:19])[S:14][CH:15]=1
Reactant: [OH-]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CC#N)c1
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1cc(CCO)cs1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)acetonitrile [Aromatic Intermediate 20, step b] (4.20 g) dissolved in ethanol (30 mL) was added to a stirred solution of potassium hydroxide (1.67 g) in water (30 mL). The resulting mixture was stirred at 100° C. for 3 hours. The mixture was partitioned between aqueous brine and ethyl acetate, and the phases separated. The aqueous layer was cooled with ice and acidified by dropwise addition of concentrated hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (×2), the combined organic phases were washed with aqueous brine, dried over sodium sulphate and the solvent evaporated under reduced pressure to give a yellow solid which was triturated with ether (20 mL) to give the subtitled compound. Yield 2.33 g.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24]C)[O:15][N:14]=1)[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[O:15][N:14]=1)[CH3:6]
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2OC)on1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCCCc1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Add boron tribromide (43 mL 43 mmol, 1.0 M solution in CH2Cl2) dropwise over 30 minutes to a stirred 0° C. solution of 5-[5-(2-methoxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (5.20 g, 17.1 mmol) in CH2Cl2 (45 mL). Allow to warm to room temperature overnight. Add boron tribromide (17 mL, 17 mmol, 1.0 M solution in CH2Cl2) and stir at room temperature under N2. After 4 hours, add boron tribromide (17 mL, 17 mmol, 1.0 M solution in CH2Cl2) and stir at room temperature under N2. After 2 hours, quench via dropwise addition of ethanol (50 mL, absolute). Concentrate, dissolve residue in CHCl3, wash with saturated NaHCO3 solution (×2), dry over MgSO4 and concentrate to get 4.7 g of a tan solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 3-20% EtOAc/hexanes to afford the title compound (3.96 g, 80%). MS (IS) 290 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]([CH3:39])[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])=[O:25])[CH:18]=1.C(N(CC)CC)C.[Cl:47]/[CH:48]=[CH:49]\[C:50](O)=[O:51].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:47]/[CH:48]=[CH:49]\[C:50]([NH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[CH:18]=[C:19]([N:23]([CH3:39])[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])=[O:25])[N:20]=[CH:21][N:22]=1)=[O:51]
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(N)c2)CC1
Reactant: O=C(O)/C=C\Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(NC(=O)/C=C\Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2C (Example 108), modifying step (g) to the following procedure: To a solution of 1-(6-((2-amino-4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (11 g, 0.019 mmol), triethylamine (9.67 g, 0.096 mmol), and (Z)-3-chloroacrylic acid (2.43 g, 0.023 mmol) in DCM (0.4 ml, 6.21 mmol) was added a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (21.9 g, 0.034 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated and the residue was purified by silica gel column to obtain the title compound (7.5 mg, yield: 59%). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=8.0 Hz, 3H) 2.90 (br. s., 4H) 3.27 (s, 3H) 3.45 (t, J=4.64 Hz, 4H) 3.91 (s, 6H) 5.90 (s, 1H) 6.32 (d, J=8.41 Hz, 1H) 6.52 (s, 1H) 6.59 (d, J=8.41 Hz, 1H) 6.73 (dd, J=8.78, 2.76 Hz, 1H) 7.09 (br. s., 1H) 7.24 (s, 2H) 7.83 (br. s., 1H) 8.36 (s, 1H) 8.69 (br. s., 1H) 12.52 (s, 1H); MS (ESI): 663.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][N:6]=[C:5](O)[C:4]1=[O:10])[CH3:2].P(Br)(Br)([Br:13])=O.C(=O)([O-])[O-].[Na+].[Na+].O>ClC(Cl)C>[Br:13][C:5]1[C:4](=[O:10])[N:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=1
Reactant: CCn1ccnc(O)c1=O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCn1ccnc(Br)c1=O
Temperature: 10 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
10.5 g (75 mM) of 1-ethyl-3-hydroxypyrazine-2(1H)-one and 23.1 g (80.5 mM) of phosphorous oxybromide in 75 ml of dichloroethane were refluxed under stirring for 2 h. The reaction mixture was then neutralized to pH 7-8 with a saturated aqueous solution of sodium carbonate, while maintaining the temperature at 10° C. The reaction mixture was then stirred at room temperature for 1 h. Water was added and the organic phase was extracted with dichloromethane. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography, using dichloromethane as eluant, to give 6.1 g of 3-bromo-1-ethylpyrazin-2(1H)-one as a solid. Yield: 40.2%.
Reaction SMILES: [P:1]([Cl:15])(Cl)([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].[Cl-].[CH2:17]([O:21][C:22](=[O:26])[C@@H:23]([NH3+:25])[CH3:24])[CH2:18][CH2:19][CH3:20].CCN(CC)CC>C(Cl)Cl>[Cl:15][P:1]([NH:25][C@H:23]([C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[O:26])[CH3:24])([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCCCOC(=O)[C@H](C)[NH3+]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cccc2ccccc12
Temperature: -78 °C

Procedure:
To 1-naphthyl dichlorophosphate in DCM (0.086 M) was added (25)-1-butoxy-1-oxopropan-2-aminium chloride (1.0 eq.). After cooling to −78° C., neat Et3N (2.0 eq.) was added and the reaction was left to warm to RT overnight. All volatiles were removed and the resulting white solid was washed with Et2O, filtered and evaporated in vacuo to obtain a colorless oil as a 1:1 mixture of diastereoisomers. 31P NMR (400 MHz, CDCl3): δ 8.39 and 8.11 ppm.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:13]>CC(C)=O.CO>[NH2:13][C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: N
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 216 h
Yield: 148.1 %

Procedure:
Performed in duplicate on identical scales in two pressure vessels, methyl 2,5-dichloronicotinate (4.5 g, 22 mmol) was dissolved in ammonia solution (250 mL, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vessels were sealed and heated at (85±5)° C. for 9 days. The two reaction mixtures were allowed to cool to rt, then combined and concentrated under reduced pressure to yield a white solid. Dissolution of the solid in 1:1 acetone-MeOH (˜500 mL), followed by adsorption onto silica gel (25 g) and then purification by flash column chromatography (25:10:1 hexane-CH2Cl2-Et2O), gave 6.08 g (75%) of methyl 2-amino-5-chloronicotinate.