Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][CH2:3][C:2]1=[O:10].[H-].[Na+].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[C:18]([O:17][C:15]([CH2:14][N:1]1[C:2](=[O:10])[CH2:3][CH2:4][N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6](=[O:9])[CH2:7][CH2:8]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCNC(=O)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(=O)N(CC(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.3 g of perhydro-1,5-diazocin-2,6-dione are suspended in 30 ml of absolute DMF, and 732 mg of sodium hydride (80%) are then added. The mixture is stirred at RT for 15 min and then cooled to 0° C., and 3.76 ml of tert-butyl bromoacetate are then added. The mixture is stirred at 0° C. for 15 min and at RT for 30 min, and is then once again cooled to 0° C., and another 732 mg of sodium hydride (80%) are added. After 15 min, a further 3.76 ml of tert-butyl bromoacetate are added using a pipette, the ice bath is removed after 15 min and the mixture stirred at RT overnight. The mixture is then diluted with dichloromethane, water is added, and the phases are then separated and the organic phase is washed twice with water. The organic phase is dried over MgSO4 and concentrated, and the residue is dried under high vacuum and recrystallized from n-hexane. This gives 2.5 g of the title compound of m.p. 180° C. The mass spectrum shows the molecular peaks MH+ and MNH4+ at 371 and 388 Da.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Yield: 44 %

Procedure:
A solution of 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) (0.29 mmol), tert-butyl isocyanate (0.29 mmol) and triethylamine (0.58 mmol) in dichloromethane (3 mL) was shaken at room temperature overnight, quenched with water, filtered through a PTFE phase separator cartridge and reduced in vacuo to yield a colourless gum (52 mg, 44%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31](O)=[C:30]([F:35])[CH:29]=1.C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:22][CH:15]([C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:30]([F:35])[CH:29]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCC(Oc1ccc(C(=O)OC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
Combine 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptan-1-ol (0.050 g, 0.15 mmol) and 3-fluoro-4-hydroxy-benzoic acid methyl ester (0.030 g, 0.18 mmol) in toluene (0.5 mL). Add 1,1′-(diazocarbonyl)dipiperidine (0.057 g, 0.23 mmol) followed by tributyl-phosphine (0.06 mL, 0.23 mmol) under inert atmosphere. Stir at room temperature for 16 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-40% ethyl acetate/hexane gradient) to provide 0.04 g of title compound (57%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:26]Cl>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:20]=3[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClI
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3ccccc3o2)CC1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3cc(I)ccc3o2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-benzoxazol-2-yl-piperazine-1-carboxylic acid benzyl ester (0.50 g, 1.48 mmol) and iodine monochloride (0.265 g, 1.63 mmol) in acetic acid (4.94 mL) was stirred at 60° C. overnight, cooled, and concentrated in vacuo to provide the title compound, which was used without further purification, in Example 3.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=O.Cl.[CH3:15][O:16][C:17](=[O:22])[C:18]([NH2:21])([CH3:20])[CH3:19].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:15][O:16][C:17](=[O:22])[C:18]([NH:21][C:11]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]=1[OH:1])=[O:13])([CH3:20])[CH3:19]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccsc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1O
Yield: 39.7 %

Procedure:
To a solution of 1.40 g 7-hydroxy-benzo[b]thiophene-6-carboxylic acid in 20 ml N,N-dimethylformamide were added 0.21 g 1-hydroxy-benzotriaziole and 1.42 g 2-amino-2-methyl-propionic acid methyl ester hydrochloride. At 0° C. 6.4 ml (4.99 g) ethyl-diiso-propyl-amine and 2.22 g (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added. After 2 days at room temperature the reaction mixture was concentrated in vacuo, and the resulting residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to afford 0.84 g 2-[(7-hydroxy-benzo[b]thiophene-6-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[NH2:24][C@H:25]([C:27]([NH:29][C@H:30]([C:32]([N:34]1[CH2:43][CH2:42][CH2:41][C@H:35]1[C:36]([NH:38][CH2:39][CH3:40])=[O:37])=[O:33])[CH3:31])=[O:28])[CH3:26].N=C=N>>[NH:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:2]([C:14]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:32]([N:34]1[CH2:43][CH2:42][CH2:41][C@H:35]1[C:36]([NH:38][CH2:39][CH3:40])=[O:37])=[O:33])[CH3:31])=[O:28])[CH3:26])=[O:16])[CH2:3][C:4](=[O:13])[OH:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)N
Agent: N=C=N
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
Condensation of BOC-Asp(OBzl) with Ala-Ala-Pro-NH-Et is achieved by the carbodiimide method as described in Example 1. Subsequent debenzylation by the procedure in Example 1 gives BOC-Asp-Ala-Ala-Pro-NH-Et in a yield of 68%; Rf =0.75(S)1. Acylation with undecanolylchloride, by the procedure in Example 3, produces the title product, Nα -Undecanoylaspartyl-alanyl-alanyl-proline ethylamide; m.p. 184°-189° C. (from water). Amino acid composition analysis yields; Asp 1.02, Pro 1.04, Ala 1.97.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CC(C)c1cc(NN)nc2ccccc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: CC(C)c1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ccccc12

Procedure:
A solution of 2-hydrazinyl-4-isopropylquinoline (97 mg, 0.48 mmol) and 91 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.74 Hz, 6 H) 3.53-3.71 (m, 1 H) 6.83 (s, 1 H) 7.09 (t, J=1.90 Hz, 1 H) 7.28 (td, J=7.47, 1.46 Hz, 1 H) 7.45-7.62 (m, 2 H) 7.69 (br. s., 2 H) 7.94 (d, J=7.62 Hz, 1 H) 8.50 (br. s., 1 H) 8.70 (s, 1 H) 9.23 (br. s., 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.O1[CH2:15][CH2:14][NH:13]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][CH2:14][NH:13][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: O=C1NCCO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cccc(N2CCNC2=O)c1
Temperature: 195 °C
Yield: 62 %

Procedure:
A mixture of 3-methylphenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 62 percent of the desired product, m.p. 137° C.-138° C.
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[O:23]>CN(C)C=O>[OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:26](=[O:27])[CH2:25][CH2:24][S:22]([CH3:21])=[O:23])=[CH:7][CH:6]=1
Reactant: CS(=O)CCC(=O)Cl
Reactant: Nc1ccc(OCC(O)CO)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)CCC(=O)Nc1ccc(OCC(O)CO)cc1
Yield: 80.4 %

Procedure:
A 1.83 g quantity of 4-(2,3-dihydroxypropoxy)aniline and 1.53 g of triethylamine were dissolved in 30 ml of dimethylformamide. To the solution was added 1.55 g of 3-(methylsulfinyl)propionyl chloride with ice cooling. The same subsequent procedure as in Example 2 was repeated and recrystallization from ethanol was effected, giving 2.42 g of N-[4-(2,3-dihydroxypropoxy)phenyl]-3-(methylsulfinyl)propionamide in a yield of 80.4%. M.p. 139° to 141° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:25]1[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:25]1[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: O=C(O)c1ccc(Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 59.8 g (0.2 mole) of 3,7,11,15-tetramethyl-1-hexadecanol and 19.2 g (0.4 mole) of sodium hydride (50% in oil) in 1 liter of toluene is refluxed with stirring for 2 hours then cooled to room temperature. To the mixture 29.3 g (0.2 mole) of 5-chloro-2-furoic acid is added and the mixture is refluxed with stirring for 24 hours. Upon cooling to room temperature the mixture is acidified with glacialacetic acid and water is added. The toluene layer is evaporated and allowed to crystallize to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12]Cl.CI>C1COCC1>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]2[O:10][CH2:11][CH2:12][C:4]=2[CH:5]=1
Reactant: COc1ccc(OCCCl)c(Br)c1
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
To a solution of 2-bromo-1-(2-chloroethoxy)-4-methoxybenzene (1.38 g, 5.22 mmol) in THF was added 190 mg (7.82 mmol) of Mg and MeI (3 mL). The mixture was sonicated for 2 h and stirred at room temperature for additional 20 h. The reaction was quenched with 3N HCl (50 mL) and extracted with 1:1 hexane/ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (3:1 hexane/ethyl acetate) of the residue gave 0.66 g (85%) of the tide compound as a colorless liquid: 1H NMR (400 MHz, CDCl3) d 6.80 (d, 1H), 6.70 (d, 1H), 6.65 (dd, 1H), 4.53 (t, 2H), 3.75 (s, 3H), 3.18 (t, 3H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-20° C. The jacket temperature was set to -5° C. and the reaction solution cooled to a temperature of +3.5° C. A 21° C. solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1° C. and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R1OSV Honeycomb filter. The filtered solution was metered into a 21° C. mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:61])([F:60])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]#[N:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:61])([F:47])[F:60])=[N:50][C:51]([C:58]#[N:59])=[C:52]2[CH2:57]1)=[O:6]
Reactant: N#Cc1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 21.9 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (210 mg, 0.70 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol), crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile 25a (100 mg, 0.46 mmol), and N,N-diisopropylethylamine (250 μL, 1.18 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carbonitrile 25 (50 mg, yield 21.9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Yield: 70.4 %

Procedure:
82 g (0.31 mol) of methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate were dissolved in 2 1 of carbon tetrachloride, and 56 g (0.31 mol) of N-bromosuccinimide were added a little at a time while the mixture was exposed to light. The reaction mixture was filtered, the filtrate was concentrated and the residue was taken up in 200 ml of methyl tert-butyl ether. The solution was admixed with petroleum ether and the precipitated solid was filtered off with suction and dried. 74.5 g (70% of theory) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=S)[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(OCC)(=[O:59])C>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:59])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=S)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamothioyl)-1H-pyrrol-1-yl)ethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate obtained in Example 5-3 was dissolved in 70 ml of ethanol, and 0.83 g of sodium hydroxide and 35 ml of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature for 3 hours. 300 ml of ethyl acetate and 200 ml of purified water were added to the reaction mixture and stirred slowly for 30 minutes, and the organic layer was separated and washed one time with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining oil. The oil was crystallized from isopropylether and heptane, thus obtaining the target compound as a solid compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ccccc1C(=O)NCCO
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NCCO)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (1.3 g, 4.4 mmol), 2-amino-N-(2-hydroxyethyl)benzamide (838 mg, 4.65 mmol), di-isopropyl-ethylamine (925 μL, 5.31 mmol) and 15 mL isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N-(2-hydroxyethyl)benzamide (1.3 g, 89%):
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O-:12])=O)[CH2:6][CH2:5]1.[Li+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:26]([NH:33][C:10]([CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:9][CH2:8]1)=[O:12])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Reaction time: 18 h

Procedure:
Lithium (R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate (32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Benzylamine (39) (33 mg; 0.312 mmol), N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes) affording the desired product (40) as an oil. CIMS (NH3Cl): 420 (MH+)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)(=O)C>[O:25]=[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 19.8 %

Procedure:
A slurry of (3-quinoxalin-2-ylphenyl)amine (200 mg, 0.904 mmol) and dietyl malonate (1.4 mL, 9.04 mmol) was heated at 160° C. in a Dean-Stark vial (Glass Solutions) for 5 hrs. The reaction mixture was diluted with ethyl acetate (25 mL), the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulphate, the solvent evaporated in vacuo and the residue dissolved in DCM (2 mL). The solution was loaded on a Isolute 20 g silica gel column and purified by flash chromatography (Flash Master, 5 g Isolute Silica column, gradient 0 to 5 min hexane, then ethyl acetate up to 50% over 20 min) to afford ethyl 3-oxo-3-(3-(quinoxalin-2-yl)phenylamino)propanoate (60 mg, 20% yield). LCMS calculated for C19H17N3O3 (M+H): 336.35. found 336. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.41 (1H, br.), 9.52 (1H, s), 8.52 (1H, m), 8.15-8.10 (2H, m), 8.05-8.08 (1H, m), 7.82-7.95 (3H, m), 7.55-7.60 (1H, m), 4.16 (2H, q, J=8 Hz), 3.54 (2H, s), 1.23 (3H, t, J=8 Hz).