Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O>[CH2:37]([NH:47][S:25]([C:2]([F:29])([F:1])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:11])([F:12])[F:10])(=[O:27])=[O:26])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 15.73 g (100.0 mmol) of decylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>Br>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccncc1
Agent: Br
Product: O=C(CBr)c1ccncc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 18.2 g (150 mmol) 4-acetylpyridine (6-1) in 20 mL 48% HBr was added a 5 mL solution of 7.70 mL bromine in 48% HBr dropwise while heating in a 70° C. oil bath. A thick precipitate formed about midway through the addition, but the reaction was allowed to stir an additional 2 h at 70° C. The reaction was cooled and the precipitate was collected by filtration and washed 3×20 mL with a 1:1 methanol:Et2O solution to provide pure 2-bromo-1-pyridin-4-ylethanone (6-2) after drying under high vacuum: 1H NMR (400 MHz, DMSO-d6) δ 9.0 (d, J=3 Hz, 2H), 8.07 (d, J=3 Hz, 2H), 5.03 (s, 2H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11](C(OC(C)(C)C)=O)[C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(F)nc2)=CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(c2ccc(F)nc2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(6-fluoropyridin-3-yl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (315 mg, 1.132 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 1 h. Reaction mixture was evaporated. Azeotrope with toluene (x=3) yielding 4-(6-fluoropyridin-3-yl)-1H-pyrrol-2(5H)-one. Proceed for next step. LCMS (m/z): 179.2 (MH+), 0.373 min. The crude yield was quantitative.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])C1C=CC=CC=1>O1CCOCC1.CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2COCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2CO)cc1
Yield: 94.9 %

Procedure:
A mixture of (2R,3S)-2-benzyloxymethyl-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methylpiperazine (330 mg) and palladium hydroxide (40 mg) in dioxane (5 ml) and MeOH (5 ml) was hydrogenated in hydrogen at 3.5 atm and ambient temperature for 1 day. The catalyst was removed by filtration through a celite pad and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt/n-hexane 60%, then MeOH/AcOEt 1%) to give 253 mg of (2R,3S)-2-hydroxymethyl-4-methanesulfonyl-1-(4-methoxybenzene-sulfonyl)-3-methylpiperazine.
Reaction SMILES: [CH:1]12[CH2:15][CH2:14]O[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C1(=O)CCCCCCCCCCC1.C(CC(O)=O)#[N:30]>>[C:1]1([CH2:15][C:14]#[N:30])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1CCCCCC2OCCC2CCCC1
Reactant: N#CCC(=O)O
Agent: O=C1CCCCCCCCCCC1
Product: N#CCC1=CCCCCCCCCCC1

Procedure:
13-oxabicyclo[10.3.0]pentadecane, a valuable ambergris fragrance, is prepared by reacting cyclododecanone with cyanoacetic acid in the presence of a Knoevenagel catalyst to form cyclododecenylacetonitrile, the nitrile is hydrolyzed to cyclododecenylacetic acid, and the acid is cyclized to the lactone, and the lactone is reduced to the corresponding diol which is cyclized to 13-oxabicyclo[10.3.0]pentadecane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:29]([F:31])([F:32])[F:30])[CH:11]=3)=[O:22])=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: NC1(C2CC2)CC1
Reactant: C#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cc2cn[nH]c2c(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 530 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-5-ethynyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of N,N-dimethylformamide, is added 465 mg (3.48 mmol) of bicyclopropyl-1-ylamine hydrochloride and 485 μL (3.48 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 3:7) affords 200 mg (31% over two steps) of the product as white solid; LC/MS:554/556 (M+H)+, m.p.: 246-248° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:16])=[CH:18][CH:19]=1)([O-:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccnc1
Product: O=C(Nc1cccnc1)c1ccc([N+](=O)[O-])cc1
Yield: 49.6 %

Procedure:
Using 3-aminopyridine (1.55 g, 16.5 mmol) and 4-nitrobenzoic acid (2.5 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.81 g (49.6%) of the title compound in the form of colorless powder.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[C:6]([C:7]1[C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1c[nH]c2ncncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1c[nH]c2ncncc12
Yield: 86.7 %

Procedure:
5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (0.320 g, 1.49 mmol) and potassium carbonate (0.513 g, 3.72 mmol) were stirred in MeOH (6 mL) for 18 hours. The mixture was diluted with EtOAc, washed with saturated ammonium chloride, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound as an orange solid (0.185 g, 87%).
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:90])[C@@H:83]([C@H:85]([C:87]([OH:89])=[O:88])[OH:86])O.CCCCCCC>CC(C)=O>[OH:86][C@H:85]([C@@H:83]1[C:82](=[O:90])[O:3][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:35])[CH3:36])[O:5]1)[C:87]([OH:89])=[O:88]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@@H]([C@@H](O)C(=O)O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.270 g, 0.246 mmol) and L-tartaric acid (149.5 mg, 0.33 mmol) were mixed in acetone (3 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. Heptane (2.5 mL) was added. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 1.5 h. The slurry was filtered to collect solid (R)-2-hydroxy-2-((R)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.388 g) which also contained a dimeric species. MS (m/z) in CH3CN: [M+H] calculated for C23H28BN4O8, 499.2000. found, 499.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:13]([O:16]C(=O)C)(=O)[CH3:14].[N+:20]([O-])([OH:22])=[O:21]>>[N+:20]([C:3]1[CH:4]=[C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:16])[CH3:14])([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-n2cncn2)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
1-(4′-Aminophenyl)-1,2,4-triazole (500 mg) was added to acetic anhydride (2.3 mL) over 10 min and the mixture was cooled down to 10° C. HNO3 (65% in water, 0.65 mL) was added slowly to keep the temperature of the reaction mixture below 15° C. After the end of the addition, the reaction mixture was allowed to warm to RT over 1 h, was quenched with ice-cold water and stirred for 10 min. The resulting mixture was basified with aq. NH4OH (25%) to pH=12 and extracted with DCM. The phases were separated and the org. phase was evaporated in vacuo. The residue was taken up in H2SO4 (2 mL), the resulting solution was cooled down to 0° C. and HNO3 ((65% in water, 0.3 mL) was added. The mixture was stirred at 0° C. for 30 min and poured onto ice. After 10 min stirring, aq. NH4OH (25%) was added until pH=2 and the mixture was extracted with DCM. The org. layer was evaporated in vacuo to afford 130 mg of orange solid. LC-MS (B): tR=0.61 min; [M+H]+: 248.09.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([F:24])[S:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([S:14]([C:13]([F:25])([F:12])[F:24])(=[O:16])=[O:15])=[CH:18][CH:19]=1)=[O:9]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-trifluoromethanesulfonyl-aniline to afford a solid. UPLC-MS (Condition 3) tR=1.23 min, m/z=−441 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:14]([CH:23]([CH3:25])[NH2:24])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:24][CH:23]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)[CH3:25])=[O:5])=[C:7]([Cl:11])[CH:8]=[CH:9][N:10]=1
Reactant: CC(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1c(Cl)ccnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1c(Cl)ccnc1Cl)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
2,4-Dichloronicotinoyl chloride (0.40 g), made as in Example 1, Step C, was added to a solution of the amine intermediate from Step A (0.66 g) and triethylamine (0.70 g) in 30 mL of methylene chloride at room temperature followed by stirring overnight. The reaction mixture was distilled under vacuum to remove the solvent, giving an oil that was filtered through silica gel using 100% methylene chloride as the eluent. The solvent was then removed under vacuum to give the title compound, a compound of the invention, as a red oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[C:11]([O:13]CC)=O.CC[O-].[Na+]>CCO>[CH2:18]([O:17][C:10](=[O:16])[C:11](=[O:13])[CH:5]([CH2:6][CH2:7][CH3:8])[C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH3:19]
Reactant: CCCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(C(=O)OCC)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a mixture of pentanoic acid ethyl ester (0.4 mol) and diethyl oxalate (compound 11 in Scheme 1) (73.1 g, 0.5 mol) is added to a solution of NaOEt (32.7 g, 0.48 mol) in EtOH (250 ml). The mixture is stirred at room temperature for 30 minutes and EtOH is distilled away. The residue is then purified by vacuum distillation, which provides the product (120) as a clear oil.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:29])([F:28])[C:7]1[NH:8][C:9]([C:24]([F:27])([F:26])[F:25])=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([CH3:18])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].N([O-])=O.[Na+]>O>[F:29][C:6]([F:5])([F:28])[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([C:24]([F:25])([F:27])[F:26])[N:8]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
A 50 ml round bottomed flask is charged with 20 ml of glacial acetic acid. To this is added 5 g (0.0133 mole) of diethyl 2,6-bis(trifluoromethyl)-4-methyl-1,4-dihydro-3,5-pyridinedicarboxylate, followed by a slow addition of 3 g (0.0434 mole) of sodium nitrite. The flask is immediately fitted with a condenser and nitrogen line, the stirring continued for 18 hours, and the mixture is poured over crushed ice and water. The organics are extracted twice with ether, washed once with saturated aqueous sodium chloride and washed twice with saturated aqueous sodium bicarbonate solution. The organics are dried over anhydrous magnesium sulfate and concentrated yielding 2.16 g (43.5%) of product, m.p. 55°-58° C.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][C:23]([CH3:25])=[N:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: Cc1ccnc(N)n1
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc2n1
Yield: 41.9 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.3 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.0 g) and 2-amino-4-methyl-pyrimidine (3.3 g). mp. 298° C. (dec.).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[N:26][CH:27]=1>>[Cl:28][C:25]1[N:26]=[CH:27][C:22]([NH:21][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Nc1ccc(Cl)nc1
Product: Cc1ccc(CNc2ccc3c(Nc4ccc(Cl)nc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=365.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 5-amino-2-chloropyridine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([S:14](Cl)(=[O:16])=[O:15])[CH:10]=[CH:11][C:12]=1[Cl:13]>>[Cl:6][C:7]1[CH:8]=[C:9]([S:14]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][S:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)(=[O:16])=[O:15])(=[O:16])=[O:15])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CNCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CN(CCOS(=O)(=O)c1ccc(Cl)c(Cl)c1)S(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-methylamino ethanol and 3,4 dichlorophenyl sulfonylchloride using the method described in Description 1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])=[O:35]>C1COCC1>[N+:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:34](=[O:35])[CH2:33][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])([O-:44])=[O:43]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccccc1[N+](=O)[O-]
Yield: 56.3 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (54 mg, 0.17 mmol), with triethylamine (118 uL, 0.84 mmol, 5.0 eq), and 2-bromo-2'-nitroacetophenone (50 mg, 0.20 mmol, 1.2 eq) in THF (5 mL), provided 46 mg (57%) of L-isoleucine, N-[1-(2-(2-nitrophenyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH2:39])=[S:38])[CH3:28].[C:40]([O-])(=[O:42])C.[Na+]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH:39][C:40]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:42])=[S:38])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCc1cccc(C)c1NC(N)=S
Agent: [Na+]
Product: CCc1cccc(C)c1NC(=S)NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39). Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.146 g, 47%): 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.07 (s, 1H), 9.39 (s, 1H), 8.14-8.00 (m, 4H), 7.68-7.59 (m, 2H), 7.45-7.33 (m, 2H), 7.23-7.02 (m, 4H), 3.17 (q, J=6.6 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.51 (p, J=1.9 Hz, 2H), 2.18 (s, 3H), 1.90-1.73 (m, 2H), 1.12 (t, J=7.5 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:34]=[CH:35][CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:20])[N:12]3[N:37]=[CH:38][C:39]([CH:40]=[C:41]4[C:45](=[O:46])[NH:44][C:43](=[O:47])[NH:42]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:36]=[CH:35][CH:34]=[C:18]([C:19]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[O:20])[CH:17]=3)[N:12]3[N:37]=[CH:38][C:39]([CH:40]=[C:41]4[NH:42][C:43](=[O:47])[NH:44][C:45]4=[O:46])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Nc3cc(Nc4cccc(Cl)c4)nc4c(C=C5NC(=O)NC5=O)cnn34)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2cnn3c(Nc4cccc(C(=O)N5CCNCC5)c4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Tert-butyl 4-(3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoyl)piperazine-1-carboxylate (27 mg, 0.04 mmol) was dissolved in 2 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour. Excess solvent and TFA were removed by evaporation under a stream of nitrogen. The residue was diluted with water then the mixture was filtered. The recovered solid was washed with water followed by 50% ethanol. The product, 5-((5-(3-chlorophenylamino)-7-(3-(piperazine-1-carbonyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was collected as a solid in 21% yield. LCMS (M+1=558)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].CN(C)C1C=CC=CC=1.Cl>O.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)CCCCl
Yield: 11.2 %

Procedure:
4-Chlorobutyryl chloride (14.1 g) was added dropwise with stirring under ice-cooling to a mixture of tert-butanol (18.5 g) and dimethylaniline (18.2 g). The resulting mixture was stirred for 2 hours in an oil bath (100° C.). Ether (200 ml), water (100 ml) and 1N hydrochloric acid (50 ml) were added to the reaction mixture and mixed with shaking. The organic layer was washed successively with 1N hydrochloric acid, an aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was subjected to distillation under reduced pressure to obtain tert-butyl 4-chlorobutyrate (13. 2 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=O)[CH2:2][CH3:3].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]1[NH:14][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1ncccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2ncccc2c(=O)[nH]1
Yield: 89.8 %

Procedure:
A stirred mixture of 2-(2-propoxybenzamido)nicotinamide (0.77 g) and pyridine (0.8 ml) in 2 Normal sodium hydroxide (20 ml) was heated under reflux for 30 minutes. The cooled reaction mixture was neutralised with 2 Normal hydrochloric acid to afford a precipitate which together with another precipitate similarly prepared from 2-(2-propoxybenzamido)nicotinamide (0.1 g) was recrystallised from ethanol-ether to afford white needles (0.65 g) which were washed with water to afford the title compound, 0.55 g. m.p. 110°-111 ° C.