Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J7) (189 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol) according to the general procedure M. Obtained as a yellow solid (273 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31].O>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (27.5 g, 0.08 Mol) was suspended in ethyl acetate (0.193 L) and 1,1-carbonyidimidazole (13.3 g, 0.082 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 15 minutes and then the reaction was stirred for a further 60 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (16.5 g, 0.078 Mol) was added to the cooled mixture, and the reaction stirred for a further 17 hours under reflux. The solution was cooled and water (0.07 L) and ethyl acetate (0.17 L) added. The slurry was warmed to 40° C. and the organic separated. The organic was concentrated to by evaporating 0.23 L solvent. The slurry was cooled, granulated at 0-−10° C. filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl)nicotinamide as an off white crystalline solid, 38.7 g, 89%. m.p.=159-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH:14]([F:16])[F:15])=[C:6]([CH:8]([CH2:11][OH:12])[C:9]#[N:10])[CH:7]=1.[OH:17][CH2:18][CH2:19]C#N>>[C:18]([O:12][CH2:11][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:13][CH:14]([F:15])[F:16])[C:9]#[N:10])(=[O:17])[CH3:19]
Reactant: N#CCCO
Reactant: N#CC(CO)c1cc(Cl)ccc1OC(F)F
Product: CC(=O)OCC(C#N)c1cc(Cl)ccc1OC(F)F

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(5-chloro-2-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-5-chloro-2-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile is described in Example 4. The recovered ester product was a colorless oil.
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](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[N:48]1[N:49]=[CH:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][C:52]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:48]1[N:49]=[CH:50][N:51]2[CH2:56][CH2:55][N:54]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:5])[CH2:53][C:52]=12
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: c1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2cnnc2C1
Reaction time: 12 h
Yield: 21.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (170 mg, 0.57 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (323 mg, 0.85 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 17a (100 mg, 0.63 mmol, prepared according to a known method “Journal of Medicinal Chemistry, 2005, 48(1), 141-151”) and N,N-diisopropylethylamine (302 mg, 1.70 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 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 17 (50 mg, yield 21.7%) as a light yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1.Cl.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:14][CH:13]=1.O1CCN([CH2:36][CH:37]([N+:45]([O-:47])=[O:46])[CH2:38]N2CCOCC2)CC1>CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[CH2:38][CH:37]([N+:45]([O-:47])=[O:46])[CH2:36][N:19]2[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])C(CN1CCOCC1)CN1CCOCC1
Reactant: COc1ccc(CNNCc2ccc(OC)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(CN2CC([N+](=O)[O-])CN2Cc2ccc(OC)cc2)cc1
Yield: 85.9 %

Procedure:
To a mixed solution of toluene (8 ml) and methanol (12 ml) were added 1,2-bis(4- methoxyphenylmethyl)hydrazine dihydrochloride (0.99 g) and 1,3- dimorpholino-2-nitropropane (0.75 g). The mixture was refluxed with heating for 3 hours. The reaction solution was concentrated under a vacuum, purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby yielding 0.88 g (86%) of 1,2-bis (4-methoxyphenylmethyl)-4-nitropyrazolidine.
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>COC(C)(C)C>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCCN1
Agent: [NH2-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Yield: 89.2 %

Procedure:
In 30 ml of t-butyl methyl ether was suspended 897 mg of sodium amide in a nitrogen stream, and 2.13 g of 2-pyrrolidinone was slowly added thereto dropwise, followed by refluxing for 2 hours. After allowing to cool, 1.97 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by refluxing for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., and the mixture was allowed to cool with stirring. The thus formed crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 2.19 g (89%) of the titled compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:44])[CH2:31][NH:30][CH2:29][C:28]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:27]1.[CH3:45][C:46]1[S:50][C:49]([C:51](O)=[O:52])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C=O)C>[F:44][C:26]1([F:25])[CH2:31][N:30]([C:51]([C:49]2[S:50][C:46]([CH3:45])=[CH:47][CH:48]=2)=[O:52])[CH2:29][C:28]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]2)[O:27]1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
HATU (0.541 g) was added in one portion to a stirred solution at 0° C. of tert-butyl 2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step c) (0.32 g) and 5-methylthiophene-2-carboxylic acid (0.171 g) and triethylamine (0.458 mL) in DMF (20 mL). The mixture was then stirred at 20° C. for 7 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.4 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken up into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford 2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10].O=O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:1])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CCc1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In this example, a solution of 0.1158 g (1.01 mmol) of N-hydroxysuccinimide, 0.544 g (5.13 mmol) of ethylbenzene and 0.1158 g (0.46 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was heated to 30° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 30° C., 233 psi of air was slowly introduced to the reactor. The mixture was stirred under pressure for one hour at 30° C., then the pressure was released, and the mixture was cooled to room temperature. A slow temperature rise (due to heat generated by the exothermic oxidation) within roughly 30 minutes following O2 introduction, accompanied by a drop in reactor pressure (due to consumption of O2 in the liquid phase reaction) indicates rapid reaction following induction. These profiles are steep and level off within minutes after induction. The reaction product mixture was extracted by ethyl acetate, then washed by water and saturated NaCl, dried over Na2SO4 to give acetophenone 80% and starting material 20% analysis by GC-MS and HPLC.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]1([OH:10])[CH2:9][CH2:8]1>C(O)(C)C>[Br:1][CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4][Cl:3]
Reactant: OC1(CCCCl)CC1
Reactant: BrBr
Solvent: CC(C)O
Product: O=C(CCBr)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (2.0 mL, 39 mmol) was added slowly to a solution of 1-(3-chloropropyl)cyclopropanol (5.0 g, 34 mmol) in isopropanol (80% solution in water, 30 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour and then was quenched with water (15 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 1-bromo-6-chlorohexan-3-one, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)#[CH:23].C(N(CC)CC)C>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[CH:3]=[C:2]([C:23]#[C:22][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH3:12])[CH3:21]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 98.1 %

Procedure:
To a solution of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1.80 g, 5.05 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (1.80 g, 8.59 mmol) in DMF (40 ml) was added triethylamine (2.82 ml, 20.2 mmol) and Copper(I) iodide (0.096 g, 0.505 mmol). The reaction mixture was degassed by bubbling nitrogen for 15 min. Then tetrakis(triphenylphosphine)palladium(0) (0.292 g, 0.253 mmol) was introduced and degassed for additional 10 min by bubbling nitrogen. The reaction mixture was heated at 80° C. for 6 h. The reaction was quenched with sat. NaHCO3, extracted with TBME (3×40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (0% to 40% AcOEt/Heptane) to give the titled compound (2.40 g, 98% yield). 1H-NMR (500 MHz) 3 ppm; 7.65 (s, 1H), 7.28 (s, 1H), 3.97 (brd, J=11.3 Hz, 2H), 3.90 (s, 3H), 3.76 (m, 2H), 3.34 (dt, J=2.0, 11.7 Hz, 2H), 3.24 (ddd, J=3.4, 8.8, 12.2 Hz, 2H), 3.08 (brs, 2H), 2.98 (brs, 1H), 2.80 (dddd, J=3.9, 3.9, 3.9, 3.9 Hz, 1H), 2.52 (s, 3H), 1.87 (m, 2H), 1.60-1.74 (m, 6H), 1.48 (s, 9H), 0.89 (t, J=6.8 Hz, 3H)); MS (ESI) [M+H]+485.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=1)[O:21][CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:37]=[CH:36][CH:35]=[C:20]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])[CH:19]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (509 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (753 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 96.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (809 mg, yield: 69%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1](=[O:11])([S:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:11])([S:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:2][CH:3]([O:17][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH3:4]
Reactant: CC(Cl)OC(=O)SC(C)(C)C
Reactant: CC(C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(OC(=O)SC(C)(C)C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 90.6 %

Procedure:
Compound (3) (392 mg, 2 mmol) was dissolved in isobutyric acid (264 mg, 3 mmol) and the solution was slowly added to a pre-mixed solution of isobutyric acid (264 mg, 3 mmol) and diisopropylethylamine (387 mg, 3 mmol). The reaction mixture was heated to 55° C. for 16 h, then diluted with ether (50 mL), washed with water (2×10 mL), saturated bicarbonate solution (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (8) as a colorless liquid (450 mg, 90%). The product was further purified by vacuum distillation (170° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=7.2 Hz, 6H), 1.47 (s, 9H), 1.48 (d, J=5.6 Hz, 3H), 2.53 (m, 1H), 6.90 (q, J=5.2 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][CH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][CH2:14][NH:13][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)#[N:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1ccc(CCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice bath cooling, 5.82 ml (15.57 mmol) of benzyl chloroformate (45% in toluene) were added to a solution of 2.37 g (12.98 mmol) of 4-(2-aminoethyl)benzonitrile hydrochloride and 4.34 ml (31.14 mmol) of triethylamine in 95 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 2:1 to 1:1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH3:15])=[N:9]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (85 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (92 mg, 0.38 mmol) and DIPEA (132 μL, 0.76 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to afford the title compound as a pale yellow oil (132 mg, 82%). LCMS (Method J): RT=2.22 min, [M+H]+=424
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:11]3=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]([CH:15]=1)=[C:10]23>C(Cl)Cl.N1C=CC=CC=1>[O:26]=[C:25]1[C:9]2[C:10]3[C:11](=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]=3[CH:15]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)[CH:22]=[N:23][NH:24]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Temperature: 22 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
Methanesulfonyl Chloride (1.5 eq, 0.003 g) was added to a solution of the title compound of Example 7 (0.005 g, 0.018 mmol) in CH2Cl2 (0.045 M, 0.4 mL) and pyridine (0.045 M, 0.4 mL). The mixture was stirred at 22° C. for 24 hours and concentrated under reduced pressure. Silica gel chromatography (triethylamine/methanol/CH2Cl2; 1:5:94) afforded the title compound (1.7 mg) in 30% yield.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].O>C1C=CC(Cl)=C(Cl)C=1>[C:8]1(=[O:9])[O:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:2]=[C:3]12
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=C1OC(=O)c2ccccc21

Procedure:
In the “In Situ ClPAMI” procedure, the five-necked flask setup described above was used. The ClPAMI was synthesized in the five-necked flask by reacting two moles of chlorophthalic anhydride with one mole of mPD using oDCB as solvent. The water formed was removed by distillation until a moisture content of less than 20 ppm in the distillate was obtained. Then, HEGCl , a phase transfer catalyst, was added in an amount of 0.6 weight %, based on the ClPAMI amount. More oDCB was distilled off to confirm that the moisture level was less than 20 ppm in the distillate. Then, a slurry of Na2BPA and NaPCP in oDCB in the second flask was transferred to the five-necked flask using the addition tube in communication with the second flask, and polymerization was conducted at 180° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].I[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-fluoro-phenol Compound 4a (3.0 g, 15.7 mmol), 2-iodo-propane Compound 4b (4.0 g, 23.6 mmol), K2CO3 (3.3 g, 23.6 mmol) and DMF (50 mL) were heated and stirred at 80° C. for 8 hrs. The excess DMF was removed under reduced pressure and the white residue was mixed with AcOEt (100 mL), washed with water and dried (Na2SO4). The filtered dry solution was evaporated to provide 1-bromo-4-fluoro-2-isopropoxy-benzene Compound 4c (3.48 g, 95%) as a yellowish oil.