Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(=O)(O)[O-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 10.1 %

Procedure:
(5R)-3-(4-((3S)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (250 mg, 0.65 mM), in dichloromethane (20 ml) was cooled to 0° and treated with 5% sodium bicarbonate solution (10 ml). The resulting suspension was stirred vigorously, methanesulfonyl chloride (290 mg, 2.5 mM) added, and stirring continued for 18 hours at ambient temperature. Dichloromethane (10 ml) was added, the organic layer separated, and diluted with isohexane (30 ml). The precipitate was filtered, triturated with 2% sodium dihydrogen phosphate, and purified by chromatography on a 2 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 8% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (28 mg).
Reaction SMILES: C(OC(=O)N[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(C)(C)C.C(Cl)Cl.[C:45]([OH:51])(C(F)(F)F)=[O:46]>>[N:37]([CH2:36][CH2:35][CH2:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:45]([OH:51])=[O:46])=[CH:25][CH:24]=2)=[O:40])=[CH:28][CH:29]=1)=[N+:38]=[N-:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN=[N+]=[N-])cc2)cc1
Solvent: ClCCl
Product: [N-]=[N+]=NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCC(=O)O)cc2)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
tert-butyl-(2-(2-(2-(2-((4-(4-(3-azidopropoxy)benzoyl)phenyl)-amino)ethoxy)ethoxy)ethoxy)ethyl)-carbamate (1.75 g, 2.91 mmol) was dissolved in a solution of DCM:TFA (2:1, 12 ml) and left to stir for ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and left on oil pump for 5 hs to yield 1.52 g (97.0% yield) of (2-(2-(2-(2-((4-(4-(3-azidopropoxy)benzoyl)phenyl)-amino)ethoxy)ethoxy)ethoxy)ethyl)carboxylic acid as colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: COc1cc2ncn(-c3nc(-c4cc(Cl)cc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 51.1 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,5-dichlorophenylboronic acid (27 mg, 0.15 mmol) gave 4-(3,5-Dichloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (23 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H); 8.15 (s, 2 H); 7.83 (s, 1 H); 7.73 (s, 1 H); 7.39 (s, 1 H); 3.89 (s, 3 H); 3.85 (s, 3 H). MS 450 m/z (M+1).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:14][C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([Cl:16])[C:11]=1[O:15][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[NH2:7]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3c(Cl)cc(N)cc3Cl)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (60 wt %, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,6-dichlorophenol (1.59 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give 0.35 g (yield 22%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[N+](=[CH2:29])=[N-]>C(O)C>[CH3:29][O:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12
Reactant: C=[N+]=[N-]
Reactant: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCCl
Solvent: CCO
Product: COc1c(CC(=O)NCCCl)c2nc3ccccc3nc2c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a suspension of 100 of 5-hydroxy-N-β-chloroethylbenzo[a]phenazine-6-carboxyamide in 10 ml of ethanol was added an excess amount of diazomethane ethereal solution, followed by stirring at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting solid was recrystallized from acetic acid to give 103 mg (99% yield) of 5-methoxy-N-β-chloroethylbenzo[a]-phenazine-6-carboxyamide as yellow needles, m.p. 211°-213° C., Anal. Calcd. (%) for C20H16N3O2Cl; C, 65.89; H, 4.29; N, 11.28; Found: C, 65.67; H, 4.41; N, 11.49
Reaction SMILES: C(O)(=O)C.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N+]([O-])=O)=[CH:8][C:7]=1[C:19]([NH:21]CCCOC1C=CC(C(CC)(C)C)=CC=1C(CC)(C)C)=[O:20]>[Fe].O>[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1ccc2ccccc2c1

Procedure:
In 500 ml of a 90% acetic acid aqueous solution, 50 g of 1-hydroxy-4-nitro-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide was reduced with 50 g of iron as a reducing agent. The reaction mixture was added to water and then was extracted with ethyl acetate. After evaporating off the ethyl acetate, the crystals were recrystallized from ligroin to provide 40 g of 1-hydroxy-4-amino-N-[γ-2,4-di-tert-amylphenoxy)propyl]-2-naphthamide having a melting point of 132° to 133° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12].O>ClCCl>[CH3:9][O:10][C:11](=[O:12])[CH:13]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: O=Cc1ccnnc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
To a solution of pyridazine-4-carboxaldehyde (3.646 mmol, 1 eq) in dry dichloromethane (25 ml), (methoxycarbonylmethylene)triphenylphosphorane (5,550 mmol, 1.2 eq) was added portionwise. The reaction mixture was stirred at room temperature overnight. Reaction mixture was poured into water (200 ml) and extraction with DCM (3×100 ml) followed. Organic layers were combined, dried over phase separator cartridge to giving crude product which was purified on Biotage SP1 Snap Si 100; 40 ml/min in the gradient of MeOH in DCM: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 3-pyridazine-4-yl-acrylic acid methyl ester (4.142 mmol, yield=89%, purity=96%). [M+H]+=165.11 1H NMR (300 MHz, CDCl3) δ/ppm 3.82 (s, 3H), 6.64-6.68 (m, 1H), 6.72 (s, 1H), 9.22 (dd, J=5.3, 1.0 Hz, 1H), 9.27 (s, 2H)
Reaction SMILES: [CH:1]([OH:6])=[CH:2][C:3](=[CH2:5])[CH3:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CS(O)(=O)=O>[CH3:5][C:3](=[CH2:4])[CH2:2][CH2:1][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: C=C(C)C=CO
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CCOC1CCCCO1
Yield: 100.5 %

Procedure:
To isoprenyl alcohol (80.0 g, 929 mmol) in CH2Cl2 (500 ml) at 0° C. was added one drop of methanesulfonic acid. To this solution was added 2,3-dihydropyran (100 ml, 1.10 mol) dropwise over 3 h. After the addition was complete triethylamine (5 ml) was added and the resulting mixture was filtered through a thin pad of SiO2 and concentrated to afford 159 g (100%) of 2-(3-methyl-3-butenyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:19]([OH:21])=[O:20])=[CH:12][N:13]2[CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:23].CO>CN1C(=O)CCC1>[CH:16]1([N:13]2[C:14]3[C:9](=[CH:8][C:7]([F:23])=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:15]=3)[C:10](=[O:22])[C:11]([C:19]([OH:21])=[O:20])=[CH:12]2)[CH2:17][CH2:18]1
Reactant: NCCO
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C(O)c1cn(C2CC2)c2cc(NCCO)c(F)cc2c1=O
Temperature: 105 °C
Reaction time: 22 h

Procedure:
To a solution of ethanolamine (55.5 ml) in N-methyl pyrrolidinone (500 ml) at 95° C., 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105° C. and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60° C. and poured into MeOH (800 ml). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 29A and Intermediate 29B (49 g ) in a 1:1 ratio.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.56 g of 2-methylbenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.27 g of the desired product as a crystalline solid, m.p. 209°-210 ° C.
Reaction SMILES: [C:1]12([CH2:9][CH:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][OH:12])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:12][CH2:11][CH:10]([NH:13][C:14]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23])[CH2:9][C:1]12[CH2:2][CH2:3][CH:4]([CH2:5][CH2:6]1)[CH2:7][CH2:8]2)(=[O:27])=[O:26]
Reactant: O=C(NC(CO)CC12CCC(CC1)CC2)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 132.4 %

Procedure:
To a solution of benzyl 1-(bicyclo[2.2.2]octan-1-yl)-3-hydroxypropan-2-ylcarbamate (668 mg, 2.1 mmol, 1 eq.), TEA (638 mg, 6.3 mmol, 3 eq.) in CH2Cl2 (100 mL) was added dropwise MsCl (289 mg, 2.52 mmol, 1.2 eq.) at 0-5° C. The resulting mixture was stirred for 2 hrs. Then the mixture was poured into water (20 mL) and extracted with CH2Cl2 (20 mL×4). The organic phase was combined and evaporated to give 2-(benzyloxycarbonylamino)-3-(bicyclo[2.2.2]octan-1-yl)propyl methanesulfonate (1.1 g, crude) as oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH:2]([C@H:13]1[C@H:15]([C:16](O)=[O:17])[C:14]1([CH3:20])[CH3:19])[C:3]([Cl:12])([Cl:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH:2]([C@H:13]1[C@H:15]([C:16]([Cl:23])=[O:17])[C:14]1([CH3:20])[CH3:19])[C:3]([Cl:12])([Cl:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1C(Cl)C(Cl)(Cl)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Cl)C(Cl)(Cl)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
14 g of trans-3-(1,2,2-trichloro-2-(4-chloro-phenyl)-ethyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid were dissolved in 100 ml of carbon tetrachloride, 75 g of thionyl chloride were added and the mixture was heated under reflux for 4 hours. The solvent and excess thionyl chloride were then stripped off in vacuo. 13.7 g of trans-3-(1,2,2-trichloro-2-(4-chloro-phenyl)-ethyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid chloride were obtained as a viscous oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:6]=2)[CH2:3][CH2:2]1.[NH:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:35]4\[NH:29][C:30](=[O:31])[NH:32][C:33]\4=[O:34])=[C:9]3[N:8]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)CC1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
The above product tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (250 mg, 0.645 mmol) was dissolved in 2.0 mL ethanol, added hydantoin (129 mg, 1.288 mmol) and piperidine (127 ul). The reaction was heated to 80° C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-tert-butyl 4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (264 mg, 87% yield). The above product was further dissolved in 1:1 mixture of DCM: TFA and stirred at room temperature for 30 minutes. Mixture was concentrated and dried to yield yellow solid of (Z)-5((7-(cyclopropylamino)-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl) methylene) imidazolidine-2,4-dione. LCMS (M+1=369)
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51](=[O:53])[CH3:52])[CH2:46][CH2:45]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:51]([NH:50][CH:47]1[CH2:48][CH2:49][N:44]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:45][CH2:46]1)(=[O:53])[CH3:52]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), N-(piperidin-4-yl)acetamide (52.5 mg, 0.37 mmol, 2.41 equiv), potassium iodide (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 80.4 mg (50%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.93-8.92 (d, J=5.2 Hz, 1H), 8.67-8.65 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 8.13-8.09 (m, 3H), 7.88-7.87 (m, 1H), 7.78-7.67 (m, 5H), 7.62-7.54 (m, 1H), 4.72 (s, 2H), 4.44 (s, 2H), 3.91 (s, 1H), 3.66-3.63 (t, J=5.2 Hz, 4H), 3.57-3.54 (m, 2H), 3.20-3.14 (m, 2H), 2.17-2.13 (m, 2H), 2.05-2.00 (m, 4H), 1.93 (s, 3H), 1.82-1.70 (m, 4H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: [CH3:1][Li].[C:3]1([C@@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC>[C:3]1([C@@H:9]([CH3:14])[CH2:10][C:11](=[O:13])[CH3:1])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C[C@H](C)c1ccccc1
Temperature: 25 °C

Procedure:
1.6 M Methyl lithium (17.8 mL, 24.9 mmol) was added over 1 hour to a stirring 0° C. solution of (S)-3-Phenylbutyric acid (2.0147 g, 12.18 mmol) in dry Et2O (61 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature for 1½ additional hours. The reaction was then poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered and concentrated to achieve pure 77 (2.0487 g, (2.0487 g, ˜100%): HPLC: 10.081 min. (Note: SM has HPLC retention time of 9.127 min.)
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C1(C)C=CC=CC=1>[C:2]([O:4][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([Br:7])[CH:9]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
In an oven dried, 1-L, 3-necked round bottom flask equipped with an addition funnel, a glass stopper, a magnetic stirbar, and a reflux condenser connected to a nitrogen inlet, potassium t-butoxide (23.6 g, 209.6 mmol) was combined with toluene (150 mL). A solution of 3-bromobenzoyl chloride (40 g, 182.3 mmol) in toluene (100 mL) was added dropwise to the potassium t-butoxide and the mixture was stirred for 16 h at room temperature. The viscous mixture was transferred to a 1-L separatory funnel, and the reaction flask was rinsed with toluene (50 mL) and added to the separatory funnel. The toluene mixture was extracted with water (200 mL), a potassium carbonate solution (10%, 250 mL), and again with water (3×200 mL). The toluene layer was dried over magnesium sulfate and filtered, and the toluene was removed in vacuo to yield the product as a yellow oil (45.1 g, 96%). HPLC: >99% pure.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:22])=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5][C:4]1=[O:25])[CH3:2].[Br:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([O:34][C:35]([F:38])([F:37])[F:36])[CH:28]=1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:23])([CH3:24])[CH2:5][C:4](=[O:25])[N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[CH3:22])=[C:29]([O:34][C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(Br)cc3OC(F)(F)F)cc21

Procedure:
Compound 5B was prepared from Compound 5A and 4-bromo-1-iodo-2-trifluoromethoxy-benzene using a the conditions described for Example 1B. MS (electrospray): mass calculated for C21H21BrF3NO2, 455.07; m/z found 456.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([O:28][CH3:29])[CH:22]=[C:23]2[C:27]=1[NH:26][CH2:25][CH2:24]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([O:28][CH3:29])=[CH:20][C:19]=3[Cl:18])[CH2:24][CH2:25]2)[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials to give a yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.74 (s, 2H), 6.67 (s, 1H), 4.90–4.80 (m, 1H), 4.34 (t, J=7.9 Hz, 2H), 3.78 (s, 3H), 3.10 (t, J=7.7 Hz, 2H), 2.60–2.50 (m, 1H), 2.18–2.12 (m, 1H), 1.90–1.70 (m, 6H), 1.55–1.43 (m, 1H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 408.1270 [(M+H)+, calcd for C20H24N3O2Cl2 408.1246].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19]O)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][Cl:23])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)c(OCc2ccccc2)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product of step (iii) (9.5 g) was dissolved in DCM (200 ml), cooled to 0° C. and thionyl chloride (3.57 ml) was added and stirred at rt for 2 h. The solvents were evaporated and the residue taken up in DCM and washed with aq. NaHCO3. The combined organics were dried, filtered and evaporated to give the subtitle compound as a brown oil, 9.60 g.