Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:38]([Si:42]([CH3:45])([CH3:44])Cl)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([O:25][Si:42]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:45])[CH3:44])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccccc1C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccccc1C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 500 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2-methoxyphenyl)methyl]hexanoic acid in 5 ml of DMF is treated, while being stirred, with 614 mg of imidazole and 796 mg of tert-butyldimethylchlorosilane. After it has been stirred at RT for 20 h, the reaction solution is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with 10% citric acid solution and saline. The silyl ester group in the crude product is detached, at RT in 2 h, in a mixture consisting of 13.29 ml of methanol, 5.13 ml of THF, 5.13 ml of water and 904 mg of potassium carbonate. The mixture is concentrated down to half its volume on a RE at approximately 30° C., and the residue is diluted with ethyl acetate, and the organic phase is washed with 10% citric acid and saline (all being cold). The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the residue is chromatographed on silica gel (eluent, hexane:ethyl acetate, 3:1 and 1:1), and the title compound is obtained. TLC Rf (hexane/ethyl acetate 2.5:1)=0.12. FAB-MS (M+H)+ =558.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[CH:33][N:32]=[CH:31]1.CN1C(CO)=CN=C1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: Cn1cncc1COS(C)(=O)=O
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Agent: Cn1cncc1CO
Product: Cn1cncc1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 3-methyl-3H-imidazol-4-ylmethyl ester (prepared by mesylation of the commercially available (3-methyl-3H-imidazol-4-yl)-methanol) gave the title compound. ES-MS m/e (%): 493.1 (M+H+).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:6][C@H:5]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([C@@H:3]1[CH2:6][C@H:5]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])[CH2:4]1)#[N:2]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](C#N)C1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](C#N)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-cyano-cyclobutyl)-ethyl]-amide (34 mg, 0.06 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then concentrated directly purified via silica gel chromatography with 50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc to afford 15 mg (58%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-cyanocyclobutyl)-ethyl]-amide as a white solid. MS: (M+H)+=418; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.86 (br. s., 1H), 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (dd, J=9.1, 5.3 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.8, 1.9 Hz, 1H), 7.25 (td, J=9.0, 2.1 Hz, 1H), 4.17-4.28 (m, 1H), 4.14 (s, 3H), 3.20 (t, J=8.7 Hz, 1H), 2.30-2.46 (m, 3H), 2.04-2.20 (m, 2H), 1.18 (d, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1)[CH3:20])[CH2:18][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](n1cccn1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](n1cccn1)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
In dimethylformamide (2 ml) was dispersed 60% sodium hydride in oil (52 mg). Imidazole (89 mg) was added to the dispersion under ice-cooling and the mixture was stirred for 15 minutes at room temperature. To the mixture was added a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-pyrazol-1-yl)ethyl]oxirane (166 mg) in dimethylformamide (1 ml). The mixture was heated for 5 hours at 50° C. and cooled. To the reaction mixture were added cold water (5 ml) and ethyl acetate (30 ml). The separated aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure. The residue was allowed to stand to crystallize. The obtained crystals were recrystallized from ethyl acetate-hexane to form the title compound (Compound 1, 193 mg) as colorless prisms.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][C:6]1=[O:15])[CH3:3].FC(F)(F)[CH:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.CN(C(Cl)[Cl:31])C>C(#N)C>[ClH:31].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:12])[F:13])[CH2:7][C:6]1([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)[OH:15])[CH3:1]
Reactant: O=C1CCCC(C(F)(F)F)C1
Reactant: CN(C)C(Cl)Cl
Reactant: CN(C)CC1CCC(C(F)(F)F)CC1=O
Solvent: CC#N
Product: CN(C)CC1CCC(C(F)(F)F)CC1(O)c1cccc(O)c1
Product: Cl

Procedure:
The 5-epimer (27) of compound (25) was prepared, under the conditions given in Example 27, from (2RS,5RS)-2-dimethylaminomethyl-5-trifluoromethyl-cyclohexanone, prepared from 3-trifluoromethyl-cyclohexanone and dimethylaminomethylene chloride in acetonitrile. (27) was obtained in a yield of 27% theoretical and had a melting point of 221°-223° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:10].Cl.Cl.[CH3:35][O:36][C:37](=[O:45])[CH:38]([NH2:44])[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].C(N(CC)CC)C>ClCCl>[CH3:35][O:36][C:37](=[O:45])[C@@H:38]([NH:44][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:10])[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Reactant: COC(=O)C(N)CCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (32.0 g, 72.2 mmol) and 2-amino-4-dimethylaminobutyric acid methyl ester dihydrochloride (19.35 g, 83.0 mmol) in dichloromethane was added triethylamine (35 mL, 253 mmol) and the mixture stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (400 mL). The solution was washed with saturated NH4Cl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organics were dried over MgSO4 and concentrated under reduced pressure to afford the crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH:7]=[C:8]1O[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-])=O.[OH2:26].O.[Sn](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(O)C.C(OCC)(=O)C>[C:8]1(=[CH:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:25]=[CH:24][CH:23]=2)[C:9]2[C:22]([O:26][CH2:13][C:15]3[CH:16]=[CH:17][CH:18]=[CH:12][C:11]=3[CH:10]=2)=[CH:21][CH:20]=[CH:19]1
Reactant: O
Reactant: O=[N+]([O-])c1cccc(C=C2Oc3ccccc3Cc3ccccc32)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(C=c2cccc3c2=Cc2ccccc2CO3)c1
Yield: 33 %

Procedure:
Dissolve 11-(3-Nitro-benzylidene-6,11-dihydro-dibenzo[b,e]oxepine (200 mg) in ethanol (10 mL) add tin chloride dihydrate (680 mg) and reflux for 5 h. Concentrate the reaction in vacuo, re-dissolve in ethyl acetate and wash with 1N sodium hydroxide solution. Separate the layers wash with brine and dry over sodium sulfate. Purity using filter chromatography eluting with 10% ethyl acetate:toluene to give 60 mg of product (56% yield).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)=O)=CC=1.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:26]2.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH3:19][CH2:18][O:17][C:15]([CH2:14][O:13][CH2:12][CH2:11][N:26]1[C:27]2[C:23](=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[C:25]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:16]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: CCOC(=O)COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCn1c(C(=O)OCC)cc2c(C)cccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 45.4 %

Procedure:
A solution of ethyl [2-(toluene-4-sulfonyloxy)ethoxy]acetate (3.90 g, 12.9 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a mixture of ethyl 4-methyl-1H-indole-2-carboxylate (2.50 g, 12.3 mmol), 60% sodium hydride (0.50 g, 12.5 mmol) and N,N-dimethylformamide (45 ml) at room temperature, and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into a 10% aqueous sodium chloride solution and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=2:98) to obtain 1.86 g of ethyl 1-[(2-ethoxycarbonylmethoxy)ethyl]-4-methyl-1H-indole-2-carboxylate as a colorless oil.
Reaction SMILES: [Li]CCCC.[C:6]([C:9](=[C:14]([NH2:19])[C:15]([F:18])([F:17])[F:16])[C:10]([O:12][CH3:13])=[O:11])(=[O:8])[CH3:7].[F:20][C:21]([F:28])([F:27])[C:22](OCC)=O.O>CCCCCC.C1COCC1>[F:16][C:15]([F:17])([F:18])[C:14]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:6]([OH:8])[CH:7]=[C:22]([C:21]([F:28])([F:27])[F:20])[N:19]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a flame dried 3-liter, four-necked flask equipped with nitrogen inlet, low temperature thermometer, 500 ml addition funnel and mechanical stirrer is charged 147 ml (1.05 ml) of diisopropylamine and 600 ml of dry tetrahydrofuran. The resulting solution is cooled to -78° C. using an acetone-dry ice bath. To this is slowly added 618 ml (1.05 mol) of 1.7M n-BuLi in hexane at such a rate that the reaction temperature was kept below -60° C. After stirring at -78° C. for 1 hour, a solution of 106 g (0.50 mol) of methyl 2-acetyl-3-amino-4,4,4-tri-fluoro-2-butenoate from Example 2 in 400 ml of dry THF was added in such a rate that the reaction temperature was kept below -60° C. The reaction mixture turned yellow and a solid suspension formed. After 1 hour of stirring at -78° C., the reaction mixture was treated with 59.5 ml (0.50 mol) of ethyl trifluoroacetate in such rate that the reaction temperature was kept below -60° C. This reaction mixture was left at -78° C. for 1 hour, then warmed to room temperature (the yellow suspension disappeared and a yellow solution was formed) and stirred for 2 hours. The resulting solution was poured into 1 L of H2O and extracted with ether (3×700 ml). The combined ether layers were washed with H2O (2×800 ml) and the combined aqueous layers were acidified with concentrated HCl (pH~2). The acidified aqueous layer was extracted with CHCl3 (3×1000 ml), dried (MgSO4) and reduced in vacuo affording 120.85 g of a yellow solid. The crude was recrystallized from ether/hexane to give 103.28 g (71%) of pyridine product; mp 62°-75° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[OH:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH2:31][OH:30])=[CH:41][CH:40]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(OCCO)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(OCCO)cc4)nc23)CC1)Nc1nccs1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.060 g, 0.15 mmol, 1 eq), EtOH (2.6 mL) and DMF (0.35 mL), 4-(2-hydroxyethoxy)benzaldehyde (0.028 g, 0.17 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a off-white solid (0.021 g, 27%); 1H-NMR (500 Mz, DMSO-d6): 2.74-2.81 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2), 3.69-3.79 (m, 6H, piperazine N(CH2)2 and OCH2), 4.07 (t, J=5.0 Hz, 2H, OCH2), 4.88 (t, J=5.5 Hz, 1H, OH), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.23 (d, J=3.5 Hz, 1H) and 7.49 (d, J=3.5 Hz, 1H) (thiazole H-4, H-5), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.12 (d, J=9.0 Hz, 2H, ArH, C6H4); LC (Method B)-MS (ESI, m/z) 3.69 min—514/516 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:34]=[CH:33][C:32]([N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:40][CH:39]=2)=[CH:24][C:6]=1[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (10 mg, 0.029 mmol) and 4-morpholinobenzoic acid (7 mg, 0.035 mmol) similar to Example 136 and isolated as a white solid (4 mg, 26%). 1H NMR (CDCl3): 8.76 (dd, J=1.8, 4.2 Hz, 2H), 8.29 (dd, J=1.8, 4.2 Hz, 2H), 7.99 (s, 1H), 7.95 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.37 (dd, J=1.8, 8.1 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.89–3.86 (m, 4H), 3.31–3.28 (m, 4H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:25]1([NH:31][N:32]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=2)[C:3]2[CH:21]=[CH:22][CH:23]=[N:24][C:2]=2[Cl:1])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=NNc2ccccc2)c2cccnc2Cl)cc(C(C)(C)C)c1O

Procedure:
A solution of 7 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol and 2.4 g of phenylhydrazine in 40 ml of pyridine is refluxed for 7 hours. After the pyridine is distilled off under reduced pressure, to the residue is added water and the precipitated crystals are washed with water to give crude crystals of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol phenylhydrazone, melting at 181° C. with decomposition in an almost quantitative amount.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH2:23][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH3:25])[N:19]3[N:32]=[CH:33][C:34]([CH:35]=O)=[C:18]3[N:17]=2)[CH:14]=1.N1CCCCC1>C(O)C.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH2:23][CH:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH3:25])[N:19]3[N:32]=[CH:33][C:34]([CH:35]=[C:7]4[NH:1][C:2](=[O:3])[NH:4][C:5]4=[O:6])=[C:18]3[N:17]=2)[CH:14]=1
Reactant: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2c(C=O)cnn12)N1CCOCC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2c(C=C3NC(=O)NC3=O)cnn12)N1CCOCC1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
Hydantoin (7 mg, 0.07 mmol) and 5-(5-chloro-2-fluorophenylamino)-7-(2-morpholinopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (15 mg, 0.035 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (7 uL, 0.07 mmol). The reaction was heated at 80° C. for 1 hour in the microwave. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 5-((5-(5-chloro-2-fluorophenylamino)-7-(2-morpholinopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (5 mg, 28% yield). LCMS (M+1=515)
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[CH2:25]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N(C(=O)c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.006M) in DMF (25 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.3 g, 0.007M). The mixture was stirred at room temperature for 0.5 hours, and then benzyl bromide (1.2 g, 0.007M) was added dropwise. The reaction mixture was warmed to 60° C. and allowed to stir for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-benzyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH2:1])[CH:3]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Cc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1N

Procedure:
Synthesized using 3-amino-4-methylphenylboronic acid (190 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 139 mg, 0.52 mmol, 84%. 1H NMR (500 MHz, CDCl3): δH (ppm): 2.22 (s, 3H), 5.16 (s, 2H), 6.92 (t, J=0.9 Hz, 1H), 7.12 (t, J=0.9 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.26 (dd, J=7.9, 1.9 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.45 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.67 (dd, J=8.2, 0.6 Hz, 1H), 8.55 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=17.2, 48.2, 113.2, 117.1, 119.0, 120.4, 123.9, 129.6, 130.2, 130.9, 135.6, 137.3, 137.4, 145.1, 148.4, 157.8; MS (ESI): m/z=264.25 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Br:35][C:36]1[CH:41]=[C:40](F)[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][C:37]=1[F:46]>CS(C)=O.CCOC(C)=O>[Br:35][C:36]1[C:37]([F:46])=[CH:38][C:39]([N+:43]([O-:45])=[O:44])=[C:40]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:41]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (12.8 g, 80 mmol) and 18-crown-6 (4.21 g, 15.94 mmol) in DMSO (100 ml) at 0° C. was added potassium tert-butoxide (1.0 M solution in THF) (80 ml, 80 mmol) and the reaction mixture was stirred at RT for 30 minutes. Next, 1-bromo-2,5-difluoro-4-nitrobenzene (19.4 g, 80 mmol) was added dropwise (in solution of 60 mL DMSO) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was triturated with methanol to give 2-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (21.3 g, 56.3 mmol, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, 1H), 7.34-7.40 (m, 1H), 7.21-7.34 (m, 2H), 2.23 (d, 3H).