Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([C@H:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:22]1=[O:37])[C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18]C(=O)O[N:15]=2)=[CH:10][CH:9]=1)(=O)C.N.CO.Cl>CCOCC>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:6](=[O:20])[C@H:5]([OH:4])[C@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:22]2=[O:37])=[CH:9][CH:10]=1)(=[NH:15])[NH2:18]
Reactant: CC(=O)O[C@@H](C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOCC
Product: N=C(N)c1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(C(F)(F)F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 96-1 (110 mg) was treated with 7 M NH3/MeOH (1 mL) and the mixture was stirred at RT for 1 h. After removal of the volatile materials on the rotavap, the residue was dissolved in MeOH (1 mL) and 3M HCl (0.25 ml). The resulting suspension was treated with a balloon of H2 over 10% Pd/C (30 mg) and stirred at RT for 2 h. The resulting mixture was filtered through Celite® and concentrated. The residue was purified by reverse phase HPLC to give EXAMPLE 96 which was converted to the HCl salt (88 mg) by treating with one equivalent HCl in ether and concentration on a rotavap.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH:20][CH2:21][CH2:22][NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:12]2[N:13]([N:15]=[C:16]([CH2:18][OH:19])[CH:17]=2)[CH:14]=1.COCCOC.CN(C=O)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH:20][CH2:21][CH2:22][NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:12]2[N:13]([N:15]=[C:16]([CH:18]=[O:19])[CH:17]=2)[CH:14]=1
Reactant: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(CO)cc23)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: COCCOC
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(C=O)cc23)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g (2.64 mmol) of 6-[(2-{[6-(2,4-dichlorophenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]-pyrazin-4-yl}amino]ethyl)amino]pyridine-3-carbonitrile (Example 42) were suspended in 80 ml of dichloromethane (shaken with water beforehand). 80 ml of 1,2-dimethoxyethane and 40 ml of DMF were then added, and the mixture was cooled to 0° C. 2.46 g (5.81 mmol) of Dess-Martin periodinane were added, ice-bath cooling was removed and the mixture was stirred at RT for 2 h. Ethyl acetate was added, and the mixture was washed first with a 10% strength sodium thiosulfate solution and then with saturated aqueous sodium bicarbonate solution. Drying of the organic phase with sodium sulfate and removal of the solvent under reduced pressure gave 1.2 g (94% of theory) of the product as a solid which was reacted without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:6]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=3)[C:14]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CC(C)n1cc(Br)cn1
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-fluoro-benzoic acid ethyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To (S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid (721 mg, 1.69 mmol), tert-butyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylcarbamate (595 mg, 2.04 mmol), and N,N-diisopropylethylamine (0.9 mL, 5.2 mmol) in THF (20 mL), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (1.29 g, 3.40 mmol) was added in one portion. The reaction was stirred at ambient temperature for 16 hours. After this time, the reaction was dry loaded onto silica and purified by silica gel column chromatography eluting with hexanes to ethyl acetate to afford (S)-tert-butyl 1-(9H-fluoren-9-yl)-24,24-dimethyl-3,8,22-trioxo-2,12,15,18,23-pentaoxa-4,9,21-triazapentacosane-5-carboxylate (1.17 g, 99%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.62-7.59 (m, 2H), 7.44-7.38 (m, 2H), 7.36-7.26 (m, 2H), 6.78 (bs, 1H), 6.07 (bs, 2H), 5.77 (bs, 1H), 4.42-4.38 (m, 2H), 4.27-4.17 (m, 2H), 3.80-3.70 (m, 2H), 3.68-3.46 (m, 9H), 3.31-3.12 (m, 4H), 2.37-2.13 (m, 3H), 2.00-1.87 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H); ESI MS m/z=700 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:6])([NH2:5])[CH3:4].[Br:7][CH2:8][C:9](Br)=[O:10]>C(Cl)Cl>[OH:1][CH2:2][C:3]([NH:5][C:9](=[O:10])[CH2:8][Br:7])([CH3:6])[CH3:4]
Reactant: CC(C)(N)CO
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)CBr
Temperature: 0 °C

Procedure:
35.6 g (0.4 mol) of 1-hydroxy-2-methyl-2-aminopropane are dissolved in 100 ml of absolute methylene chloride, the solution is cooled to 0° C., and 40.4 g (0.2 mol) of bromoacetyl bromide, dissolved in 100 ml of methylene chloride, are added dropwise to this solution in the course of 3 hours 50 minutes, in the absence of moisture and while maintaining the temperature of 0° C. The mixture is allowed to react further for 2 hours at room temperature. The 1-hydroxy-2-methyl-2-aminopropane hydrobromide is filtered off under suction and washed with methylene chloride. The plate yellow oil obtained from the filtrate by evaporating off the solvent is chromatographed over silica gel, using ethylene chloride/isopropanol (95:5; 9:1; 4:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.CCOC(C)=O>[N:20]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)=[N+:21]=[N-:22]
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-Chloro-5,6-diphenylpyrazine (45 mg, 0.17 mmol) in 500 μL DMF at room temperature under nitrogen was added sodium azide (11 mg, 0.17 mmol) and the reaction was warmed to 100° C. After stirring overnight, the reaction was cooled to room temperature, diluted with EtOAc (30 mL) and washed 4×30 mL with H2O and 1×30 mL with saturated NaCl. The organics were isolated, dried (MgSO4), filtered and concentrated to the 2-azidopyrazine, which exists as a yellow solid (45 mg, quantitative). 1H-NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.58-7.42 (m, 6H), 7.36-7.23 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C(N(C(C)C)CC)(C)C.Cl[CH:20]([CH3:29])[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>C(Cl)Cl>[CH2:20]([C:21]1[N:1]=[C:2]2[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[N:4][N:3]2[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29]
Reactant: Cc1cc(C)c(N)nn1
Reactant: CCOC(=O)CC(=O)C(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CC)nc2c(C)cc(C)nn12
Temperature: 75 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a suspension of 0.598 g (4.86 mmol) of 3-amino-4,6-dimethylpyridazine in 10 mL of CH2Cl2 in a high pressure vessel was added 0.941 g (1.27 mL; 7.28 mmol) of diisopropylethylamine and 1.301 g (7.28 mmol) of ethyl a-chloropropionylacetate. The reaction mixture was equipped with a magnetic stir bar, tightly sealed, then heated and stirred in an oil bath at 75° C. for 16 hours. The flask was then cooled to room temperature, opened and the reaction mixture was evaporated in vacuo. The residue was partitioned between EtOAc and water, and the organic layer was separated. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The residual brown solid was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 0.874 g (73%) of the title compound.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:32][SiH:33]([CH3:39])[O:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>C1(C)C=CC=CC=1.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:32][Si:33]([CH3:39])([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:20]=2)=[O:13])=[CH:10][CH:9]=1)[O:34][Si:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: C=CCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCCCC)cc2)cc1
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OCCCCCC[Si](C)(C)O[Si](C)(C)C)cc2)cc1

Procedure:
0.94 g (0.024 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution (dichloromethane) was added to a solution of 20.0 g (47.2 mmol) of 4-octyloxyphenyl 4-(5-hexenyloxy)benzoate and 7.10 g (48.0 mmol) of pentamethyldisiloxane in 20.0 g of toluene, and the mixture was refluxed for 5 hours. After complete hydrosilylation of the olefin, the reaction mixture was flushed with nitrogen, and the toluene was removed by vacuum distillation on a rotary evaporator. The crude product was purified by chromatography on silica gel. The 4-octyloxyphenyl 4-(6-pentamethyldisiloxanylhexyloxy)benzoate obtained was additionally recrystallized from ethanol and exhibited the following phase behavior: c 38 s 50 i.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3Br)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1.C[Sn](C)(C)[Sn](C)(C)C>O1CCOCC1.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Brc1ncoc1-c1ccc2c(c1)OCO2
Reactant: Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: C1COCCO1
Product: Cc1cccc(-c2ncoc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A solution of 5-benzo[1,3]dioxol-5-yl-4-bromo-oxazole (156 mg, 0.58 mmol), 2-bromo-6-methyl-pyridine (100 mg, 0.58 mmol, 1 equiv), 1,1,1,2,2,2-hexamethyl-distannane (190 mg, 0.58 mmol, 1 equiv) and tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol, 0.1 equiv) in 1,4-dioxane (6 mL) was heated to reflux overnight. The resulting reaction mixture was cooled to ambient temperature and concentrated in vacuo. Silica gel chromatography (gradient from hexane to 30% ethyl acetate in hexane) provided 2-(5-Benzo[1,3]dioxol-5-yl-oxazol4-yl)-6-methyl-pyridine (114 mg, 70%).[LCMS: Rt=1.79 min, M+H=281.2]
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:16](=[O:18])[NH:26][CH2:25][CH2:24][C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: NCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of N-Boc-L-phenylglycine (H, 17.2 g, 68.5 mmol) and (4-fluorobenzyl)methylamine (10.47 g, 75.3 mmol) in CH2Cl2 (550 mL) was cooled to 0° C. Disopropylethylamine (35.8 mL, 205 mmol) and PyBroP (38.3 g, 82.1 mmol) were then added sequentially. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the title compound (24.5 g, 96%) was isolated by chromatography on silica gel eluting with a gradient of 40% to 60% ethyl acetate in hexane. 1H NMR (selected signals, CDCl3): □6.02 (d, 0.3H), 5.56 (d, 0.7H), 2.83 (s, 0.9H), 2.78 (s, 2.1H), 1.40 (s, 6.3H, 1.39 (s, 2.7H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=1.Cl[CH2:32][CH2:33][CH2:34]/[C:35](=[CH:40]\[C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]2)=[C:43]([O:53][CH3:54])[CH:42]=1)/[C:36]([NH:38][NH2:39])=[O:37].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(Cl)CCl>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]([NH:39][N:38]2[CH2:32][CH2:33][CH2:34]/[C:35](=[CH:40]\[C:41]3[CH:46]=[CH:45][C:44]([N:47]4[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]4)=[C:43]([O:53][CH3:54])[CH:42]=3)/[C:36]2=[O:37])=[O:30])=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NN)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(/C=C2\CCCN(NC(=O)Cc3ccc(Br)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.9 %

Procedure:
EDC (109 mg), HOBT (76.9 mg) and IPEA (408 μL) were added to a mixture of 4-bromophenylacetic acid (102 mg), 5-chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-pentanoic acid hydrazide (200 mg) and DMF (4 mL), and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was heated to 80° C. and stirred for two hours. The reaction solution was brought to room temperature. A saturated sodium bicarbonate solution was added, followed by separatory extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=8:1) to obtain the title compound (111 mg). The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[Cl:17]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([Cl:17])=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C=NNc1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Method A. A solution of [(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (33, 4.0 g, 18.0 mmol) in anhydrous THF (40 mL) was treated with N-chlorosuccinimide (NCS, 2.52 g, 18.9 mmol, 1.05 equiv) at 0-5° C. under N2, and the resulting reaction mixture was stirred at 0-5° C. for an additional 30 min before being gradually warmed to 25° C. for 12 h. When HPLC and TLC showed the reaction was deemed complete, the solvent was removed in vacuo. The residue was directly purified by column chromatography (SiO2, 0-25% EtOAc/hexane gradient elution) to afford the desired chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 3.51 g, 4.62 g theoretical, 76%) as pale-yellow solids, which was found to be essentially pure to do the following reaction without further purification. For 34, CIMS m/z 255/257 (M+−H, C11H13ClN2O3).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[F:24][C:25]([F:31])([F:30])[C:26]1([NH2:29])[CH2:28][CH2:27]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(#N)C.[OH2:43]>>[C:26]([OH:21])([C:25]([F:31])([F:30])[F:24])=[O:43].[CH3:22][C:3]1[C:2]([NH:29][C:26]2([C:25]([F:31])([F:30])[F:24])[CH2:28][CH2:27]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: NC1(C(F)(F)F)CC1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C(F)(F)F)CC1
Product: O=C(O)C(F)(F)F
Temperature: 120 °C
Yield: 0.1 %
Yield: 14 %

Procedure:
Prepared similarly to that described in Example 254 using 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 254c; 23 mg, 0.074 mmol), 1-(trifluoromethyl)cyclopropanamine hydrochloride (47.5 mg, 0.294 mmol, Astatech, Inc., Bristol, Pa.), Pd(tBu3P)2 (Strem, Newburyport, Mass.; 3.76 mg, 7.35 μmol), and K3PO4 (94 mg, 0.441 mmol), heating at 120° C. for 16 h. Purification by silica gel (100% DCM to 3% 2 M NH3 in MeOH/DCM) then by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(2-methyl-3-((1-(trifluoromethyl)cyclopropyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (14% yield). MS (ESI, pos. ion) m/z: 402.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.29-1.33 (m, 2H) 1.58-1.62 (m, 2H) 2.62 (s, 3H) 2.95 (t, J=6.85 Hz, 2H) 3.66 (td, J=6.85, 2.54 Hz, 2H) 5.31 (br. s., 1H) 5.45 (s, 1H) 7.17 (d, J=2.15 Hz, 1H) 7.48 (t, J=7.63, 1 H) 7.71 (dd, J=8.12, 1.27 Hz, 1H) 7.99 (dd, J=7.53, 1.27 Hz, 1H) 12.47 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −72.08 (3F, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
6.16 g (40 mM) of 2-amino-3-nitrophenol, 60 ml of dimethylformamide and 6.62 g (48 mM) of dipotassium carbonate are introduced into a round-bottomed flask. 4.75 ml (40 mM) of benzyl bromide are then added dropwise and the reaction mixture is brought to 80° C. After havingbeen stirred under an inert atmosphere for 1.5 hours, the mixture is pouredinto ice-cold water and then extracted with 200 ml of ethyl acetate. The organic phase is separated by settling and, after washing with a saturatedsodium chloride solution, it is dried over magnesium sulphate and evaporated to dryness. The product is chromatographed on a silica column (eluent: 10% ethyl acetate and 90% hexane) to lead to 8.8 g (90%) of the expected compound in the form of an orangey oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][S:15][C:13]1[O:14][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:11][N:12]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: CCOC(=O)CSc1nnc(-c2ccc3c(c2)CCO3)o1
Yield: 54 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and ethyl bromoacetate instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 54%) was obtained as colorless crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Sc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(OC)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(4-methoxyphenylthio)imidazole in 100 ml of dichloromethane. The solution is agitated for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 3.92 g of 4,5-bis(4-methoxyphenyl)-2-(4-methoxyphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]2[N:11]3[N:12]=[CH:13][CH:14]=[C:10]3[N:9]=[C:8]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:7]=2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl.CN([CH:32]=[O:33])C>>[CH:2]1([NH:5][C:6]2[N:11]3[N:12]=[CH:13][C:14]([CH:32]=[O:33])=[C:10]3[N:9]=[C:8]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:7]=2)[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile hydrochloride (205 mg, 0.62 mmol) was dissolved in anhydrous DMF (1 mL) and the solution was cooled to 0° C. by an external ice bath. POCl3 (115 μL, 1.25 mmol) was added dropwise keeping the internal temperature <5° C. After addition, the ice bath was removed. After 5 h, the solution was poured into H2O (20 mL) and the pH was adjusted to 11 by the addition of 6N NaOH. The solution was allowed to stir for 1 h, and the precipitate was filtered off. The crude product was triturated with EtOH (7 mL), filtered, and dried under high vacuum (1 mmHg) to provide 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (129 mg, 64%) as an orange solid. LCMS (ES): >90% pure, m/z 319 [M+1]+.