Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].Br[C:16]1[CH:21]=[C:20]([CH:22]=[CH:23][C:24]2[S:25][CH:26]=[C:27]3[O:32][CH2:31][CH2:30][O:29][C:28]=23)[CH:19]=[CH:18][N:17]=1>C1(C)C=CC=CC=1.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>[CH2:30]1[CH2:31][O:32][C:27]2[C:28](=[C:24]([CH:23]=[CH:22][C:20]3[CH:21]=[CH:16][N:17]=[C:18]([C:3]4[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][N:12]=4)[CH:19]=3)[S:25][CH:26]=2)[O:29]1
Reactant: COC(=O)c1ccnc([Sn](C)(C)C)c1
Reactant: Brc1cc(C=Cc2scc3c2OCCO3)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2cc(C=Cc3scc4c3OCCO4)ccn2)c1
Yield: 53.4 %

Procedure:
A solution of (12) (95 mg, 0.32 mmol) in toluene (5 mL) was added to a solution of (10) (105 mg, 0.32 mmol) in the same solvent (5 mL). Tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) was added and the resulting mixture was refluxed for 20 min. A brown precipitate was obtained which was collected upon filtration, extensively washed with toluene, and dried under vacuum, yielding the product (8) (65 mg, 53%) which was directly used without further purification in the next step. 1H NMR (500 MHz, CDCl3) δ 8.98 (s, 1H), 8.88 (d, J=4.9 Hz, 1H), 8.65 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 7.90 (d, J=4.2 Hz, 1H), 7.48 (d, J=16.1 Hz, 1H), 7.37 (d, J=4.4 Hz, 1H), 6.93 (d, J=16.2 Hz, 1H), 6.35 (s, 1H), 4.36-4.34 (m, 2H), 4.28-4.26 (m, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.C[O:23][C:24](=[O:31])[CH2:25][CH2:26][CH:27](N)[CH2:28][CH3:29].C[N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.[NH2:33][CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:24]([OH:23])=[O:31]
Reactant: CCC(N)CCC(=O)OC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Coumarin 343 (5 mmol, Aldrich No. 393029) and each 5.5 mmol of 4-aminohexanoic acid methyl ester and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) as well as 11 mmol triethylamine were dissolved in 100 ml DMF and stirred for 1.5 h at room temperature. The solvent is removed by evaporation on a rotary evaporator and the residuum is dissolved in trichloromethane. Residual HBTU is removed by extraction with water with 0.5 mol/l hydrochloric acid. The organic solvent is separated and evaporated to dryness in a rotary evaporator. The crude product (2.37 g) is purified by flash chromatography (silica gel 60, Merck, No: 11452134001) with a mobile phase consisting of trichloromethane:ethyl acetate 2:1 (v/v) (yield: 1.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:44]([NH2:47])[CH2:45][NH2:46]>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:46][CH2:45][CH2:44][NH2:47])=[O:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCNC(=O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
80 mg (0.24 mmol) of N-[3-chloro-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 70.8 mg (0.36 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 42 mg (0.36 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethylformamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° within a period of 30 minutes to a solution of 0.77 ml (11.8 mmol) of ethylenediamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with 30 ml of water. The organic phase is dried (sodium sulfate) and concentrated. Crystallisation from isopropanol/ethanolic hydrochloric acid gives N-[3-chloro-phenyl]-4-[2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine hydrochloride; m.p. 161°-163°, FAB-MS: 369 (M+ +H).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[C:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)=[O:18])=[O:14])[CH2:9][CH2:10]1)(=[O:4])[CH3:3]
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CC(=O)N1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 31.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-acetylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 230, (S)-2-(2-(4-acetylpiperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (13.4 mg, 31.3%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 8.03 (d, 1H), 7.99 (s, 1H), 7.61 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.00 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.73 (m, 2H), 3.34 (m, 4H), 3.06 (s, 2H), 2.41 (m, 4H). MS (EI) for C29H31FN4O5: 535.4 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[O:11][CH:8]1[CH2:9][CH3:10]>O>[OH:11][CH:8]([CH2:9][CH3:10])[CH2:7][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: CCC1CO1
Solvent: O
Product: CCC(O)CNC(C)(C)CO
Yield: 82 %

Procedure:
In this example, 1780 g (20 mol) of 2-amino-2-methyl-1-propanol and 10 g water were added to a 5-liter three-necked flask equipped with a thermometer, condenser, magnetic stirrer, dropping funnel, and nitrogen inlet. 1,2-butylene oxide (1584 g, 22 mol) was added into the flask slowly at 90° C.-100° C. with stirring and under a nitrogen atmosphere. The resulting crude product was N-(2'-hydroxybutyl)-2-amino-2-methyl-1-propanol (82% yield with 90% alkanolamine conversion as determined by GLC).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[O:18]C)[C:5]([NH2:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.[NH4+].[Cl-]>ClCCl>[NH2:20][C:5]1[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[OH:18])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CCCc1ccc(Oc2nc(Cl)ccc2N)c(OC)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCc1ccc(Oc2nc(Cl)ccc2N)c(O)c1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
To a solution of 6-chloro-2-(2-methoxy-4-propyl phenoxy)pyridin-3-amine (0.1 mmol; 30 mg) under argon, in dichloromethane (2 mL), cooled to −78° C., was added BBr3 (0.5 mmol; 0.5 mL) dropwise. The reaction mixture was allowed to stir for 5 hr, with gradual warming to −20° C. At −20° C., the reaction was hydrolysed with saturated NH4Cl (4 mL), extracted with dichoromethane (3*10 mL). Combined organic phases dried over Na2SO4, concentrated in vacuo, to give the desired product as a light brown solid without further purification (27 mg; 0.1 mmol; 97%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@@H:5]([NH:14]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)#[N:2].Cl>C(Cl)Cl.O1CCOCC1.CCOCC>[ClH:12].[NH2:14][C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:4][CH2:3][C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCC[C@@H](N)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 104.6 %

Procedure:
To a stirred solution of 368 (534 mg, 1.62 mmol) in DCM (5 mL) was added 4M HCl (811 μL, 3.24 mmol) in dioxane and stirring was continued for 12 h. The mixture was diluted with ether, filtered and dried to afford 225 mgs (52%) of (R)-4-amino-4-(3,4-dichlorophenyl)butanenitrile hydrochloride (370) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]>[Pd].C(O)C>[NH2:14][C:13]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(=O)N(C)C)ccc1N
Yield: 37.4 %

Procedure:
A mixture of 3-methoxy-N,N-dimethyl-4-nitro-benzamide (185 mg) and palladium on carbon (10%, 20 mg) in ethanol (6 mL) was stirred under hydrogen atmosphere (balloon pressure), at room temperature, overnight. The reaction mixture was filtered on a CELITE™ pad and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 98/2) to afford 60 mg of 4-amino-3-methoxy-N,N-dimethyl-benzamide.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:17]([CH2:19][NH2:20])[OH:18].[C:21]([O-:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>[Pd].C(O)C>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:17]([CH2:19][NH2:20])[OH:18].[C:21]([O-:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCC(=O)[O-]
Solvent: NCCO
Solvent: CCO
Product: C[C@H](N)C(=O)O

Procedure:
Alanine-Ethanolamine-palmitate (AEP) was prepared by hydrogenation of Z-Ala-Ethanolamine-palmitate in a Parr hydrogenator in the presence of palladium on charcoal (10%) in ethanol. The removal of the benzyloxycarbonyl group was monitored by HPLC (System B). After removing the catalyst by filtration and evaporation of the solvent the title compound was obtained in quantitative yield.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:8][CH2:7]1.[OH-].[Na+].CN([CH:19]=[O:20])C>>[CH:6]1([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:19]=[O:20])[CH2:8][CH2:7]1
Reactant: c1ccn(C2CC2)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
POCl3 (44.5 ml) was added to a stirred solution of 1-cyclopropyl-1H-pyrrole (46.5 g) in DMF (37 ml) at 0° C., then the mixture was stirred at room temperature overnight. The mixture was poured into aqueous 5N NaOH (336 ml) at 0° C., and the mixture was made basic with an additional aqueous 5N NaOH. The mixture was extracted with CH2Cl2 and the organic extract was dried over Na2SO4, concentrated, and the residue was purified on silicagel column chromatography (hexane/EtOAc) to give intended compound as colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCN(CC)CC>C(O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)O
Temperature: 90 °C
Reaction time: 24 h

Procedure:
The Merrifield resin (2.1 g) was suspended in 30 ml of ethanol. A solution of 0.70 g (2.71 mM) of Boc-Leu and 0.9 equivalent of Et3N (2.43 mM, 0.34 ml) in 3 ml of ethanol was added to the resin suspension. The mixture was stirred slowly at 90° C. under anhydrous conditions for 24 hours using a magnetic stirrer. The esterified resin was washed successively with EtOH, H2O, MeOH and CH2Cl2 ; floated 3 times with CH2Cl2 to get rid of fine resin particles; and dried in vacuo over P2O5. Amino acid analysis gave a value of 0.25 mM of Leu/g of substituted resin.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:4]([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:4]([C:7](=[N:24][OH:25])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: NO
Reactant: Cc1ccccc1-n1c(C)nnc1C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-n1c(C)nnc1C(Cc1ccccc1)=NO

Procedure:
To a suspension of 10D and hydroxylamine hydrochloride (420 mg, 6 mmol) in ethanol (5 mL), sodium hydroxide (480 mg, 12 mmol) was added. It was refluxed for two hours. The reaction was acidified with 1 N hydrochloride and extracted with ethyl acetate (50 mL twice). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash column) to provide the desired product. MS (m/z) 307 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:7]([O:14][CH3:13])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (1.29 g, 6.23 mmol) and dry MeOH (2 mL), a 25 wt % solution of sodium methoxide in MeOH (10 mL) was added and the mixture stirred for 6 h at 100° C. in a sealed tube. The mixture was cooled to 23° C., poured into water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (25 mL), dried, filtered, and concentrated under reduced pressure to afford the titled compound (0.700 g, 56%). The crude material was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(=O)(=O)(O)O>C(O)CCC>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]([C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:11][CH3:12])[CH2:1][CH3:2])=[CH:5][C:6]=2[CH3:10])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH3:10])[CH:5]=1)[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)c1cccc(C)c1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCN(CC)c1ccc(C(c2ccccc2)c2ccc(N(CC)CC)cc2C)c(C)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
Into a 100 milliliter round bottom flask fitted with a mechanical stirrer and a dropping funnel is placed 8.85 grams (0.05 moles) of N,N-diethyl-m-toluidine and 3.0 grams (0.03 moles) of benzaldehyde and 10 milliliters of n-butanol containing 0.75 grams of concentrated sulfuric acid. The flask is flushed with nitrogen to remove air and refluxed for 18 hours with a nitrogen atmosphere. The material is then cooled to room temperature. A sufficient amount of sodium bicarbonate is added in order to neutralize the acid. 10 milliliters of methanol is added whereby a yellowish white precipitation is formed. The yellowish white material is filtered out. The material may then be washed with cold methanol in order to remove the yellow color. The material may be recrystallized from either methanol or ethanol. In order to further purify the material, it may be put through a neutral alumina column. The material is eluted with benzene. The first material to be fractionated off of the column is a clear liquid. This liquid is placed in a rotary evaporator and the solvent is removed. The residue is either a clear liquid or a white solid. The material may be recrystallized using methanol or ethanol. White crystals are obtained. A 70 percent yield based upon the benzaldehyde is obtained. The product is vacuum dried in order to remove the remaining solvent.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].FC(F)(F)S(O[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1[CH3:28])(=O)=O>CN(C=O)C.O>[CH3:24][C:23]1[CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=[C:19]([CH3:28])[C:18]=1[N:6]1[CH:7]=[C:3]([C:2]([F:9])([F:8])[F:1])[N:4]=[CH:5]1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a 0° C. solution of 2,6-dimethyl-4-nitrophenol (3 g, 17.9 mmol) and pyridine (4.25 g, 53.7 mmol) in dichloromethane (30 mL) was slowly added triflic anhydride (7.6 g, 26.8 mmol). The solution was stirred at room temperature for 2 h. The mixture was concentrated poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude 2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.5 g) as a yellow solid. To a 0° C. solution of 4-(trifluoromethyl)-1H-imidazole (1.82 g, 13.4 mmol) in DMF (20 mL) was added sodium hydride (0.81 g, 20.1 mmol). The mixture was stirred at room temperature for 1 h. The crude 2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate prepared above (4.0 g, 13.4 mmol) was added. The mixture was stirred at 80° C. for 12 h. The reaction was diluted with water and extracted with ethyl acetate (30 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 1-(2,6-dimethyl-4-nitrophenyl)-4-(trifluoromethyl)-1H-imidazole (805 mg, 21%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 2H), 7.47 (s, 1H), 7.23 (s, 1H), 2.11 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][CH2:21][CH2:20][C:19]4=[O:23])=[C:14]([F:24])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl[C:26]1[CH:27]=[CH:28][N:29]=[C:30]2[C:35]=1[N:34]=[CH:33][C:32]([O:36][CH3:37])=[CH:31]2.CC(O)CC>>[F:24][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([CH2:2][NH:1][C:26]4[C:35]5[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][N:34]=5)[N:29]=[CH:28][CH:27]=4)=[N:4][N:5]=3)[N:8]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23]
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Solvent: CCC(C)O
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(N6CCCC6=O)c(F)c5)nn34)ccnc2c1
Reaction time: 4 h

Procedure:
A 0.5-2 mL microwave vial was charged with 1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one (0.0792 g, 0.243 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (0.0590 g, 0.303 mmol), and butan-2-ol (1.00 ml, 0.243 mmol), sealed, then placed in a Personal Chemistry Microwave for 4 hours at 120° C. The mixture was concentrated, then triturated with MeOH to give 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one as the hydrochloric salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CCOC(C)=O.O>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH:11]=[O:12])=[CH:6]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
To a suspension of 5-chloro-1H-indole-3-carbaldehyde [827-01-0] (500 mg, 2.78 mmol) and K2CO3 (885 mg, 6.40 mmol) in (14 mL) was added tert-butyl 2-bromoacetate (0.576 mL, 3.90 mmol) dropwise at RT. The resulting mixture was then heated to reflux for 18 h. After cooling to RT, the mixture was diluted with EtOAc and water. The organic layer was separated, subsequently washed with water (1×) and brine (1×), dried (Phase separator) and concentrated in vacuo to give the crude title compound. MS (LC/MS): 294 [M+H]+; tR (HPLC conditions b): 5.45 min. The product was used in the next reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]2[C:20](OCC)=[O:21])=[O:7])=[CH:4][CH:3]=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:20](=[O:21])[C:9]3[C:8]=2[C:12](=[O:13])[NH:11][C:10]=3[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)NC(=O)C1C(=O)c1ccc(Br)cc1
Solvent: CO
Product: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc(Br)cc3)=C12
Temperature: 250 °C
Yield: 94.7 %

Procedure:
The p-bromobenzoylpyrrolinone ester 5 (154 mg, 0.37 mmol) was irradiated with microwave radiation (at a frequency of 2 to 45 GHz, and a forward power of 300 Watts) without solvent, heating to 250° C. for 10 minutes. The crude product was then allowed to cool, methanol was added and the solid filtered off and washed with methanol. This gave the furopyrrole 6 as a red solid (129 mg, 94%). M.p. 295° C. (subl., decomp.); δH (DMSO d6) 11.88 (1H, s, NH), 8.13-8.17 (2H, m, Ar—H), 7.98 and 7.66 (2×2H, AA′BB′, J 8.7, C6H4) and 7.43-7.47 (3H, m, Ar—H); m/z 370 (M+1 81Br, 94%) and 368 (M+1 79Br, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][CH:55]4[CH:54]3[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][CH:55]4[CH:54]3[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 50.4 %

Procedure:
A solution of 0.174 g of ethyl 2-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]hexahydro-pyrrolo[1,2-b]isoxazole-3-carboxylate in 2.0 ml of ethanol and 1.0 ml of chloroform containing 2.0 ml of 3M HC1 in ethyl acetate is stirred at room temperature for 1 hour. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 9:1 chloroform-methanol to give 0.063 g of the desired product as a solid. FAB Mass spec 620 (M+H).