Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)C.Cl.[OH-].[Na+]>C1COCC1>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13]/[CH:12]=[CH:11]/[C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)=[CH:20][CH:19]=1
Reactant: CCOC(OCC)c1ccc(/C=C/COc2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(OC/C=C/c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 1-(diethoxymethyl)-4-[(E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzene (1.270 g) in THF (20 mL) was added 6 M HCl (4 mL) at room temperature. The mixture was stirred at room temperature for 0.5 hour. To the mixture was added 5 M NaOH (4 mL), and the mixture was evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 4-[(E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzaldehyde (0.942 g) as a colorless solid.
Reaction SMILES: [CH2:1](Br)C#C.C[CH:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:15].[CH3:1][NH:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCBr
Reactant: CC(N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCc1ccccc1

Procedure:
A solution of propargyl bromide (1.1 g, 9.1 mmol) in acetonitrile (8.5 ml) was added dropwise to a stirred mixture of 3-(N-Me, N-Et carbamyloxy)α-methyl phenethylamine.HCl (2.4 g, 8.8 mmol) and potassium carbonate (2.8 g) in acetonitrile (25 ml), and the mixture was stirred at RT for 7 hrs. The reaction mixture was filtered and the filtrate was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc 2:1) to give 1.76 g of the title compound as the free base (73%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>O1CCCC1.[Ni]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([Cl:1])[CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(O)c(Cl)c1

Procedure:
A solution of 86.8 g of 2-chloro-4-nitrophenol in 200 ml of tetrahydrofuran containing 2 g of Raney nickel catalyst was hydrogenated in a Parr shaker at 50 p.s.i. hydrogen pressure. The mixture was filtered and the solvent was evaporated from the filtrate. The residue was recrystallized from ether to give 4-amino-2-chlorophenol (1A), as a tan solid, mp: 144°-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:24][C@H:25]([C:30]([OH:32])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27].C(N(CC)CC)C.C(O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([NH:24][C@H:25]([C:30]([OH:32])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 24.5 %

Procedure:
The title compound is prepared by the procedure of Example 255 using 14.73 g of product from Example 254, 6.07 g of L-isoleucine, 12.73 ml of triethylamine and 556 ml of 4:1 ethyl alcohol:water to give 3.52 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][N:19]1[CH:23]=[C:22]([CH:24]2[CH2:26][O:25]2)[CH:21]=[N:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH:24]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[OH:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Cn1cc(C2CO2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cnn(C)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (160 mg, 0.8 mmol) in DMF (3 mL) was added NaH (60%, 96 mg, 2.4 mmol). After stirring for 5 min at RT, 1-methyl-4-(oxiran-2-yl)-1H-pyrazole (150 mg, 1.2 mmol) was added into the reaction mixture, which was stirred at RT for 26 h. The progress of reaction was monitored by TLC, NMR and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOH-Hex) to yield 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethanol. The product was further purified by chiral HPLC separation. 1H NMR (CDCl3, freebase) δ (ppm): 7.46 (s, 1H), 7.2 (s, 1H), 7.19 (s, 1H), 7.15 (d, 1H), 6.98 (d, 1H), 5.0 (t, 1H), 4.2 (d, 2H), 3.82 (s, 3H), 3.6 (s, 2H), 2.9 (m, 1H), 2.8 (m, 2H), 2.7 (m, 1H), 2.5 (s. 3H), 2.42 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[C:19](=O)[CH2:18][CH2:17][CH2:16]2>C(Cl)Cl>[N:5]1([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])[CH2:16][CH2:17][CH:18]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: O=C1CCCc2cccc(O)c21
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1cccc2c1C(n1ccnc1)=CCC2
Yield: 46.1 %

Procedure:
227 g (1.9 mols) of thionyl chloride are added dropwise to a mixture of 503 g (7.4 mols) of imidazole and 1.6 liter of methylene chloride at 5° C., while stirring. The mixture is subsequently stirred for 20 minutes and 157 g (0.97 mol) of 8-hydroxy-1-tetralone are then added. The reaction mixture is stirred for a further 2 hours and then filtered and the filtrate is poured into ice water. The organic phase is separated off and concentrated under reduced pressure. The residue is taken up in 1 liter of toluene and the solution formed is boiled under reflux for one hour. The mixture is concentrated again under reduced pressure and the residue which remains is dissolved in methylene chloride. The organic phase is washed with water and concentrated under reduced pressure. The residue is triturated with toluene, the product separating out as crystals. 95 g of 3,4-dihydro-1-(imidazol-1-yl)-8-hydroxynaphthalene of melting point 186° C. are obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH:33]1[C:42]2[N:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:36][CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][NH2:32].CCN(CC)CC>C(Cl)Cl.CN(C=O)C.C1COCC1>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH:33]1[C:42]2[N:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:36][CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][NH:32][C:4](=[O:6])[C:3]1[C:7]([Cl:11])=[CH:8][N:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1c(Cl)cncc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
To a mixture of 3,5-dichloro-isonicotinic acid (52 mg, 0.27 mmol) in CH2Cl2 (1.1 mL) cooled to 0° C. was added oxalyl chloride (70 μL, 0.81 mmoL) and DMF (1 drop) and the resulting mixture was stirred at 0° C. for 5 minutes and at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and dried in vacuo for 5 minutes. To the resulting beige solid in THF (3 mL) was added N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine from above (100 mg, 0.30 mmol) and Et3N (76 μL, 0.54 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc (40 mL) and washed consecutively with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL). The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) afforded COMPOUND 153 (55 mg, 40%) as a white foam. 1H NMR (CDCl3) δ 1.70-1.94 (m, 4H), 2.04-2.15 (m, 1H), 2.26-2.33 (m, 1H), 2.64-2.96 (m, 4H), 3.10-3.15 (m, 1H), 3.68 (d, 1H, J=15.6 Hz), 3.80 (d, 1H, J=15.6 Hz), 3.98-4.07 (m, 1H), 4.19-4.25 (m, 1H), 6.83 (dd, 1H, J=7.8, 4.8 Hz), 7.20-7.23 (m, 2H), 7.35-7.40 (m, 2H), 7.66-7.68 (m, 2H), 8.34 (s, 2H), 8.78 (br s, 1H); 13C NMR (CDCl3) δ 21.69, 21.92, 26.70, 29.38, 39.04,49.41, 49.87, 59.45, 111.10, 119.37, 122.63, 122.95, 129.27, 135.68, 138.29, 143.68, 146.10, 147.70, 154.94, 157.51. 162.27. ES-MS m/z 510 (M+H). Anal. Calcd. for C26H26N6Cl2O.0.3CH2Cl2.0.1H2O: C, 58.86; H, 5.03; N, 15.66; Cl, 17.17. Found: C, 59.22; H, 5.21; N, 15.74; Cl, 16.80.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:10](O)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OS(O)(=O)=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[CH:26]1[CH:27]=[CH:28][C:23]([C:10]([NH:5][C:4]([CH2:3][C@H:2]([NH2:1])[C:7]([OH:9])=[O:8])=[O:6])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:24][CH:25]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Bpoc-Asn(Trt)--OH: H-Asn(Trt)--OH was prepared according to the procedure of Sieber and Riniker (40) with the following modifications. H-Asn-OH (13.2 g, 0.1 mol), trityl alcohol (52 g, 0.2 mol), conc. H2SO4 (6.1 mL, 0.115 mol) were suspended in glacial acetic acid (300 mL) for 10 min. Acetic anhydride (9 mL, 0.2 mol) was added and the reaction was heated to 60° C. After 4 h the solution was slowly added to cold water (600 mL) and adjusted to pH 6 by addition of 10 N NaOH. After 1 h at 0° C., white crystals were collected and washed thoroughly with water and toluene. Drying under vacuum for 24 h yielded white crystals (36 g, 94%). mp>240 dec., lit. >240 dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2
Reactant: Fc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNc2c3ccc(Cl)cc3nc3ccc(F)cc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-fluoroacridine and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=373).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][O-:12].[Na+]>CN(C)C=O.CO.C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: N#Cc1c(N)cccc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(N)c1C#N

Procedure:
A solution of 70 g (0.5 mol) of 2-amino-6-fluorobenzonitrile (prepared, e.g. according to U.S. Pat. No. 4,504,660) in 250 ml of N,N-dimethylformamide was prepared, and a solution of 30.6 g (0.55 mol) of sodium methoxide in 70 ml of methanol was added dropwise at room temperature while stirring. The mixture was then refluxed for 5 hours with stirring. The completion of the reaction was monitored by TLC. An additional 25 g of sodium methoxide in 35 ml methanol were added and the reaction mixture was refluxed for an additional 4 hours while stirring. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with water, filtered off with suction and the solids obtained were dissolved in ethyl acetate. The resulting solution was concentrated in vacuo. The obtained residue was triturated with petroleum ether and filtered off with suction. Yield: 48 g (63% of theory) of a brownish solid having a melting point of 143-146° C.
Reaction SMILES: C(N(CC)C(=S)[O-])C.NN.O.[F:12][C:13]1[C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:18][C:17]=2[CH:16]=[C:15]([OH:27])[C:14]=1[F:28].I[CH:30]([CH3:32])[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+]>CCO.CCOC(C)=O.CCOCC.O.CN(C=O)C>[F:12][C:13]1[C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:18][C:17]=2[CH:16]=[C:15]([O:27][CH:30]([CH3:32])[CH3:31])[C:14]=1[F:28]
Reactant: CC(C)I
Reactant: Oc1cc2c(c(F)c1F)Sc1ccccc1O2
Agent: CCN(CC)C([O-])=S
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Oc1cc2c(c(F)c1F)Sc1ccccc1O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
A suspension of O-[1,2-difluoro)phenoxathiin-3yl] N,N-diethylthiocarbamate (200 mg, 0.54 mmol) (Example 16) and H2NNH2.H2O (2.64 mL, 54.4 mmol) in 20 mL absolute EtOH was refluxed for 2 h. After cooling, to room temperature the reaction was diluted with EtOAc (75 mL), washed with 10% aqueous HCl (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo to 130 mg of crude 1,2-difluoro-3-phenoxathiinol as a yellow-brown solid: TLC (EtOAc/hexane, 40:60) Rf =0.46; 1H-NMR (CDCI3) δ 6.53 (dd. J=6 Hz, J=2 Hz, 1 H, C4 -H), δ 6.97-7.15 (m, 4 H). A mixture of crude 1,2-difluoro-3-phenoxathiinol (110 mg, 0.44 mmol), 2-iodopropane (0.09 ml, 0.87 mmol), Cs2CO3 (0.28 g, 0.87 mmol) and 7 ml anhydrous DMF was stirred under nitrogen at 0° C. for 5 h. The reaction was diluted with Et2O (50 ml) and water (50 ml), the Et2O fraction washed with brine (50 ml), dried (Na2SO4), and concentrated in vacuo to 118 mg of an orange oil. Filtration of the crude product through 10 g of silica gel with 200 ml of EtOAc/hexane (5:95) gave 116 mg (91%) of 1,2-difluoro-3-isopropoxyphenoxathiin as a pale orange oil: TLC (EtOAc/hexane, 20:80) Rf =0.58; 1H-NMR (CDCI3) δ 1.36 (d, J=6 Hz, 6 H), δ 4.50 (m, J=6 Hz H), δ 6.50 (dd, J=Hz, J=2 Hz, 1 H, C4 -H), δ 6.96-7.15 (m, 4 H); 19F-NMR (CDCI3) C1 -F (d, J=21.4 Hz), C2 -F (dd, J=21.4 Hz, J=6 Hz). A solution of 1,2-difluoro-3-isopropoxyphenoxathiin (112 mg, 0.38 mmol) and 30% aqueous H2O2 (0.4 ml, 3.8 mmol) in 3 ml glacial AcOH was heated at 80° C. for 2.5 h. After cooling to room temperature the solution was concentrated in vacuo to a white solid. Refrigeration of the crude product in 4 ml of 1:1 EtOAc/hexane overnight afforded 79 mg (44% from O-[1,2-(difluoro)phenoxathiin-3-yl] N,N-diethylthio-carbamate) of the title compound as yellow crystals: mp 174-175° C. (EtOAc/hexane); 1H-NMR (DMSO-d6) δ 1.33 (d, J=6 Hz, 6 H), δ 4.94 (m, J=6 Hz, 1 H), δ 7.31 (dd, J=6 Hz, J=2 Hz, 1 H, C4 -H), δ 7.30-7.57 (m, 2 H), δ 8.04 (dt, J=7 Hz, J=1 Hz, 1H, C8 -H), δ 8.06 (dd, J=8 Hz, J=1 Hz, 1 H, C9 -H); 19F-NMR (DMSO-d6) C1 -F (dd, J=21.2 Hz, J=6 Hz); MS m/e (relative intensity) 327 (MH+, 100).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Solvent: CCO
Product: CCN(CC)c1ccc(C(C)=O)cc1S(N)(=O)=O

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (6.5 g), diethylamine (7.0 ml) and absolute ethanol (200 ml) was heated under reflux for 22 hours. The solution was concentrated to a gum under reduced pressure and partitioned between ethyl acetate (100 ml) and water (120 ml). The organic phase was separated and evaporated to dryness. Trituration of the residue with aqueous isopropanol gave the diethylamine compound as cream crystals, 5.9 g, m.p. 103°-105°.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][C@@H:40](O)[C@H:39]([F:43])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:38][C@H:39]([F:43])[C@H:40]([N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:41]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
3-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-(cis)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and (trans)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure J.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([C:16]4[N:26]=[C:19]5[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]5[N:17]=4)[CH:13]=[CH:12][N:11]3[CH:27]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Br-]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:28]1([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[CH:15]=[C:14]([C:16]5[N:26]=[C:19]6[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]6[N:17]=5)[CH:13]=[CH:12][N:11]4[CH:27]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:30][CH2:29]1
Reactant: OB(O)C1CC1
Reactant: Cc1ncc(C)n2nc(-c3ccn4cc(-c5cccc(Br)c5)nc4c3)nc12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc(C)n2nc(-c3ccn4cc(-c5cccc(C6CC6)c5)nc4c3)nc12
Temperature: 110 °C
Yield: 65.9 %

Procedure:
To a microwave vial was added 2-(2-(3-bromophenyl)imidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (37 mg, 0.088 mmol), cyclopropylboronic acid (22.74 mg, 0.265 mmol), TRICYCLOHEXYLPHOSPHINE (12.37 mg, 0.044 mmol), Toluene (1 mL), Water (0.3 mL) and potassium phosphate tribasic (74.9 mg, 0.353 mmol). The solution was purged with nitrogen for 5 min and then PALLADIUM(II) ACETATE (1.981 mg, 8.82 μmol) was added. The reaction vial was sealed and heated to 110° C. for 16 hours. The reaction turned black and was checked by LC/MS. The reaction was complete as indicated by no starting bromide being present. The reaction was cooled to rt and extracted with EtOAc 4×. The organic fractions were combined, dried over Na2SO4 and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 5% Acetone/95% Hexanes to 60% Acetone/40% Hexanes. The pure fractions were combined and evaporated in vacuo affording 2-(2-(3-cyclopropylphenyl)imidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (24 mg, 0.058 mmol, 66.1% yield) as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (br. s., 1H), 8.29 (d, J=4.5 Hz, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.78 (d, J=4.5 Hz, 1H), 7.38 (t, J=4.5 Hz, 1H), 7.10 (d, J=4.5 Hz, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 2.01 (m, 1H), 1.02 (m, 2H), 0.86 (m, 2H), LC/Mass spec. (Method 1) RT=1.89 min. Mass=381.2 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[N:15]=CC=N2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CC1C(N2N=CC=N2)=[C:19](C=CC=1)[C:20]#[N:21]>>[CH3:1][C:2]1[C:3]([N:11]2[CH:19]=[CH:20][N:21]=[N:15]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C#N)c1-n1nccn1
Reactant: Cc1cccc(C(=O)O)c1-n1nccn1
Product: Cc1cccc(C(=O)O)c1-n1ccnn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 37, substituting 3-methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile for 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile. 1H NMR (500 MHz, CDCl3): 8.17 (s, 1H), 7.94 (s, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.63-7.56 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1.[N:23]1([C@@H:29]([CH3:33])[C:30]([OH:32])=O)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.C(Cl)(Cl)Cl>N1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:30](=[O:32])[C@@H:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH3:33])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CNc1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Reactant: C[C@@H](C(=O)O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](C(=O)N(C)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1)N1CCOCC1
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution of N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylamine (45 mg, 0.15 mmol) in pyridine (1 ml) were added (S)-2-(morpholin-4-yl)propionic acid obtained in Reference Example 3 (110 mg, 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.55 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture were added chloroform and water, and the organic layer was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, the residue was dissolved in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml). To the solution was added 2 N aqueous sodium hydroxide solution (0.35 ml) at room temperature, and the mixture was stirred for 20 min. To the reaction mixture were added chloroform and water, and the organic layer was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (52 mg, yield 78%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9])#[CH:2].C(N(CC)C(C)C)(C)C.Br[C:20]1[C:21]2[N:22]([N:26]=[C:27]([Cl:29])[N:28]=2)[CH:23]=[CH:24][CH:25]=1.Cl>CN(C)C=O.[Cu]I>[Cl:29][C:27]1[N:28]=[C:21]2[C:20]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:9])=[CH:25][CH:24]=[CH:23][N:22]2[N:26]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: C#Cc1ccccc1N
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1C#Cc1cccn2nc(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-ethynyl-phenylamine (126.0 mg, 1.075 mmol) and N,N-diisopropylethylamine (2 mL, 10 mmol) in N,N-dimethylformamide (1 mL) at room temperature under an atmosphere of nitrogen was added 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol), bBis(triphenylphosphine)palladium(II) chloride (10.0 mg, 0.0142 mmol) and copper(I) iodide (7.0 mg, 0.037 mmol). The mixture was stirred at room temperature for 18 hours then was poured into 0.1N hydrochloric acid (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (2×20 mL) and saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified using prepartory silica gel plates (20 cm×20 cm 100% dichloromethane). 2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenylamine was isolated as a yellow solid (0.158 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.7 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.07 (t, J=7.0 Hz, 1H), 6.77-6.67 (m, 2H), 4.81 (br s, 2H). MS=269, 271 (MH)+.