Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[C:19]([F:25])=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:34]2)[CH2:29][O:28]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.200 g, 0.56 mmol) in N,N-dimethylformamide (7 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.139 g, 0.70 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.374 g, 0.85 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.193 g, 1.49 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 50% to 90% ethyl acetate/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.193 g, 64%) as a pale brown solid: HR-ES-MS m/z calculated for C26H32F2N4O6 [M+H]+ 535.2363, observed 535.2363, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3 H), 1.36-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.84 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 3.87 (s, 3H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 4.27 (d, J=18.7 Hz, 1H), 4.35 (t, J=5.7 Hz, 1H), 4.62 (d, J=18.7 Hz, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 5.06 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.18 (td, J=9.3, 5.1 Hz, 1H), 7.30 (td, J=9.5, 1.8 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: O[C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1.P(Cl)(Cl)([Cl:13])=O.Cl>ClC1C=CC=CC=1>[Cl:13][C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)sc1CCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1nc(Cl)sc1CCCl
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A suspension of 177.6 g (1 mole) of 2-hydroxy-4-methyl-5-(2-chloroethyl)-thiazole in 530 cm3 of anhydrous chlorobezene is heated to 100° C. under stirring. 306.6 g (2 moles) of phosphoryl chloride are flown into the solution in 30 minutes, then it is stirred at a temperature of 125°-130° C. until the formation of hydrogen chloride ceases (about 2 hours). The reaction mixture is cooled to 20° C., then it is poured onto 1.5 kg of ice. The phases are separated, the aqueous phase is extracted twice with 200 cm3 of chlorobenzene each. The combined phases containing the chlorobenzene are washed acid-free with water and then with a 5% sodium hydrogen carbonate solution and then evaporated under reduced pressure. The brown residue is fractionated in vacuo. 145 g (74%) of 2-chloro-4-methyl-5-(2-chloroethyl)thiazole are obtained. The boiling point is 102° C. at a pressure of 53.2 Pa, n20D =5512, n30D =1,5468.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1.[BrH:22].CN(C=O)C>CCOC(C)=O>[Br:22][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [O-][n+]1nc(Br)nc2cc3c(cc21)CC(CO)C3
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
NaNO2 (23 mg, 0.33 mmol) was added to a stirred mixture of amine 124 (77 mg, 0.33 mmol), HBr (48%, 2 mL) and DMF (2 mL) at 20° C. and the mixture stirred at 20° C. for 1 h. CuBr (57 mg, 0.40 mmol) was added and the reaction mixture stirred at 20° C. for 90 min. The mixture was diluted with EtOAc (50 mL) and washed with water (3×20 mL). The organic solution was dried and the solvent evaporated to give an orange oil, that was purified by chromatography, eluting with a gradient (0-30%) of EtOAc/pet. ether, to give bromide 125 (40 mg, 41%) as an oil: 1H NMR δ 8.19 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.72 (d, J=6.5 Hz, 2H, CH2O), 3.22-3.33 (m, 2H, CH2), 2.96-3.08 (m, 2H, CH2), 2.80-2.89 (m, 1H, CH), OH not observed; HRMS calcd for C11H1079BrN3O2 (M+) m/z 294.9956, found 294.9949; calcd for C11H1081BrN3O2 (M+) m/z 296.9936, found 296.9943.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1)#[N:28]
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Reactant: N#Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2cc(-c3ccccc3C#N)nc(N3CCOC[C@@H]3C)n2)cc1
Yield: 41.4 %

Procedure:
(S)-1-(4-(6-chloro-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)-3-ethylurea (Intermediate 2) (90 mg, 0.24 mmol), 2-cyanobenzeneboronic acid (43 mg, 0.29 mmol), cesium carbonate (235 mg, 0.72 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (10 mg, 0.01 mmol) in dioxane/water (1:3, 1 mL) were irradiated in a Biotage microwave for 40 min at 110° C. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMSO, filtered and purified by prep HPLC (low pH) to afford a green solid (44 mg, 41%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+]>CN(C=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([F:6])[CH:15]=2)[CH:11]=[CH:12]1
Reactant: ClCCCBr
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2ccn(CCCCl)c2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
To a solution of 1-bromo-3-chloropropane (700 mg, 4.44 mmol) in DMF (2.4 mL) was added 6-fluoroindole (200 mg, 1.48 mmol) and powder KOH (92 mg, 1.63 mmol) at 20° C. The reaction mixture was stirred for 15 h at 20° C. then quenched by addition of H2O and extracted with Et2O. The combined organic solution was successively washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed to give 1-(3-chloropropyl)-6-fluoroindole (190 mg, 66%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[CH2:25][CH3:26].CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][C:19]=1[CH2:25][CH3:26]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1Cl
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-3-ethylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[NH:10][N:9]=1)[CH3:2].NC1C2C(=C([I:30])C=CC=2)NN=1>>[CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[C:12]([I:30])[CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1n[nH]c2ccc(I)cc12
Reactant: Nc1n[nH]c2c(I)cccc12
Product: CCN(CC)CCCNc1n[nH]c2c(I)cccc12
Yield: 54 %

Procedure:
The same procedures for preparing 3-(3-diethylaminopropylamino)-5-iodoindazole as described in Example 71 were repeated except that 3-amino-7-iodoindazole was employed instead of the 3-amino-5-iodoindazole. As a result, 7.57 g of 3-(3-diethylaminopropylamino)-7-iodoindazole having the following analytical values was obtained in a yield of 54%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[S:13].[OH-].[K+]>>[CH3:10][N:11]([CH3:15])[C:12](=[S:13])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=S)Oc1ccccc1C#N
Yield: 94 %

Procedure:
If the procedure described in Preparation XVI is followed starting from 15 g (126.10-3 mol) of 2-hydroxybenzonitrile, 17.9 g (145.10-3 mol) of dimethylthiocarbamoyl chloride and 7.4 g (126.10-3 mol) of potassium hydroxide, 24.1 g (yield: 94%) of the expected product are obtained.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.C([O:20][C:21](=O)[CH:22]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])[C:23](OCC)=[O:24])C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:2][O:3][N:4]1[CH2:10][CH2:9][N:8]2[C:21](=[O:20])[CH:22]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[C:23](=[O:24])[N:7]2[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C)cc(C)cc1C
Reactant: CON1CCNNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (350 mg, 1.71 mmol) and triethylamine (1.0 ml, 726 mg, 7.17 mmol) in xylene (8 ml) was stirred under argon at 60° C. for one hour. After further addition of 2-(2,4,6-trimethyl-phenyl)-malonic acid diethyl ester (482 mg, 1.73 mmol), the reaction mixture was heated at 150° C. (oil bath temperature) for 18 hours. The cooled reaction mixture was poured on ice, the pH made alkaline by addition of 5N aqueous sodium hydroxide, the aqueous layer extracted twice with ethyl acetate and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The base-acidification workup protocol is repeated a second time. Yield: 24 mg of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.1) as a beige solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCCNCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CCOC)S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A premixed solution of bis-methoxyethylamine (15.0 ml, 102 mmol, 1.00 equiv.) and triethylamine (21.3 ml, 153 mmol, 1.50 equiv.) was added dropwise to a solution of sulfuryl chloride (20.7 ml, 153 mmol, 1.50 equiv.) in CH2Cl2 at 0° C. The reaction mixture was continued stirred at 0° C. for 2 h, poured into ice and extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with a saturated NaCl soln (1×100 ml), the organic layer dried (Na2SO4), filtered and concentrated under vacuum to afford the title compound (18.5 g, 80%) which was used without further purification. 1HNMR (CDCl3): 3.37 (s, 6H), 3.64-3.64 (m, 8H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Cl
Reactant: OCCCCc1ccccc1
Solvent: ClCCl
Product: CCCC(=O)OCCCCc1ccccc1
Reaction time: 36 h
Yield: 98.9 %

Procedure:
To 4-phenyl-1-butanol (7.0 g, 0.047 mol) was added anhydrous dichloromethane (20 mL). A solution of butyryl chloride (4.79 g, 0.045 mol) in anhydrous dichloromethane (20 mL) was added dropwise. The solution was stirred for 36 hours. At this point the reaction was concentrated under reduced pressure to give a crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate (3:1)] provided the desired product (9.8 g, 94%) as a clear viscous liquid. 1H (CDCl3) δ(ppm): 0.94 (t, 3H); 1.61-1.71 (m, 6H); 2.27 (t, 2H); 2.64 (t, 2H); 4.08 (t, 2H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(OC[C@@H]2CCN2)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The compound of step 109b was dissolved in CH2Cl2 (10 mL) and TFA (10 mL) was added at 0° C. After 30 minutes of stirring the reaction was warmed to room temperature and stirred for an additional 45 minutes. Solvent was removed, and the residue was partitioned between sat'd K2CO3 solution and CH2Cl2. The aqueous layer was further extracted with CH2Cl2 (4×), and the combined organic extracts were dried over MgSO4 and concentrated. The crude material was chromatographed eltuing with 10% methanol/CHCl3 followed by 10% methanol/CHCl3 /0.5% NH4OH to give 475 mgs of a pale solid, 64% yield. m.p.=59-60° C. MS (CI) m/e 233 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.01 (d, J=2.8 Hz, 1H), 7.37 (d, J=2.8 Hz, 1H), 4.33-4.24 (m, 1H), 4.08-3.98 (m, 2H), 3.73 (dd, J=15.8, 8.4 Hz, 1H), 3.49-3.41 (m, 1H), 2.44-2.21 (m, 2H).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH2:3][CH2:4][CH3:5].Br[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=[O:12]>O1CCCC1>[CH2:2]([C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=[O:12])[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: CCCC[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1cc(F)cc(C=O)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Add butylzinc bromide (49.3 mL, 24.6 mmol, 0.5 M in THF) followed by Pd(dppf)2Cl2 dichloromethane complex (1.01 g, 1.23 mmol) to a solution of 3-bromo-5-fluorobenzaldehyde (5.00 g, 24.6 mmol) in tetrahydrofuran (123.1 mL). Stir at room temperature in a sealed vessel flushed with nitrogen for 18 hours. Add saturated aqueous ammonium chloride (125 mL). Separate the layers and extract the aqueous layer with ethyl acetate (1×300 mL). Wash combined organic layers with saturated aqueous sodium chloride, dry over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the title compound (3.43 g, 77.3%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]1>CS(C)=O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:22]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(C)(O)C1CCNC1
Solvent: CS(C)=O
Product: CC(C)(O)C1CCN(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 80 °C

Procedure:
A mixture of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (0.150 g, 0.502 mmol) and 2-(pyrrolidin-3-yl)propan-2-ol (0.187 g, 1.447 mmol) in 3 mL of DMSO was sealed in a microwave tube and heated at 80° C. overnight. The reaction was cooled to RT, filtered and purified by purified by reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA CH3CN (9:1→1:9). The fractions containing the desired product were combined and basified with satd NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 filtered and concentrated to dryness to give the title compound as a light-yellow crystalline solid. MS (ESI, pos. ion) m/z: 392 (M+1). IC50 (uM) 0.02882.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: COc1cc(-c2cc(F)c(N)c(Cl)c2)ccc1Cl
Yield: 65.1 %

Procedure:
The title compound (82 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 4-chloro-5-methoxyphenylboronic acid (107 mg, 0.62 mmol) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.S(=O)(=O)(O)O.[CH3:32]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:32])=[O:22])=[CH:19][CH:20]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=C(O)c1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
0.5 g (1.37 mmol) of 4-(3-chloro-anilino)-6-(4-carboxy-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine suspended in 100 ml of methanol is heated under reflux for 24 hours with 0.1 ml of concentrated sulfuric acid. The solution is concentrated and stirred in methanol/diethyl ether. The crystals are filtered off and then suspended in methanol/water. The suspension is adjusted to pH 7-8 with sodium hydrogen carbonate solution and stirred at RT for 30 min. The crystals are filtered off with suction, washed with water, methanol and diethyl ether and dried. The title compound is obtained in the form of colorless crystals, m.p.>300° C.; TLC-Rf =0.6 (toluene/ethyl acetate [3:7]); FAB-MS: (M+H)+ =378.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[O:32][C:31]([Si](C(C)C)(C(C)C)C(C)C)=[N:30][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O.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:32]1[C:28]([C:2]2[C:3]3[N:4]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[CH:29][N:30]=[CH:31]1
Reactant: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
A mixture of ethyl 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (500 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (573 mg), tetrakis(triphenylphosphine)palladium(0) (171 mg), potassium carbonate (410 mg), DME (12 mL) and water (3 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (6 mL), and 1N hydrochloric acid (2 mL) was added thereto. The mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.13 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1cccc(F)c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(F)c4)ccc31)C1CCC(C2)N1
Yield: 46 %

Procedure:
Intermediate 2 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, hexanes/ethyl acetate) to give tert-butyl 2-(3-fluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (110 mg, 46%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.13-8.23 (m, 1H), 7.71-7.76 (m, 1H), 7.58-7.70 (m, 2H), 7.38-7.49 (m, 1H), 7.28-7.35 (m, 1H), 7.12-7.23 (m, 1H), 5.16-5.38 (m, 1H), 4.32-4.51 (m, 1H), 3.60 (s, 3H), 3.20-3.50 (m, 1H), 2.50 (d, J=16.2 Hz, 1H), 2.10-2.40 (m, 2H), 1.85-1.98 (m, 1H), 1.56-1.68 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:15])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].C1(O)C=CC=CC=1.I[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:29]=1[CH2:39][CH2:40][CH3:41]>>[CH3:37][C:35]([CH3:36])([CH3:38])[CH2:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][O:14][C:11]2[CH:12]=[CH:13][C:7]3[O:6][C:5]([CH3:15])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=3[CH:10]=2)=[C:29]([CH2:39][CH2:40][CH3:41])[CH:30]=1
Reactant: CCCc1cc(CC(C)(C)C)ccc1OCCCI
Reactant: COC(=O)C1(C)Cc2cc(O)ccc2O1
Solvent: Oc1ccccc1
Product: CCCc1cc(CC(C)(C)C)ccc1OCCCOc1ccc2c(c1)CC(C)(C(=O)O)O2

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the intermediate prepared in Example 1, Step 1 as the phenol and the iodide prepared in Step 2.