Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:48])[C:16](=[O:47])[C:17]([CH3:46])=[C:18]2[C:23]=1[C:22](=[O:24])[N:21](CC1C=CC(OC)=CC=1)[C:20](=[O:34])[N:19]2[C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][C:43]([NH2:45])=[O:44])[CH:38]=[CH:39][CH:40]=1>C1(OC)C=CC=CC=1>[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:48])[C:16](=[O:47])[C:17]([CH3:46])=[C:18]2[C:23]=1[C:22](=[O:24])[NH:21][C:20](=[O:34])[N:19]2[C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][C:43]([NH2:45])=[O:44])[CH:38]=[CH:39][CH:40]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(CCC(N)=O)c3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)[nH]c(=O)n(-c3cccc(CCC(N)=O)c3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
Aluminium chloride (2.82 g, 21.14 mmol) was added in small portions to a solution of 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (1c) (1.500 g, 2.114 mmol) in anisole (15 ml). The resulting reaction mixture was stirred at room temperature for 24 h, then quenched by addition of MeOH (15 ml) and 2N HCl (0.5 ml). The resulting mixture was concentrated under vacuum and the residue thus obtained was purified by silica gel column chromatography to yield the titled compound (1) (0.450 g, 44%) [m/z=590.1 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[H-].[Na+]>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:11][C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:12])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]3)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CNC(=O)OC(C)(C)C)cc3)c2n1C
Yield: 74.1 %

Procedure:
The reaction was carried out in a manner similar to Example 196 a) except for using 0.44 g (1.74 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate, 0.66 g (2.58 mmol) of 4-(tert-butoxycarbonylaminomethyl)-benzyl chloride, 0.07 g (1.74 mmol) of 60% sodium hydride and 20 ml of dimethylformamide. Thus, 0.61 g (73.1%) of ethyl 7-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate was obtained.
Reaction SMILES: [Br-].[F:2][C:3]([F:9])([F:8])[CH2:4][C:5](=[O:7])[CH3:6].[CH2:10](OCC)C>>[F:2][C:3]([F:9])([F:8])[CH2:4][C:5]([CH3:10])([OH:7])[CH3:6]
Reactant: CCOCC
Reactant: CC(=O)CC(F)(F)F
Agent: [Br-]
Product: CC(C)(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Methylmaganesium bromide (1.454 mL, 4.36 mmol) was added dropwise via syringe to a solution of 4,4,4-trifluorobutan-2-one (500 mg, 3.97 mmol) in Diethyl ether (25 mL) at 0° C. and stirred at this temp for 1 hr before warming up to RT. The reaction was quenched with sat. ammonium chloride and extracted with ether. The organic layer was washed with brine, collected, dried over MgSO4, filtered and partially evaporated to give the crude product 4,4,4-trifluoro-2-methylbutan-2-ol (500 mg, 89% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.34 (q, J=11.5 Hz, 2H), 1.88 (br. s, 1H), 1.37 (d, J=0.8 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1(C)C=CC=CC=1.C(O)C.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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:14][CH:13]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OB(O)c1ccc(F)cc1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine 5-bromoindole (5.00 g, 25.50 mmol) and Pd(Ph3P)4 (1.47 g, 1.28 mmol) in toluene (510 ml). After 30 minutes, add a solution of 4-fluorobenzeneboronic acid (5.35 g, 38.26 mmol) in ethanol (153 ml) then add saturated NaHCO3 (255 ml). Heat to reflux. After 4 hours, cool to ambient temperature, pour into saturated NaCl (250 ml), and separate the organic layer. Extract the aqueous layer with ethyl acetate. Combine the organic extracts, wash with brine, dried, then evaporate to residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexanes (10/90) to give the title compound: mp 84-89° C. MS (ACPI): m/e 212.0 (M+1). Analysis for C14H10FN: Calcd: C, 79.60; H, 4.77; N, 6.63. found: C, 79.33; H, 4.92; N, 6.64.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]([CH3:43])([CH:41]=O)[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]3[C:16]=2[CH2:17][CH2:18][C@H:19]3[O:25][C:26]2[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)=[C:10]([CH3:40])[CH:9]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCCl.ClCCl>[CH3:1][N:2]([CH3:3])[CH2:41][C:5]([CH3:43])([CH3:4])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]3[C:16]=2[CH2:17][CH2:18][C@H:19]3[O:25][C:26]2[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)=[C:10]([CH3:40])[CH:9]=1
Reactant: CNC
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)C=O)cc5C)ccc(F)c43)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)CN(C)C)cc5C)ccc(F)c43)ccc21
Reaction time: 0.33 h

Procedure:
Dimethylamine (95 μL of a 2 M solution in tetrahydrofuran) is added to a solution of methyl 2-((S)-6-((R)-4-(4-(2,2-dimethyl-3-oxopropoxy)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (83 mg) and acetic acid (13 μL) in 1,2-dichloroethane (2 mL). The mixture is stirred for 20 minutes and then treated with sodium triacetoxyborohydride (130 mg). After stirring for 12 hours the mixture is diluted with dichloromethane, washed with water and brine, dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. Yield: 20 mg; LC (method 13): tR=1.18 min; Mass spectrum (ESI+): m/z=576 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]([O:19][CH3:18])=[O:21])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1

Procedure:
The procedure described in Example 3 is followed. Starting from 1.5 g (4.88 mmol) of 5-bromo-2-(4-chlorophenyl)pyrazolo[1,5-a]pyridine, obtained according to the protocol described in Examples 1.3 or 2.3, 1.05 mg (5.83 mmol) of 3-methoxycarbonylphenylboronic acid, 4.6 g (14.61 mmol) of caesium carbonate, 0.400 g (0.49 mmol) of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and 20 ml of a THF/water (9/1) mixture and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (9/1), 1.6 g (90%) of the expected product are obtained in the form of a yellow-white powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[OH:17])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:38][CH:39]=2)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N\O)c1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 48.2 %

Procedure:
Sodium hydride (60%, in oil, 203 mg) was added to a solution of ethyl Z-2-(3-bromophenyl)-2-hydroxyiminoacetate (1.15 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.33 g) in N,N-dimethylformamide (15 ml) at room temperature under nitrogen atmosphere and stirred for 1 hour. 1N hydrochloric acid (7 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl Z-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (1.12 g, yield 48%) as a pale-yellow oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: COC1C=CC(C[N:8]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][O:17][C:16]=3[CH:31]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:31]=[C:12]([S:9]([NH:8][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2)(=[O:29])=[O:28]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2S(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
To a solution of N-(4-methoxybenzyl)-4-(2-(methylsulfonyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (200 mg, 0.350 mmol) in DCM (5 mL) was added TFA (2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material (71% by LCMS) that was purified by prep purification to obtain 4-(2-(methylsulfonyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (28 mg, 17.8%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.85 (t, J=7.7 Hz, 1H), 7.77-7.54 (m, 2H), 7.19 (dd, J=15.2, 3.4 Hz, 2H), 7.08 (dd, J=8.7, 2.1 Hz, 1H), 6.77 (d, J=4.7 Hz, 1H), 6.21 (d, J=8.5 Hz, 1H), 4.42 (dt, J=10.9, 3.3 Hz, 1H), 4.34 (dd, J=10.9, 5.4 Hz, 1H), 3.61 (t, J=3.9 Hz, 2H), 3.18 (s, 3H); MS (ESI, positive ion) m/z: 452.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:12][NH:13][C:14](=O)[CH3:15])=[N:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CC#N.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([C:14]([CH3:15])=[N:13][N:12]=2)[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])cnc1NNC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cn2c(C)nnc12
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To a suspension of N′-(3-methoxy-5-nitropyridin-2-yl)acetohydrazide (Step 84.2) (23.3 g, 84 mmol) in CH3CN (200 mL) was added DIEA (11.1 mL, 63.3 mmol) and dropwise POCl3 (11.8 mL, 127 mmol) and the reaction mixture was stirred for 3.5 hr at 90° C. The cooled mixture was slowly added to water (600 mL), stirred for 30 min before the mixture was neutralized with solid NaHCO3 to pH 6.5. The product was extracted with CH2Cl2/MeOH 6:1. Combined extracts were washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc/MeOH 50:50:5 to 0:50:5) followed by recrystallization from CH2Cl2/EtOAc/Et2O. tR: 0.49 min (LC-MS 2); ESI-MS: 209 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.79 (s, 3H) 4.10 (s, 3H) 7.29 (d, J=1.7 Hz, 1H) 9.25 (d, J=1.7 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 48 h

Procedure:
1 M NaOH (23 ml) is added to a solution of ethyl 4-(4-benzylpiperazin-1-yl)cyclohexanecarboxylate (2.56 g) in Methanol (30 ml). The mixture is stirred for 2 days and the solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC (Varian C18 Microsorb) eluting with a gradient of 10-100% acetonitrile in water containing 0.2% trifluoroacetic acid to give 4-(4-benzylpiperazin-1-yl)cyclohexanecarboxylic acid: (2.33 g). m/z(+) 303 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:24])[C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][C:14]=2[O:15][CH3:16])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:68]([Zn]C#N)#[N:69].CC(N(C)C)=O>CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:24][C:11]1[C:12]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[C:2]([C:68]#[N:69])=[CH:7][N:6]=2)[CH:10]=1
Reactant: N#C[Zn]C#N
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
A mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 63, 157 mg, 0.34 mmol), zinc (2.209 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium(0) (30.9 mg, 0.03 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 32.2 mg, 0.07 mmol), and dicyanozinc (23.8 mg, 0.20 mmol) were placed in a reaction tube under N2 and then degassed DMA (0.9 mL) was added. The resulting suspension was stirred to 95° C. for 1.5 h. The mixture was then diluted with EtOAc and washed five times with water, then brine. The solution was then dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid was collected by filtration, and washed with diethyl ether. The solid was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was allowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE (available from Polymer Laboratories) under gravity. The resulting solution was concentrated in vacuo to give the title compound (87 mg, 57%) as a yellow solid; 1H NMR: (100° C.) 2.28 (3H, s), 2.49-2.58 (4H, m), 2.90-2.98 (4H, m), 3.70 (3H, s), 4.28 (2H, br s), 6.77 (1H, s), 6.99 (1H, s), 7.14 (1H, t), 7.37 (1H, t), 8.37 (1H, d), 8.55 (1H, s), 8.78 (1H, d), 8.85 (1H, s), 8.92 (1H, s); m/z: ES+ MH+ 456.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH3:50])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:51].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:51][C:37]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH3:50])[CH2:44][CH2:43]4)=[CH:41][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCCN1CCN(c2ccc(N)c(OC)c2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 175 °C
Yield: 68.2 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol) and [2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amine (54 mg, 0.22 mmol) in 2,2,2-trifluoroethanol (1.1 mL) was added 4 M HCl in dioxane (108 μL, 0.43 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (103 mg, 0.15 mmol, 70%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ10.24 (s, 1H), 9.40 (brs, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.20 (d, 1H, J=5.13 Hz), 8.05 (d, 1H, J=7.69 Hz), 7.82 (d, 1H, J=7.69 Hz), 7.73 (d, 1H, J=8.97 Hz), 7.61 (t, 1H, J=7.78 Hz), 7.36-7.49 (m, 3H), 7.21 (t, 2H, J=8.15 Hz), 6.98 (t, 1H, J=6.87 Hz), 6.68 (d, 1H, J=2.20 Hz), 6.45-6.50 (m, 2H), 3.80 (s, 3H), 3.12-3.17 (m, 4H), 2.45-2.55 (m, 4H), 2.28 (t, 2H, J=7.42 Hz), 1.47 (q, 2H, J=7.39 Hz), 0.87 (T, 3H, J=7.32 Hz). MS (ESI): 675 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][NH2:31]>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][NH:31][CH2:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)=[N:12]1
Reactant: NCc1cccs1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCNCc2cccs2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, C-Thiophen-2-yl-methylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a graded solvent mixture of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=357.
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([CH:14]2[CH2:16][CH2:15]2)[CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[NH:6][N:5]=[C:4]([CH:14]3[CH2:15][CH2:16]3)[CH:3]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Temperature: 25 °C
Yield: 69 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 118a (455 mg, 1.95 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (0.40 g, 1.5 mmol), and cesium carbonate (1.22 g, 3.75 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, XantPhos (87 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.075 mmol) were added, and the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 50:1 DCM/MeOH to afford 118b as a yellow solid (320 mg, 50%). LCMS: (M+H)+ 309. 1H NMR (500 MHz, DMSO) δ 11.85 (s, 1H), 8.23 (s, 1H), 8.02 (d, J=2.5, 1H), 7.35 (d, J=2.5, 1H), 5.77 (d, J=2, 1H), 3.46 (s, 3H), 1.83 (m, 1H), 0.90 (m, 2H), 0.64 (m, 2H)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:7]=[CH:6][N:5]=1.Br[CH2:27][CH2:28][F:29].[Cl-].[NH4+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[N:18]([CH2:27][CH2:28][F:29])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(-c2c(-c3ccnc(Cl)c3)[nH]c3cccnc23)cc1
Reactant: FCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FCCn1c(-c2ccnc(Cl)c2)c(-c2ccc(F)cc2)c2ncccc21
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Sodium hydride (371 mg, 9.3 mmoles 60% in oil) is added to a solution of 1 g (3.1 mmoles) of 2-(2-Chloro-pyridin-4-yl)-3-(4-fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridine (prepared following the procedure for example 6) in 20 mL of dimethylformamide at room temperature. After 30 min. at room temperature, 2.75 g of 1-bromo-2-fluoro-ethane (21.6 mmoles) is added to the reaction mixture. After 10 hour at room temperature, the reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the solid residue is purified by chromatography on silica gel (ethyl acetate/hexane 1/1) to give 720 mg of 2-(2-Chloro-pyridin-4-yl)-1-(2-fluoro-ethyl)-3-(4-fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridine as white solid.