Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:19]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCC(=O)CC
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(O)(CC)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (3.00 g, 12 mmol) in dry diethylether (100 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 7.50 mL, 12 mmol) in dry diethylether (100 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled 3-pentanone (1.29 mL, 12 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 50 mL) and water (50 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIa) as a green oil (1.7 g, 56%). 1H-NMR (CDCl3): δ=7.35 (dd, J=5.2 Hz, J=1.2 Hz, 1H), 7.24 (d, J=5.4 Hz, 1H), 7.10 (dd, J=3.6 Hz, J=1.2 Hz, 1H), 7.00 (dd, J=5.2 Hz, J=3.6 Hz, 1H), 6.95 (d, J=5.4 Hz, 1H), 1.75 (q, J=7.7 Hz, 4H), 0.80 (t, J=7.4 Hz, 6H). 13C-NMR (CDCl3): δ=145.33, 136.11, 129.99, 129.76, 128.97, 127.87, 127.40, 125.54, 79.29, 35.79, 8.80.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC[B-](F)(F)F
Reactant: O=Cc1cc2cc(Br)ccc2s1
Agent: [K+]
Product: CCCCc1ccc2sc(C=O)cc2c1
Yield: 84.7 %

Procedure:
The compound was prepared as in Example 3.1 using 5-bromo-2-formylbenzothiophene (241 mg, 1.0 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (246 mg, 1.5 mmol) in place of hexylboronic acid to give 5-butyl-2-formylbenzothiophene (185 mg, 85%). Used without further characterization.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: Brc1n[nH]c2cccnc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ncccc21
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg) in DMF (10 mL) were added 2-iodopropane (0.20 mL) and K2CO3 (168 mg) at room temperature. After stirring overnight, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (147 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[F:17])[S:5][N:4]=1)[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:7]([CH2:8][O:9][C:24]2[C:23]([F:26])=[CH:22][C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20][C:19]=2[F:18])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[F:17])[S:5][N:4]=1)[CH3:2]
Reactant: CCc1nsc(-c2ccc(C)cc2F)c1CO
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(CC)nsc2-c2ccc(C)cc2F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-4-yl]methanol (50 mg, 0.20 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (69 mg, 0.30 mmol, 1.51 equiv), ADDP (104 mg, 0.42 mmol, 2.09 equiv), Bu3P (60 mg), toluene (10 mL). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 40 mg (43%) of ethyl 3-(4-[[3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:6]1[CH:5]=[C:4]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CC1(C)OB(c2cc(Cl)c(C(F)(F)F)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 53 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.62 g, 1.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.38 g, 2.16 mmol), Cs2CO3 (1.8 mL, 2M, 3.6 mmol) and Pd(PPh3)2Cl2 (38 mg) in THF (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.295 g; yield 53%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.433 (s, 2H), 6.073 (s, 1 H), 5.846 (s, 1 H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:24][CH2:25][C:26](Cl)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][CH2:25][C:26]([NH:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)cnc1Br
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)Nc1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To the solution of 2,5-Dibromo-pyridin-3-ylamine (8.6 g, 34.12 mmol) in 50 ml of DCM was added triethylamine (5.3 ml, 37.53 mmol). Cooled the reaction mixture to 0° C. To this added the solution of 2-benzyloxy acetyl chloride (7.45 g, 40.95 mmol) in 35 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (10:90) as the eluent to provide the title compound (3.2 g, 24.17%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH:29]1[CH2:32][C:31](=[CH:33][CH2:34][CH3:35])[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:29]3[CH2:32][C:31](=[CH:33][CH2:34][CH3:35])[CH2:30]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=C1CC(OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC=C1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Yield: 67.3 %

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.743 g, 0.00245 mol) in N,N-dimethylformamide (20 mL) was reacted with 3-propylidenecyclobutyl methanesulfonate (0.699 g, 0.00367 mol) and cesium carbonate (0.866 g, 0.00367 mol) at 70° C. for three days. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give 3-(4-phenoxyphenyl)-1-(3-propylidenecyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.655 g, 0.00165 mol) as a tan solid.
Reaction SMILES: ClC1C=C(C2SC(C([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=O)=CC=2C2C=C(C#N)C=CC=2)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[C:40]([C:51]([OH:53])=O)[S:41][C:42]=2[C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Cl:50])[CH:44]=2)[CH:34]=[CH:35][C:36]=1[F:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[C:40]([C:51]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:53])[S:41][C:42]=2[C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Cl:50])[CH:44]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cc(F)cc(Cl)c2)c1
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)c(-c3cc(F)cc(Cl)c3)s2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 1 starting with 49.1 mg (0.13 mmol) of the compound from Example 20A. 40.9 mg (71% of theory) of the title compound are obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[N:29]6)=[CH:41][CH:40]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-n2cccn2)cc1

Procedure:
The title compound, white solid (107 mg, 86%), MS (ISP) m/z=501.4 [(M+H)+], mp 225.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-pyrazol-1-yl-benzoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:5]([F:20])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([Cl:24])=[O:12])=[C:5]([F:20])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(OCc2ccccc2C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoic acid (1.0 g, 3.68 mmol) in dichloromethane (15 ml) was added oxalyl chloride (0.45 ml, 4.79 mmol), followed by a drop of N,N-dimethylformamide, and stirred for 12 h at 25° C. The resulting clear solution was evaporated in vacuo and the crude product was used in the next step without any further purification (99%). MS (Turbo Spray): m/z=290.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7]([CH3:34])[N:6]=[CH:5]2.FC(F)(F)C(O)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[N:7]([CH3:34])[N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cnn(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cnn(C)c12

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-1-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (22 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 17 mg (97%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.78 (s, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.31-7.37 (m, 4H), 7.20-7.23 (m, 1H), 6.89 (m, 1H), 4.91 (q, J=6.4 Hz, 1H), 4.16 (s, 3H), 3.40 (d, J=9.2 Hz, 1H), 3.35 (d, J=9.2 Hz, 1H), 2.89-2.95 (m, 2H), 2.71-2.79 (m, 2H), 2.12-2.20 (m, 2H), 1.94-2.03 (m, 2H), 1.44 (d, J=6.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 145.7, 144.3, 135.4, 128.3, 127.8, 127.3, 126.1, 123.2, 122.7, 122.4, 117.1, 78.4, 74.0, 42.8, 42.0, 40.5, 33.4, 22.6. Mass spec.: 384.17 (MH)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9].P(Br)(Br)[Br:16]>C1(C)C=CC=CC=1.ClCCl>[Br:16][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CS(=O)(=O)c1ccc(CO)cc1C#N
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CBr)cc1C#N
Temperature: 40 °C

Procedure:
A flask is charged with 5-hydroxymethyl-2-methylsulfonyl-benzonitrile (0.788 g, 3.73 mmol) in toluene (5 mL) and heated at 40° C. PBr3 (0.175 mL, 1.86 mmol) is added and the reaction is refluxed for 0.5 h. It is then cooled to room temperature, diluted with dichloromethane and washed with water. The aqueous layer is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford 5-bromomethyl-2-methanesulfonyl-benzonitrile as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.28 (s, 3H), 4.89 (s, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.18 (d, J=8.1 Hz, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:20]1[CH:25]=[C:24]([N:26]([CH:34]2[CH2:36][CH2:35]2)C(=O)OC(C)(C)C)[N:23]2[N:37]=[C:38]([CH3:42])[C:39]([CH:40]=[O:41])=[C:22]2[N:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:10][C:20]3[CH:25]=[C:24]([NH:26][CH:34]4[CH2:35][CH2:36]4)[N:23]4[N:37]=[C:38]([CH3:42])[C:39]([CH:40]=[O:41])=[C:22]4[N:21]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1nn2c(N(C(=O)OC(C)(C)C)C3CC3)cc(Cl)nc2c1C=O
Reactant: Nc1ccc(-n2cccn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1nn2c(NC3CC3)cc(Nc3ccc(-n4cccn4)cc3)nc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
To 4-(1H-pyrazol-1-yl)aniline (54 mg, 0.34 mmol), Cs2CO3 (130 mg, 0.4 mmol) were added to tert-butyl 5-chloro-3-formyl-2-methylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (100 mg, 0.29 mmol) dissolved in 1,4-dioxane (1.1 mL). Racemic BINAP (11 mg, 0.017 mmol) and palladium(II) acetate (8 mg, 0.011 mmol) were then added. The mixture was sealed and irradiated at 110° C. for 60 min in the microwave. Et2O (3 mL) was added and the solution was filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After stirring at room temperature for 1 hour, the solution was concentrated under a stream of air. The crude material was purified by silica gel chromatography (15% acetone/dichloromethane) to yield the product, 5-(4-(1H-pyrazol-1-yl)phenylamino)-7-(cyclopropylamino)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (24 mg, 23% yield). LCMS (M+1=374)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(#N)C>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([NH:5][C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]4[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=5)[CH:18]=[CH:19][CH:20]=4)=[N:10][N:9]3[CH:34]=2)=[O:4])[CH2:38][CH2:37]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CC#N
Product: CN1CCN(CC(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C(F)(F)F)c5)c4)ccc3n2)CC1
Yield: 50 %

Procedure:
Using N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (120 mg, 0.244 mmol), 1-methylpiperazine (1 mL) and acetonitrile (2 mL) as starting materials and in the same manner as in Example 398, the title compound (67 mg, 50%) was obtained as a white powder.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1.O>[C:1]1([O:11][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(Oc1cccc2ccccc12)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.60 g of 1-naphthol, 1.188 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl)acetate in 10 ml of benzene. The solution is refluxed overnight and then poured into 100 ml of water. The mixture is extracted with 2 × 75 ml of ether. The combined extracts are washed with 2 × 50 ml of 5% NaOH, 50 ml of water, saturated brine and dried (MgSO4). Evaporation of the solvent yields a red oil. Chromatography on 100 g of silica gel (benzene, 400 ml) affords a pink oil which solidifies on trituration with petroleum ether to yield a pink solid, mp 107°-109.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[F:37])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:38][N:39]1[C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:37][C:15]1[CH:16]=[CH:17][C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:43]3[N:39]([CH3:38])[N:40]=[CH:41][CH:42]=3)=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:12]
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)CC1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(-c5ccnn5C)ccn34)c2)CC1
Temperature: 25 °C

Procedure:
A mixture comprising 7-bromo-N-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzyl carbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (step 1) (120 mg, 0.212 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44.2 mg, 0.212 mmol), cesium carbonate (69.1 mg, 0.212 mmol) and PdCl2(dppf).CH2Cl2 adduct (17.33 mg, 0.021 mmol) in DMF (5 ml) under N2 was heated at 85° C. for 2 hrs. After cooling to RT, the reaction mixture was partitioned between with EtOAc and water. A precipitate formed which was removed by filtration and discarded. The organic portion was separated and washed with NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-20% MeOH/DCM and the product fractions were combined and concentrated in vacuo. The product was dissolved in MeOH and passed through a 1 g 2,4,6-trimercaptotriazine silica column under gravity. The column was washed with MeOH and the combined eluents were concentrated in vacuo. The product was triturated with THF (1% MeOH) followed by ether to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCO[C@@H](c2ccc(F)cc2)C1
Reaction time: 3 h
Yield: 125.9 %

Procedure:
To a solution of (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (1.00 g, 3.67 mmol) in toluene (10 mL) was added a solution of ethyl chloroformate (0.39 mL, 4.04 mmol) in toluene (5 mL) at 89° C. The mixture was stirred for 3 hrs and the solvent was evaporated to give ethyl (S)-2-(4-fluorophenyl)morpholine-4-carboxylate (1.17 g) as a black oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[S:7][C:6]2=[N:8][CH:9]=[C:10]([CH:11]=[O:12])[N:5]2[N:4]=1.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OO)(C)(C)C>C(#N)C.O>[CH2:16]([N:15]([CH3:14])[C:11]([C:10]1[N:5]2[C:6]([S:7][C:3]([N:2]([CH3:13])[CH3:1])=[N:4]2)=[N:8][CH:9]=1)=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1nn2c(C=O)cnc2s1
Reactant: CNCc1ccccc1
Agent: CC(C)(C)OO
Solvent: CC#N
Solvent: O
Product: CN(Cc1ccccc1)C(=O)c1cnc2sc(N(C)C)nn12
Temperature: 80 °C
Yield: 29 %

Procedure:
2-Dimethylamino-imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (116 mg, 0.591 mmol) was dissolved in dry acetonitrile (4 mL) and N-methylbenzylamine (0.768 mmol, 0.1 mL) and t-butylhydroperoxide (0.768 mmol, 5.5M, 0.14 mL) were added. The mixture was heated at 80° C. for 10 hours. The reaction mixture was diluted with water (4 mL) at room temperature and extracted with dichloromethane (3×8 mL). The combined organic layer was dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute cartridge SiII, ethyl acetate:dichloromethane, 1:9 to 10:0) yielding 54 mg of 2-dimethylamino-imidazo[2,1-b][1,3,4]thiadiazole-5-carboxylic acid benzyl-methyl-amide as yellowish solid (29% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[CH2:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: CCCc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-propylaniline to yield 2-[(4-propylphenyl)amino]phenylacetic acid.