Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15](Br)=[C:16]([CH3:17])[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.COCCOC>C(#N)C.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>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[C:16]([CH3:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1N
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2sc(-c3cccnc3)c(C)c2c1N
Temperature: 70 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
A mixture of ethyl 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (260 mg, 0.790 mmol) (Description 31), tetrakis(triphenylphosphine)palladium(0) (45.6 mg, 0.039 mmol), sodium carbonate (167 mg, 1.580 mmol) and 3-pyridineboronic acid (116 mg, 0.948 mmol) in acetonitrile (3 mL) and water (0.75 μl) was heated at 70° C. under nitrogen, for 30 min. 1,2-Dimethoxyethane (2 mL) was added and the mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in DCM, afforded the title compound (141 mg). LCMS (A) m/z: 328 [M+1]+, Rt 0.88 min (acidic), Rt 1.14 min (basic).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:5]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([CH3:2])[CH:4]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: Cc1ccc(NN)cc1C
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1C
Yield: 89.6 %

Procedure:
A black solution of 3,4-dimethylphenyl hydrazine hydrochloride (Apollo, 1.73 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.38 g, 11.0 mmol) in EtOH (20 mL) was stirred at reflux for 5 h. The cooled solution was concentrated in vacuo, redissolved in diethyl ether (20 mL) and washed with aqueous NaOH solution (1M, 20 mL). The aqueous was extracted with diethyl ether (2×20 mL), then the combined organics washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave the title compound (2.18 g, 90%). LCMS (Method 3): Rt 2.75 min, m/z 244 [MH+].
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[I:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21

Procedure:
610 mg (2.49 mmol) of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 2.5 mL DMF. 110 mg (2.74 mmol) of 60% sodium hydride was added followed by 480 μL (2.74 mmol) of trimethylsilylethoxymethyl chloride. Yield: 750 mg of an oily product, 90% pure.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([CH3:18])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C=C(C)c1ccc(NC(C)=O)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc(NC(C)=O)nc1
Reaction time: 48 h

Procedure:
A solution of (E/Z) ethyl 3-(6-acetylamino-pyrid-3yl)-but-2-enoate (27.3 g, Reference Example 22) in ethanol (500 mL) was hydrogenated (3bar hydrogen pressure) at 50° C. using 10% palladium on charcoal (1.0 g) as catalyst. After 48 h, the mixture was degassed, filtered through a pad of diatomaceous earth and the pad rinsed through with ethanol. The filtrate was evaporated to give the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[N:23][CH:24]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:24][N:23]=5)=[CH:30][CH:29]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[5-(trifluoromethyl)-2-pyridyl]benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:21])[CH3:20]
Reactant: O=C(O)CCCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCCC(=O)O
Yield: 99.9 %

Procedure:
9-Hydroxynonanoic acid (8.7 g, 50 mmol) in pyridine (8.1 ml, 100 mmol) was treated with acetic anhydride (4.7 ml, 50 mmol) at below 20° C. for 2 h. The mixture was poured onto ice and acidified. Two ether extractions gave 9-acetoxynonanoic acid as a colourless oil (10.8 g, 100%); δH (CDCl3) 10.0(1H, s, CO2H), 4.0(2H, t, H9), 2.3(2H, m, H2), 2.0(3H, s, OAC), 1.1-1.8(12H, m, H3-H8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (34.7 g, 115.5 mmol) in acetonitrile (300 ml) were added 4-trifluoromethylbenzyl bromide (27.6 g, 115.5 mmol) and potassium carbonate (31.9 g, 231 mmol), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was diluted with water (1 L) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Hexane was added to the residue and the precipitated crystals were washed with hexane to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (31 g, 76%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8]#[N:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][C:17]1([CH3:20])[CH2:19][O:18]1.O>COCCOC>[CH3:16][C:17]1([CH3:20])[O:18][C:8](=[NH:9])[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:19]1
Reactant: N#CNC[C@H]1CCCO1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)CN(C[C@H]2CCCO2)C(=N)O1

Procedure:
A mixture of Example 32A (0.6 g, 4.9 mmol), cesium carbonate (1.6 g, 4.9 mmol) and 2,2-dimethyloxirane (0.35 g, 4.9 mmol, Alfa-aesar) in 1,2-dimethoxyethane (20 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford the title compound. LCMS (APCI+) m/z 198 (M+H)+.
Reaction SMILES: CC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][C:24]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][C:24]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(OC)c1
Agent: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: COc1cc(C(=O)O)ccc1-c1ccccc1C
Yield: 82.6 %

Procedure:
The title compound was prepared following procedure described for Intermediate 5, step 2, but starting from methyl 2-methoxy-2′-methylbiphenyl-4-carboxylate (2.50 g; 9.75 mmol; 1 eq.), affording the title compound as a beige solid (1.95 g, 83%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.06 (s, 1H), 7.66-7.61 (m, 2H), 7.31-7.23 (m, 4H), 7.15-7.13 (d, J=7.28 Hz, 1H), 3.80 (s, 3H), 2.07 (s, 3H). LC/MS (Method A): 240.9 (M−H)−. HPLC (Method A) Rt 4.05 min (Purity: 97.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccc(F)cc1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1

Procedure:
2-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 720 mg of 2-(2,4-difluorophenyl)chroman-6ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.0, 3.0 Hz), 7.61 (m, 1H), 7.31 (m, 1H), 7.21 (d, 1H, 9.0 Hz), 7.17 (m, 1H), 7.02 (d, 1H, J 2.9 Hz), 6.97 (dd, 1H, J 8.9, 2.9 Hz), 6.91 (d, 1H, 8.9 Hz), 5.34 (dd, 1H, J 9.9, 2.0 Hz), 3.03 (m, 1H), 2.78 (m, 1H), 2.17 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:44]([C:47]1[CH:51]=[C:50]([CH2:52][OH:53])[O:49][N:48]=1)(=[O:46])[NH2:45]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:53][CH2:52][C:50]4[O:49][N:48]=[C:47]([C:44](=[O:46])[NH2:45])[CH:51]=4)[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(CO)on1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: NC(=O)c1cc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)on1

Procedure:
A solution of 0.25 g (0.54 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-ethylcarbamate, prepared in step 1.5., 0.139 g (1.08 mmol) of N,N-diisopropylethylamine, 0.033 g (0.27 mmol) of N,N-dimethylaminopyridine and 0.084 g (0.59 mmol) of 3-carbamoylisoxazol-5-ylmethanol in 5 mL of 1,2-dichloroethane is heated in a sealed tube at 90° C. for 12 hours.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.CC1CCCO1.[Zn+2].[Br-].[Br-].C(#N)C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 56 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.901 g; 4.00 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then 2-methyltetrahydrofuran (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0564 g; 10 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in 2-methyltetrahydrofuran (2 ml). The reaction mixture was then heated to 65° C. and stirred for 5 days; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.12 mmol (56% yield) of diphenylacetylene and 0.10 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=[C:7]2[N:6]=1)([F:4])[CH3:3].Br[C:28]1[CH:29]=[CH:30][C:31]([F:40])=[C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH:33]=1>>[F:4][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:28]3[CH:29]=[CH:30][C:31]([F:40])=[C:32]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[CH:33]=3)=[CH:12][N:13]=[C:7]2[N:6]=1)([F:1])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(F)F)ccn12
Reactant: Fc1ccc(Br)cc1-c1ccncc1
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4ccncc4)c3)cnc2n1

Procedure:
7-(1,1-Difluoroethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine was reacted with 4-(5-bromo-2-fluorophenyl)pyridine following the procedure described in Example 32 to give 7-(1,1-difluoroethyl)-3-[4-fluoro-3-(pyridin-4-yl)phenyl]imidazo[1,2-α]pyrimidine as a white solid: δH (360 MHz, CDCl3) 2.16 (1H, t, J 19), 7.31 (1H, d, J 7), 7.43 (1H, dd, J 10 and 8), 7.54 (2H, dd, J 6 and 1), 7.57-7.66 (2H, m), 8.00 (1H, s), 8.67 (1H, d, J 7), 8.74 (2H, d, J 6); m/z (ES+) 355 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([CH3:41])[N:26]=[C:27]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=4)[CH:31]=[N:30][CH:29]=3)[C:20]=12>C(#N)C>[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([N:32]2[C:28]([C:27]3[C:20]4[C:21](=[N:22][CH:23]=[N:24][C:19]=4[N:5]4[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)[N:25]([CH3:41])[N:26]=3)=[CH:29][N:30]=[CH:31]2)=[CH:34][CH:35]=1)[CH3:40]
Reactant: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(Cl)c23)cc1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(N4CC[C@@H](N(C)C)C4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (12.4 mg, 0.109 mmol) and N,N-diisopropylethylamine (14.5 mg, 0.109 mmol) were added to a solution of 4-chloro-3-[1-(4-ethylphenyl)-1H-imidazol-5-yl]-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C22) (37 mg, 0.11 mmol) in acetonitrile (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. After removal of volatiles in vacuo, the residue was chromatographed on silica gel (Gradient: 0% to 15% ethyl acetate in methanol) to afford the product as a glass. Yield: 13 mg, 0.031 mmol, 28%. LCMS m/z 417.1 (M+1). 1H NMR (500 MHz, CDCl3), characteristic peaks: δ 1.17 (t, J=7.6 Hz, 3H), 2.49-2.65 (m, 8H), 3.51-3.61 (br m, 1H), 3.72-3.81 (br m, 1H), 4.08 (s, 3H), 7.10 (br d, J=8.3 Hz, 2H), 7.22-7.29 (m, 2H, assumed; partially obscured by solvent peak), 7.40 (br s, 1H), 7.90 (br s, 1H), 8.29 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl.CCOC(C)=O>[C:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:9][CH3:10])(=[O:19])[CH3:18]
Reactant: COc1cc(F)ccc1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 4-fluoro-2-methoxyphenol (569 mg, 4.0 mmol) and pyridine (0.56 mL, 7.0 mmol) in CH2Cl2 (8.0 mL) at 0° C. was added acetyl chloride (0.33 mL, 4.6 mmol). The mixture was stirred at rt for 2.0 h and then diluted with EtOAc and washed with 4.0 N HCl. The organic layer was washed with brine and dried over Na2SO4. After evaporation of the solvent, 64A (680 mg, 92% yield) was obtained as a solid used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.29 (s, 3H) 3.79 (s, 3H) 6.62 (m, 1H) 6.68 (dd, J=10.33, 2.86 Hz, 1H) 6.95 (dd, J=8.79, 5.71 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:41])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[CH:32]([F:34])[F:33])[N:20]=[C:19]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:18]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].Br[CH2:43][CH:44]([CH3:46])[CH3:45]>CN(C)C=O>[C:3]([O:7][C:8](=[O:41])[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]([C:17]2[CH:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[CH:32]([F:33])[F:34])[N:20]=[C:19]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:18]=2)[CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1cc(-n2c(C(F)F)nc3ccccc32)nc(N2CCOCC2)n1)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (110 mg) was suspended in N,N-dimethylformamide (20 mL), and tert-butyl[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexyl]carbamate (1 g) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a 1-bromo-2-methylpropan (807 mg), followed by stirring at room temperature for 12 hours. After the completion of the reaction, to the reaction solution was added ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified using silica gel chromatography to obtain tert-butyl{trans-4-[{6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}(isobutyl)amino]cyclohexyl}carbamate (163 mg).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([O:22][C:23]([C:25]12[CH2:42][CH:41]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:43])[C:33](=[O:44])[N:32]1[CH:28]([CH2:29][CH:30]([OH:45])[CH2:31]1)[C:27](=[O:46])[NH:26]2)=[O:24])[CH3:21].[F:47][C:48]1[CH:49]=[C:50]([C:54]2[N:63]=[C:62](O)[C:61]3[C:56](=[C:57]([CH3:67])[C:58]([O:65][CH3:66])=[CH:59][CH:60]=3)[N:55]=2)[CH:51]=[CH:52][CH:53]=1.N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CN(C=O)C>[CH2:20]([O:22][C:23]([C:25]12[CH2:42][CH:41]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:43])[C:33](=[O:44])[N:32]1[CH:28]([CH2:29][CH:30]([O:45][C:62]3[C:61]4[C:56](=[C:57]([CH3:67])[C:58]([O:65][CH3:66])=[CH:59][CH:60]=4)[N:55]=[C:54]([C:50]4[CH:51]=[CH:52][CH:53]=[C:48]([F:47])[CH:49]=4)[N:63]=3)[CH2:31]1)[C:27](=[O:46])[NH:26]2)=[O:24])[CH3:21]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Reactant: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(Oc3nc(-c4cccc(F)c4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Reaction time: 18 h
Yield: 74.7 %

Procedure:
PPh3 (415 mg, 1.58 mmol) was added to a stirred solution of the alcohol 51 (300 mg, 0.79 mmol) and the quinazolinol 127 (247 mg, 0.87 mmol) in dry THF (35 mL) and dry DMF 7 mL. The reaction was placed under an inert atmosphere (N2) at room temperature. DIAD (311 μL, 1.58 mmol) was added. The reaction mixture was stirred for 18 h. A precipitation was formed in the flask and more white solid precipitated after addition of 40 mL diethyl ether. The precipitation was filtered off and washed with diethyl ether and dried under vacuum which gave the pure title compound (381 mg, 75%). LRMS (M+H) 646.
Reaction SMILES: Cl[C:2]1[N:29]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:38]=[C:39]([NH:40][C:2]3[N:29]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([N:16]6[CH2:21][CH2:20][CH:19]([N:22]7[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]7)[CH2:18][CH2:17]6)=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:35][CH2:36]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN1CCN(C2CCN(c3ccc(-c4cccn5nc(Cl)nc45)cc3)CC2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(N6CCC(N7CCN(C)CC7)CC6)cc5)cccn4n3)c2)CC1

Procedure:
206 a) 2-Chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3241 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (66.0 mg, 0.360 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.023 g, 17%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.7 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.10 (t, J=6.8 Hz, 1H), 7.03 (d, J=8.3 Hz, 2H), 3.87 (d, J=12.5 Hz, 2H), 2.82 (t, J=12.6 Hz, 2H), 2.70-2.35 (m, 9H), 2.30 (s, 3H), 1.95 (d, J=11.9 Hz, 2H), 1.75-1.60 (m, 2H). MS=411 (MH)+. 206 b) [3-(4-Methyl-piperazin-1-yl)-phenyl]-(8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 2-chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine (23.0 mg, 0.0560 mmol) and 3-(4-methylpiperazin-1-yl)aniline (12.0 mg, 0.0627 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (5.0 mg, 0.0091 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.014 g, 44%). MP=222-225° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.33 (d, J=6.6 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.52 (d, J=7.7 Hz, 1H), 7.48 (s, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.03 (d, J=7.9 Hz, 2H), 6.95-6.89 (m, 2H), 6.82 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.86 (d, J=13.2 Hz, 2H), 3.31-3.26 (m, 4H), 2.81 (t, J=12.2 Hz, 2H), 2.70-2.38 (m, 13H), 2.37 (s, 3H), 2.30 (s, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.75-1.63 (m, 2H). MS=566 (MH)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:35])=[O:34]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: CC(C)CS(=O)(=O)N1CCC[C@@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[(R)-1-(2-Methyl-propane-1-sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2-methyl-propane-1-sulfonyl chloride.