Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[N:10]([CH2:11][CH3:12])[C:9](=[O:13])[CH2:8][O:7][C:6]=2[N:14]=1.CC1(C)C(C)(C)OB([C:29]2[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:11]([N:10]1[C:9](=[O:13])[CH2:8][O:7][C:6]2[N:14]=[C:2]([C:29]3[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:31][CH:30]=3)[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][C:5]1=2)[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Temperature: 50 °C
Yield: 65.3 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.150 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (60.0 mg, 0.180 mmol), and CESIUM CARBONATE (244 mg, 0.750 mmol) in a mixture of 1,4-Dioxane (2814 μl) and water (938 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)-CH2Cl2Adduct (24.51 mg, 0.030 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give an off-white solid. The resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column) to give the title compound (45 mg, 65.3%) as off-white solid. 1H NMR (500 MHz, CDCl3): 7.31-7.27 (6H, m), 7.19-7.18 (2H, d), 7.11-7.10 (2H, d), 4.87 (2H, s), 4.84 (1H, br), 4.27 (2H, s), 4.03-3.98 (2H, q), 1.45 (9H, br), 1.32-1.30 (3H, t).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[S:19][C:18]3[C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:16][C:15]([C:26]4[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=4)=[N:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[OH:32][C:28]1[CH:27]=[C:26]([C:15]2[N:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:18]3[S:19][C:11]([CH2:10][N:7]4[CH2:6][CH2:5][CH:4]([NH:3][C:40](=[O:42])[CH3:41])[CH2:9][CH2:8]4)=[CH:12][C:13]=3[N:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: NC1CCN(Cc2cc3nc(-c4cccc(O)c4)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(Cc2cc3nc(-c4cccc(O)c4)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-[6-(4-Amino-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenol di-hydrochloride salt (80 mg, 0.16 mmol) in dichloromethane (1.5 mL) and triethylamine (5 eq., 110 μL) was added acetyl chloride (2.5 eq., 29 μL). After stirring at rt for 2 hours, the reaction mixture was diluted with dichloromethane, washed with brine, separated and dried (MgSO4). The crude product was evaporated in vacuo, re-dissolved in methanol (2 mL), to this was added sodium carbonate. The reaction mixture was stirred at RT overnight, evaporated in vacuo, diluted with dichloromethane, washed with brine, separated and dried (MgSO4). The residue was purified by chromatography to give the title compound as a white solid (55 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C(Cl)Cl.[C:8]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9]>C(OC(=O)C)C>[Br:1][CH2:2][CH2:3][O:4][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.8 %

Procedure:
To a solution of 2-bromoethanol (3.4 mL, 48.34 mmol) in dry DCM (25 mL) imidazole (9.86 g, 143 mmol) and tert-butylchlorodimethylsilane (10.9 gm, 72.52 mmol) were added at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (350 mL) and washed with water (4×20 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.2:9.8 Ethyl acetate:Pet. Ether) to afford title compound (204 mg, 77.5%) as liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][C:9]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15](C([O-])=O)[CH2:14]2)=[N:10][CH:11]=1.[ClH:22]>ClCCCl.O1CCOCC1>[ClH:22].[ClH:22].[NH:15]1[CH2:16][CH2:17][C@@H:13]([NH:12][C:9]2[N:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:21])=[N:7][CH:8]=2)[CH2:14]1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)[O-])C2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate (10.50 g) in 1,2-dichloroethane (100 mL) was added a 4N HCl in dioxane (100 mL) and the mixture was stirred at 20-25° C. for 2 hours under nitrogen atmosphere to give a solid. The solid was collected by filtration to give methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (9.73 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][F:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[NH:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].C([O:19][C:20](=O)[CH:21]([Cl:23])[Cl:22])C>>[Cl:22][CH:21]([Cl:23])[C:20]([NH:1][C@H:2]([CH2:15][F:16])[C@H:3]([OH:4])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[NH:13])=[O:12])=[CH:9][CH:10]=1)=[O:19]
Reactant: CS(=N)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)C(Cl)Cl
Product: CS(=N)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
To a solution of (1R,2S)-2-amino-3-fluoro-1-(4-(S-methylsulfonimidoyl)phenyl)propan-1-ol (76 mg, 0.308 mmol) Methanol (5 mL) is added TEA (0.047 mL, 0.462 mmol) followed by addition of ethyldichloroacetate (0.048 mL, 0.308 mmol) The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo to get crude which is purified by combi-flash chromatography using 0.6% MeOH in DCM as an eluent to get 40 mg of the compound which is re-purified by prep HPLC to afford title compound (25 mg) white solid. 1H-NMR (400 MHz, DMSO) δ: 3.0 (s, 3H), 4.19-4.25 (m, 2H), 4.28-4.32 (m, 0.5H), 4.40-4.44 (m, 0.5H), 4.56-4.59 (m, 0.5H), 4.67-4.71 (m, 0.5H), 4.96 (bs, 1H), 6.12 (d, 1H, J=3.6 Hz), 6.47 (d, 1H, J=1.88 Hz), 7.56 (d, 2H, J=8.28 Hz), 7.54 (d, 2H, J=8.28 Hz), 8.82 (d, 1H, J=8.28 Hz). LC-MS (m/z): M+H=357.0.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C@H:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH2:17][O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:15][CH2:14]3)[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=1
Reactant: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3)cc1
Yield: 40.2 %

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane (Example 17; 1.51 g, 2.81 mmol) was dissolved in ethyl acetate (20 ml) and glacial acetic acid (2 ml) and 10% palladium hydroxide (200 mg) added and hydrogenated at 45 psi overnight. The reaction mixture was filtered then concentrated in vacuo. The oil was basified (4N sodium hydroxide) and the solution extracted with ethyl acetate (×3). The organics were dried (MgSO4) and concentrated in vacuo. The mixture was purified by flash column chromatography [7.5% methanol in dichloromethane] to give a yellow oil which solidified on standing to give the title compound (506 mg, 40%). The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to the title compound (31 mg, 0.06 mmol). A white solid formed which was triturated in diethyl ether and filtered then dried at 60° C. in vacuo (29.8 mg, 89%).
Reaction SMILES: C(OC(=O)[CH:5]([C:14]#[N:15])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])C>CS(C)=O.O>[CH:8]1([C:6](=[O:7])[CH2:5][C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(C#N)C(=O)C1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: N#CCC(=O)C1CCCCC1

Procedure:
A solution of 2-cyano-3-cyclohexyl-3-oxo-propionic acid ethyl ester in DMSO:water (10:1) was stirred at 120° C. for 2 hours. The reaction mixture was partitioned between ether and 1N HCl, the organic phase was dried with MgSO4 and the solvent removed under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:20]=2[N:19]=1>>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:25]=[CH:26][C:20]2[N:19]=[C:18]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)[NH:22][C:21]=2[CH:23]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The title compound was prepared from 1-(3-trifluoromethylpyridin-2-yl)piperazine (Maybridge) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (Example 1c) under the conditions of Example 3c. MS (ESI, pos. ion) m/z: 416 (M+1). M.p. 221-224° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Br:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1/[CH:8]=[N:9]/[C@@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][OH:12]>O1CCCC1.[Zn]>[Br:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[C@@H:8]([NH:9][C@@H:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][OH:12])[CH2:3][CH:2]=[CH2:1]
Reactant: OC[C@@H](/N=C/c1ccccc1Br)c1ccccc1
Reactant: C=CCBr
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC[C@H](N[C@H](CO)c1ccccc1)c1ccccc1Br
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a stirred suspension of zinc (70.8 mmol, 4.63 g, <10 micron) in tetrahydrofuran (35 mL) under nitrogen was added allyl bromide (70.8 mmol, 6.16 mL, 8.57 g) over 1 minute at room temperature. There was a moderate exotherm and the resultant grey suspension was stirred for 1.5 h then cooled in an ice/brine bath. A solution of (S,E)-2-(2-bromobenzylideneamino)-2-phenylethanol (compound 1; 23.60 mmol, 7.18 g) in tetra-hydrofuran (20 mL) was added dropwise over 30 minutes and stirred 10 minutes at 0° C. The bath was replaced with a 25° C. water bath and the grey suspension was stirred for 30 minutes at room temperature then quenched by addition of water, in one portion (50 mL). Methylene chloride (100 mL) was added and the mixture stirred for 1 h then to this mixture was added saturated sodium hydrogen carbonate (50 mL). The mixture was filtered through dicalite and layers separated. The separated aqueous layer was extracted further with methylene chloride and the organic extracts dried over sodium sulfate and evaporated to a pale yellow oil which was purified on 200 g silica pad using ethyl acetate/heptane (10-30%) to give pure (S)-2-((S)-1-(2-bromophenyl)but-3-enylamino)-2-phenylethanol (4.52 g), MS (ES): m/z [M+H]+ 346 and 348.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CCN(CC)CC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])#[N:9]
Reactant: CCCC(=O)Cl
Reactant: Cc1nsc(N)c1C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1snc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (5.31 g, 38.2 mmol) in DCM (200 mL) at 0° C., NEt3 (5 g, 50 mmol) was added followed by the dropwise addition of a solution of the butyryl chloride (4.88 g, 45.8 mmol) in DCM (50 mL). After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was washed with water (100 mL), 1N HCl (100 mL), brine (200 mL) and dried over Na2SO4. Concentration of the DCM layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate the pure N-(4-cyano-3-methyl-isothiazol-5-yl)-butyramide (7.57 g, 95%) as an orange solid.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=[O:10].C(C1(C2C=C(F)C=C[C:19]=2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=O)CC1)#N>O>[C:37]([C:34]1([C:28]2([C:27]3[CH:25]=[CH:19][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:29][O:10]2)[CH2:35][CH2:36]1)#[N:38]
Reactant: C[S+](C)(C)=O
Reactant: N#CC1(c2cc(F)ccc2C(=O)c2ccc(F)cc2C2(C#N)CC2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(C2(c3ccc(F)cc3)CO2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
130 ml of abs. DMSO are slowly added dropwise at 10° C. to 6.6 g (0.22 mol) of sodium hydride (80% in oil) and 34.2 g (0.16 mol) of trimethylsulphoxonium iodide. The mixture is stirred for one hour at 20° C. and then 26.3 g (0.14 mol) of 1-cyanocyclopropyl-4-fluorophenyl ketone (compound II-2, Example 19, dissolved in 65 ml of abs. DMSO) are added dropwise. The mixture is stirred for 14 h at 20° C. The solution is poured into water and the mixture is extracted with ethyl acetate. The combined organic phases are washed with H2O and dried over Na2SO4, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel and 15 g (54% of theory) of 2-(1-cyanocyclopropyl)-2-(4-fluorophenyl)oxirane are obtained in the form of a colorless oil after evaporating the solvent, 1H--NMR (CDCl3):
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=2[O:22][CH3:23])[CH:6]=[CH:5][C:4]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[Br:17][C:15]1[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([O:22][CH3:23])=[C:11](/[CH:10]=[CH:9]/[C:7]2[CH:6]=[CH:5][C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:3]([CH:8]=2)[CH2:2][NH:1][C:35](=[O:37])[CH3:36])[CH:16]=1
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CN)c2)cc(Br)cc1C(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CNC(C)=O)c2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
step 2—To a solution of 210 (0.150 g, 0.321 mmol), pyridine (100 L) and DCM (10 mL) cooled to 0° C. was added acetic anhydride (70 μL). The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with DCM, washed with sat'd. CuSO4 and twice with 1N HCl, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (50 to 75% EtOAc) to afford 45 mg of N-{5-[(E)-2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-vinyl]-2-methanesulfonylamino-benzyl}-acetamide (212).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC.O1CCOCC1>CO.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:29]=[C:11]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)=[C:3]2[NH:10][CH:9]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]#[N:22])[CH2:16][CH2:15]1)=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-c4nccs4)ccnc23)CC1)c1ccccc1
Yield: 16.2 %

Procedure:
A mixture of Example 101 (30 mg, 0.074 mmol), 2-tributylstannanyl thiazole (111 mg, 0.30 mmol), Pd(PPh3)4 (172 mg, 0.149 mmol) and dioxane (1 mL) in a sealed tube was heated at 120° C. for 15 h. The reaction mixture was diluted with MeOH, filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (5.6 mg, 0.012 mmol, 19%) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:14]=3[CH:27]=2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]=3[CH:27]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
tert-Butyl 2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285 mg, 0.70 mmol) was dissolved in 5 mL dichloromethane. 2 mL trifluoroacetic acid was added and the mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under vacuum and the residue was crystallized from ethyl acetate/hexane to give 2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid (160 mg, 0.453 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1(C)C=CC=CC=1>[C:16]1([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 31.3 g (0.2 mol) of 2-chlorobenzoic acid and 180 g of toluene are placed. To the above mixture in the flask, 25.0 g (0.21 mol) of thionyl chloride is added dropwise over 30 minutes while stirring at a temperature of from 60° to 65° C. to be allowed to react with each other for about 30 minutes. To the above reaction mixture, a solution containing 27.9 g (0.3 mol) of aniline dissolved in 100 g of toluene is dropwise added to be allowed to react with each other at a temperature of from 70° to 75° C. for 30 minutes. After completion of the reaction, the reaction mixture is cooled to room temperature, and 70 g of a 5% by weight hydrochloric acid solution is added to the above mixture. The mixture is vigorously shaken and kept standing for separation of the toluene layer from the aqueous layer. After separation of the toluene layer, it is condensed to precipitate white crystals, followed by recrystallization (in a water/methanol mixture of 3/7), to give 43.1 g of N-phenyl-2-chlorobenzamide (melting point: 116° to 117° C.). The yield of the product against 2-chlorobenzoic acid is 93%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH2:30][CH:29]2[NH:31][CH:26]([CH2:27][CH2:28]2)[CH:25]=1.CS(C)=O>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH2:25][CH:26]2[N:31]([CH2:2][CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[CH:8][NH:9]4)[CH:29]([CH2:28][CH2:27]2)[CH:30]=1
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Reactant: ClCCOc1cccc2[nH]ccc12
Solvent: CS(C)=O
Solvent: O
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2CCOc1cccc2[nH]ccc12
Temperature: 23 °C
Yield: 63 %

Procedure:
4-(2-Chloro-ethoxy)-1H-indole (170 mg, 0.87 mmol), 469 mg (1.74 mmol) of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene and 10 mL of DMSO are heated at 100° C. for 24 h. After cooling to 23° C., the orange reaction mixture is poured into 100 mL H2O. Extraction with CH2Cl2 (2×50 mL), combining the organic layers and washing with H2O (4×50 mL), brine (1×50 mL), drying over MgSO4, and evaporation gives an orange oil. Flash chromatography on SiO2 gel, eluting with CHCl3/MeOH (40/1 to 10/1), gives 216 mg (0.59 mmol, a 63% yield) of the title compound as an off-white solid. The corresponding oxalate salt is prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH. A white solid precipitates. Recrystallization from EtOH/Et2O gives the oxalate salt of the title compound as an off-white solid. mp: 212-215° C.; MS (ES) m/z 395 (MH)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:16])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=1[C:44]1[C:48]([CH2:49][OH:50])=[C:47]([CH:51]([CH3:53])[CH3:52])[O:46][N:45]=1>ClCCl>[C:11]([O:10][C:9](=[O:15])[N:8]([O:50][CH2:49][C:48]1[C:44]([C:38]2[C:37]([Cl:36])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:43])=[N:45][O:46][C:47]=1[CH:51]([CH3:53])[CH3:52])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH3:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccccc1N(OCc1c(-c2c(Cl)cccc2Cl)noc1C(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-hydroxy-2-methylphenylcarbamate (3.0 g, 13.4 mmol), triphenylphosphine (3.53 g, 13.4 mmol), and [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (3.85 g, 13.4 mmol) in dichloromethane (40 mL) at 0° C. was treated with a solution of diisopropylazidodicarboxylate (2.65 mL, 13.4 mmol) in dichloromethane (10 mL) dropwise. The reaction was allowed to stir at 0° C. for 30 minutes, then warmed to ambient temperature for 1 h after which time the solvent was removed in vacuo. The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes. Yield=4.34 g (66%) of tert-butyl 4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([NH2:40])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cn3)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(N)=O)CC4)cn3)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamine (50 mg, 0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL), was added 2-bromo-acetamide (25 mg, 0.18 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by RP-HPLC to afford 2-(4-(6-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidin-1-yl)acetamide as a white solid; 1H NMR (400 MHz, MeOD-d4) δ 8.30 (s, 1H), 8.21 (s, 1H), 7.28 (s, 1H), 6.19 (s, 1H), 4.0 (s, 2H), 3.80-3.73 (m, 2H), 3.33-3.21 (m, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 2.37-2.32 (m, 2H), 2.20-2.16 (m, 2H); ESMS m/z 456.2 (M+H+).