Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([C:18]([F:21])([F:20])[F:19])=[N:14][O:15][C:16]=1[CH3:17])=O)C.C(OCC)(=O)C.O>C1COCC1>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[C:12]=1[CH2:10][OH:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1onc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of 0.16 g (4.2 mmoles) of lithium aluminum hydride dissolved in 15 ml of THF was cooled to 0° C. Thereto was gradually added a solution of 0.93 g (4.2 mmoles) of 4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole dissolved in 15 ml of THF. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 60.0%) of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol.
Reaction SMILES: [C:1]1([PH:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([OH:23])(=[O:22])[C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH2:17].C(O)(=O)CC>>[C:1]1([P:7]([CH2:17][CH:16]([CH2:18][C:19]([OH:21])=[O:20])[C:15]([OH:23])=[O:22])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCC(=O)O
Product: O=C(O)CC(CP(=O)(c1ccccc1)c1ccccc1)C(=O)O
Yield: 6 %

Procedure:
303 g (1.5 mol) of diphenylphosphine oxide, 214.5 g (1.65 mol) of itaconic acid and 470 g of propionic acid are refluxed under a nitrogen atmosphere for 8.5 hours with lively stirring. The mixture is then cooled. After crystallization, an additional 500 g of propionic acid are added, the product is filtered off with suction, washed and dried. This gives 390 g of product having a melting point of from 169° to 172° C. and a purity of 98.8% (determined by means of the 31P-NMR spectrum). A further 30 g of desired product are isolated from the filtrate. The total yield is 84% of theory, based on diphenylphosphine oxide used.
Reaction SMILES: N1([C:6]2[CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.[O:20]1CCOCC1>>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][CH:6]1[CH2:7][CH2:8][CH2:9][C:10]1=[O:20]
Reactant: C1COCCO1
Reactant: BrCc1ccccc1Br
Reactant: C1=C(N2CCCC2)CCC1
Product: O=C1CCCC1Cc1ccccc1Br
Yield: 45 %

Procedure:
In a manner similar to that described in Example 82, 1-pyrrolidino-1-cyclopentene (15.1 g, 0.11 mole) in dioxane (100 ml) was treated with 2-bromobenzyl bromide (30.0 g, 0.12 mol) to give the title compound as a clear oil (12.5 g, 45%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1>N1C=CC=CC=1.C(N(CC)CC)C.ClCCl>[CH3:14][O:15][C:16]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)=[O:5])=[O:22])=[CH:19][CH:18]=1)=[O:26]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 2-amino-4′-methoxyacetophenone hydrochloride (5.33 g) in pyridine (4.28 ml), triethylamine (3.68 ml) and dichloromethane (50 ml) was added dropwise a solution of terephthalic acid monomethyl ester (5.25 g) in dichloromethane (10 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, and stirred for 3 hours. To the reaction mixture was added dichloromethane (200 ml), washed with 1N-sodium hydroxide (100 ml×2), saturated hydrogen carbonate aqueous solution (100 ml×2) and brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in n-hexane, and collected by filtration to give 2-(4-methoxycarbonyl-benzamido)-4′-methoxyacetophenone (7.97 g).
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.C([O:25]CC)C>C(O)(C)(C)C>[CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][C:7]3=[O:25]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: CCOCC
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,2β-methylenandrost-4-ene-3,17-dione (0.2 g) in tert-butanol (5 ml) potassium tert-butoxide (0.26 g) is added and the mixture stirred vigorously for 24 hours at room temperature. Then ice water and diethyl ether are added, the ethereal extract washed with water, dried, and concentrated under reduced pressure. The residue is chromatographed on silica gel using n-hexane/ethyl acetate to give 0.15 g of 1,2β-methylenandrost-4-ene-3,6,17-trione. Found: C 81.01, H 8.05. C20H24O2 requires: C 81.04, H 8.16.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][C:4]=1CC)#[CH:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.[CH2:30](N(CC)CC)[CH3:31]>[Cu]I.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>[CH:13]([O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:25]3[CH:26]=[CH:27][C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:29])=[CH:23][CH:24]=3)=[CH:8][C:7]=2[CH2:30][CH3:31])[CH2:10][CH2:11]1)([CH3:14])[CH3:15]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95, 130.0 mg, 0.57 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 157.0 mg, 0.57 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 150.0 mg (70%) of the title compound as an orange oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-:22])C.[K+].[CH2:25](OC(Cl)=O)[CH2:26][CH2:27][CH3:28]>C1COCC1.CCOCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:22])[O:17][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)[O-]
Reactant: CCCCOC(=O)Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 40.0 g acetic acid 3-(4-tert-butyl-phenyl)-2- methyl-propenyl ester in 250 ml of THF was cooled to −70° C. A solution of 25.0 g potassium-tert-butoxide in 100 ml of THF was added at −70° C. during 35 min. and the resulting reaction mixture was stirred for 60 min. at the same temperature. 23.3 g butyl-chloroformate was dropped in during 40 min. and the reaction mixture was stirred for another 90 min. at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was thin-layer distilled and purified by chromatography to yield a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:8]([C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=3[N:5]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1cccc(C#N)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1cccc(C#N)c1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
A mixture of 3-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]benzonitrile (54 mg, 0.21 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (69 mg, 0.29 mmol) and DIPEA (65 mL, 0.37 mmol) in n-butanol (0.5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford 170 as a white solid (29 mg, 37%). LCMS (Method K): RT 3.03 min [M+H]+ 381.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.25-7.49 (8H, m), 7.32-7.17 (2H, m), 7.09 (1H, d, J=7.84 Hz), 5.60 (1H, s), 1.64 (3H, d, J=6.81 Hz)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:41]([N:49]1[CH:53]=[C:52]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([NH:17][CH:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 70.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-((3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (intermediate 66E) (200 mg, 0.297 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (133 mg, 0.446 mmol) using Pd(PPh3)2Cl2 (11 mg, 0.014 mmol) and sodium carbonate (79 mg, 0.744 mmol) in toluene/ethanol/water (5/2/1 ml) to afford 150 mg (70.4% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=717.3 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[OH:25])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:25])[C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOC(=O)N[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -50 °C
Yield: 50 %

Procedure:
To a mixture of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.59 mmol) and THF (6 mL) was added triethylamine (165 μL, 1.18 mmol) to form a clear solution. The mixture was cooled to −50° C. external temperature, and a 1:1 mixture of 2-methoxyethyl chloroformate (65 μL) and THF (65 μL) was added dropwise. After complete addition, the reaction was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 gave (R)-2-methoxyethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-Page 66 of 141 yl)pyrrolidin-3-ylcarbamate (compound 1) (130 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.7 Hz, 1H), 7.71 (d, J=6.1 Hz, 1H), 7.58 (s, 1H), 7.33 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.69 (m, 1H), 4.22 (m, 1H), 4.04 (m, 5H), 3.84 (m, 1H), 3.48 (t, J=4.6 Hz, 2H), 3.23 (s, 3H), 2.52 (s, 3H), 2.20 (m, 1H), 2.02 (m, 1H) ppm. LC/MS: m/z 441.5 (M+H)+ at 2.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Zn:1].II.[Br:4][CH2:5][CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1>CC(N(C)C)=O>[Br-:4].[F:12][C:9]1([F:13])[CH2:10][CH2:11][CH:6]([CH2:5][Zn+:1])[CH2:7][CH2:8]1
Reactant: [Zn]
Reactant: FC1(F)CCC(CBr)CC1
Agent: II
Solvent: CC(=O)N(C)C
Product: FC1(F)CCC(C[Zn+])CC1
Product: [Br-]
Temperature: 70 °C
Reaction time: 42 h

Procedure:
Zinc powder (1.43 g, 21.87 mmol) was added to a dried flask and was heated at 70° C. under vacuum for 30 minutes. Dry DMA (29 mL) and iodine (0.092 g, 0.37 mmol) were added and the mixture was heated at 70° C. until the red-brown colour had disappeared (approx. 5 minutes). 4-(Bromomethyl)-1,1-difluorocyclohexane (3.1 g, 14.55 mmol) was added and heating was continued for ca. 42 h. The resulting solution was used in the next transformation.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[C:6]=1[CH3:15])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].O>C(Cl)Cl>[CH3:15][C:6]1[C:7]2[CH2:11][O:10][C:9](=[O:12])[C:8]=2[CH:13]=[CH:14][C:5]=1[CH:3]([CH3:4])[CH:2]=[O:1]
Reactant: Cc1c(C(C)CO)ccc2c1COC2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(C)C=O)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-Hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one (161 mg, 0.781 mmol, 1.0 eq) was dissolved in DCM (6 ml). To above solution was added Dess-MartinPeriodinane (397 mg, 0.937 mmol, 1.2 eq). The reaction was stirred at rt for 2 hr. To the reaction was added DCM (10 Ml), Na2S2O3 (6 mL) and H2O (6 mL). The mixture was stirred at r.t. for 30 minutes and formed two layers. The bottom layer was separated and washed with aqueous NaHCO3, brine and water, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was used to next step without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 9.70 (1H, s, CHO), 7.79 (1H, d, J=7.8 Hz), 7.28 (1H, d, J=7.8 Hz), 5.28 (2H, s), 3.27 (1H, m), 2.32 (3H, s), 1.50 (3H, d, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[S:30][C:5]2[C:6](=[O:29])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([O:27][CH3:28])[CH:11]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1.CCO.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[S:30][C:5]3[C:6](=[O:29])[N:7]([C:10]4[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([O:27][CH3:28])[CH:11]=4)[CH2:8][CH2:9][C:4]=3[CH:3]=2)=[CH:37][CH:36]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cc(N2CCc3cc(Br)sc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
Dissolve 2-bromo-6-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (2.87 g, 5.46 mmol) in dimethoxyethane (28 mL) followed by addition of EtOH (4 mL) and water (8 mL). Add 4-chlorophenylboronic acid (1.28 g, 8.19 mmol) followed by 2M Na2CO3 (4 mL, 8.19 mmol). Allow dry argon gas to bubble through the reaction mixture for 15-20 min. Add Pd(PPh3)4 (315 mg, 0.27 mmol) and then warm to 90° C. under an argon atmosphere. After 3 h, filter the reaction through Celite® and elute with CH2Cl2. Concentrate and purify via silica gel chromatography using a 0-25% gradient of EtOAc/hexanes to give 2.37 g (80% yield) of the desired product. MS/ES m/z (35Cl) 542.1 [M+H]−.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:11]1[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[CH2:7][CH2:8][CH2:9][C:10]2=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Product: COc1ccc2[nH]c3c(c2c1)CCCc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using 6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.10 g, 6.87 mmoL) and 4-methoxy-phenylhydrazine HCl salt (1.20 g, 6.87 mmoL) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26].C(N(CC)CC)C.Cl>C(O)C.C(OCC)C>[ClH:1].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:30]1[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: CCN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(C3CCOCC3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CCOCC2)CC1
Yield: 83.8 %

Procedure:
Heat a solution of 6-chloro-8-(2-chlorophenyl)-2-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purine (0.0005 mol, 0.2 g), N-ethyl piperazine (0.0006 mol, 0.069 g, 1.1 equiv.), and triethylamine (0.0006 mol, 0.061 g, 1.1 equiv.) in ethanol (5.0 mL) at reflux for 20 hours. Alternatively, heat the reaction with microwave irradiation. Upon reaction completion, concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give the residue. Purify by silica gel chromatography eluting with hexanes:acetone 90:10 to give the freebase. Add HCl (2M solution in ethanol) (1.0 equiv.) to the freebase (0.23 g, 0.500 mmol) in diethyl ether (5 mL) at 0° C. and stir for 2 hours at room temperature. Filter and wash precipitate with diethyl ether. Dry the precipitate under vacuum to give the title compound (0.2 g). MS (m/z): 441.28 (M+1). Alternatively, prepare the HCl salt by dissolving the freebase in acetone, 1:1 acetonitrile:water, or another suitable organic solvent, then add with stirring a solution of aqueous or ethereal HCl. Then lyophilize to afford the hydrochloride salt.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])=[CH:11][CH:10]=2)O1.[Cl:21][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([O:32][C@H:33]3[CH2:38][O:37][C@H:36]([CH2:39][OH:40])[C@@H:35]([OH:41])[CH2:34]3)=[N:29][C:25]2=[N:26][C:27]=1I.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([O:32][C@H:33]3[CH2:38][O:37][C@H:36]([CH2:39][OH:40])[C@@H:35]([OH:41])[CH2:34]3)=[N:29][C:25]2=[N:26][C:27]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])=[CH:18][CH:19]=1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Reactant: CC(CO)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(CO)Oc1ccc(-c2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-1-ol (61.3 mg, 0.220 mmol), (2R,3S,5R)-5-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (75 mg, 0.176 mmol) and potassium phosphate tribasic (150 mg, 0.70 mmol) were dissolved in dioxane (600 μl) and water (600 μl). The mixture was sparged with N2 with for 15 min and [1,1′-Bis(Diphenyl-phosphino)Ferrocene]Dichloropalladium(II) (25.8 mg, 0.035 mmol) was added. The reaction was stirred 3 h at 80° C., then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2), and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C21H24ClN3O6 449.14 observed m/e: 449.92 (M+H)+ (Rt 1.03/2 min); 1H NMR δ (ppm) (CD3OD): 7.77 (s, 1H), 7.58 (d, 2H), 7.02 (d, 2H), 5.10 (septet, 1H), 4.57-4.54 (m, 2H), 4.32 (dd, 1H), 3.88 (d, 1H), 3.73-3.59 (m, 3H), 3.36 (t, 1H), 3.17-3.14 (m, 1H), 2.75-2.73 (m, 1H), 1.67 (dd, 1H), 1.31 (d, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17]CC)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([OH:17])=[O:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccnc(NC(=O)CCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of ethyl 2-[(3-phenylpropanoyl)amino]isonicotinate (3.41 g, 11.43 mmol), 1 M aqueous sodium hydroxide solution (15 mL), ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hr. The reaction mixture was neutralized with hydrochloric acid, and the precipitate was collected by filtration and washed with water to give the title compound (3.09 g, yield 100%) as colorless crystals.