Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:3]=1.[C:17]([NH:20][NH2:21])(=[O:19])[CH3:18]>CCO>[C:17]([NH:20][N:21]=[CH:8][C:7]1[C:2]([F:1])=[N:3][C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:5][CH:6]=1)(=[O:19])[CH3:18]
Reactant: CN1CCN(c2ccc(C=O)c(F)n2)CC1
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NN=Cc1ccc(N2CCN(C)CC2)nc1F
Reaction time: 72 h

Procedure:
2-Fluoro-6-(4-methyl-1-piperazinyl)pyridine-3-carboxaldehyde (3.35 g, 0.015 mole) was dissolved in 20 mL of EtOH and treated with acetylhydrazine (2.2 g, 0.030 mole). This reaction mixture was stirred for 72 hours and then the product was filtered off and recrystallized from EtOAc to give 2.85 g, mp 210°-212° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:13]=[N:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[N:10]=1.I[C:30]1[CH:35]=[CH:34][N:33]([CH2:36][CH2:37][C@@:38]([CH3:53])([S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([NH:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)=[O:40])[C:32](=[O:54])[CH:31]=1.O>O1CCOCC1.[Pd]>[CH3:7][O:8][C:9]1[CH:13]=[N:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:30]3[CH:35]=[CH:34][N:33]([CH2:36][CH2:37][C@@:38]([CH3:53])([S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:40])[C:32](=[O:54])[CH:31]=3)=[CH:18][CH:19]=2)[N:10]=1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: COc1cnn(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)n1

Procedure:
Pd EnCat (98 mg, 0.03 mmol) was added to a mixture of potassium carbonate (171 mg, 1.24 mmol), 4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (138 mg, 0.457 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2B(T6) (190 mg, 0.381 mmol) in dioxane:water (6 ml, 5:1mix) in a 20 ml vial. The reaction was cooled and filtered through celite (approx 1 inch). The celite was washed with additional methanol (100 ml). The filtrate was concentrated in vacuo and the crude material was purified by chromatography on silica gel (4:1heptane:EtOAc to 100% EtOAc to 85% EtOAc:15% methanol) to furnish a light tan gum (120 mg, 58% TY). MS (LC/MS) m/z 546.2 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28 (s, 1H) 1.57-1.70 (m, 2H) 1.68-1.81 (m, 3H) 1.78-1.92 (m, 3H) 2.36-2.50 (m, 1H) 2.55-2.72 (m, 1H) 3.09-3.21 (m, 3H) 3.56-3.70 (m, 1H) 4.07 (s, 3H) 4.12 (d, J=7.22 Hz, 2H) 4.15-4.25 (m, 1H) 4.25-4.42 (m, 1H) 5.01-5.14 (m, 1H) 6.76-6.85 (m, 1H) 6.87 (s, 1H) 7.49 (s, 1H) 7.68-7.80 (m, 1H) 7.85 (d, J=9.17 Hz, 2H) 8.08 (d, J=8.98 Hz, 2H)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.[F-].[Cs+].[C:19]([O:22][C@H:23]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@:27]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46]Br)[CH:40]=3)[O:38][C@@:24]1([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:25][O:26]2)(=[O:21])[CH3:20]>O1CCOCC1.C(OC(=O)C)C>[C:19]([O:22][C@H:23]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@:27]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:9]4[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=4)[CH:40]=3)[O:38][C@@:24]1([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:25][O:26]2)(=[O:21])[CH3:20]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 110 °C
Yield: 41 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (500 mg, 2.25 mmol), CsF (865.83 mg, 5.70 mmol) in Dioxane (9.5 mL), (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1.07 g, 1.90 mmol, Intermediate 2) and Pd(PPh3) (173.3 mg, 0.15 mmol) were added under N2 atmosphere. The reaction mixture was heated to 110° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:hexane) to provide title compound (450 mg, 41.3%) as off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].[Na].Cl[CH2:27][C:28]#[N:29]>C(OCC)C.C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:27][C:28]#[N:29])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: O=C(NCCc1ccc(O)cc1)OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: N#CCOc1ccc(CCNC(=O)OCc2ccccc2)cc1
Reaction time: 5 h

Procedure:
48.82 g. (0.18 mol) of the above-prepared N-(benzyloxycarbonyl)-p-hydroxyphenethylamine are introduced into a sodium ethylate solution freshly prepared from 5.17 g. sodium and 270 ml. ethanol, 11.4 ml. (0.18 mol) chloroacetonitrile are slowly added dropwise thereto and the reaction mixture is heated to the boil. After 5 hours, the solvent is stripped off, the residue is taken up in diethyl ether, extracted twice with 2N aqueous sodium hydroxide solution, washed neutral, dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue is recrystallised from ligroin/diethyl ether (8:2 v/v). There are obtained 44.74 g. (80% of theory) of the desired product in the form of colourless crystals; m.p. 110°-115° C.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[CH:10](=[O:12])[CH3:11].B(F)(F)F.CCOCC>ClCCCl>[CH3:3][C:2]1=[CH:4][CH2:8][CH2:7][CH2:6][C:5](=[O:9])[O:12][CH:10]([CH3:11])[CH2:1]1
Reactant: C=C(C)C1CCCC1=O
Reactant: CC=O
Agent: C/C1=C/CCCC(=O)OC(C)C1
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CCOCC
Product: CC1=CCCCC(=O)OC(C)C1

Procedure:
Following the general procedure as described in Example 1, 2-(prop-1-en-2-yl)cyclopentanone (1.24 g, 10 mmol), acetaldehyde (0.53 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (0.59 g, 35% yield). Single Z-isomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[CH:21][CH:22]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.Cl.C([O-])(O)=O.[Na+]>COCCO.C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:18]3[NH:19][N:20]=[CH:21][C:22]3=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([OH:23])=[CH:25][CH:26]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1ccn[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: COCCO
Product: Oc1ccc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nc3[nH]ncc23)cc1
Yield: 41.1 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (0.30 g, 1.4 mmol, obtained in reference example 1) in 2-methoxyethanol (2 mL), 3-amino-2H-pyrazole (0.13 g, 1.5 mmol), 4-hydroxybenzaldehyde (0.17 g, 1.4 mmol), 2-methoxyethanol (2 mL) and 37% HCl (0.04 g, 0.4 mmol) were added under argon atmosphere. The mixture was heated to reflux overnight. It was allowed to cool and concentrated. The solid obtained was dissolved in CHCl3 and some drops of MeOH. Saturated NaHCO3 was added and the aqueous phase was extracted 3 times with CHCl3. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.22 g of the desired compound (yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH3:29])=[O:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:26](=[O:27])[O:28][CH3:29])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 63 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.1 eq of methyl chloroformate in dioxane/water (2:1) in the presence of sodium acetate (2.5 eq). The crude product is recrystallized from isopropyl ether:cyclohexane to give pure [[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxycarbamic acid, methyl ester (63%); mp 113°-114° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH2:18])[CH3:17].Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[NH:22][CH:23]=[N:24]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH:18][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2)[CH3:17]
Reactant: CC(N)c1cc2ccsc2nc1-c1ccccn1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc2ccsc2nc1-c1ccccn1
Temperature: 110 °C

Procedure:
To a reaction flask containing 1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine (134 mg, 0.525 mmol), 6-chloropurine (97 mg, 0.63 mmol, 1.2 eq) and diisopropylethylamine (137 μL, 0.79 mmol, 1.5 eq) was added 5 mL of n-butanol. The reaction was heated to 110° C. for 24 h, then cooled to rt and concentrated in vacuo. The residue was dissolved in ethyl acetate (˜50 mL) with heat and sonication, then washed with 5 mL water and 5 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 0-80% gradient of (90:9:1 DCM:MeOH:NH4OH) in dichloromethane afforded racemic N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. The room temperature NMR spectrum in CDCl3 exists as a roughly 3:1 mixture of isomers. 1H NMR (400 MHz, CDCl3) δ 8.80 (br d, J=4.3 Hz, 0.75 H), 8.73 (br d, J=3.1 Hz, 0.25 H), 8.55 (s, 0.25 H), 8.36-8.26 (series of m, 1.75 H), 8.15-8.03 (series of m, 1.5 H), 7.93 (br s, 0.75 H), 7.88 (m, 1.4 H), 7.56 (m, 0.5 H), 7.55 (d, J=5.9 Hz, 0.75 H), 7.37 (dd, J=6.6, 5.1 Hz, 0.75 H), 7.26 (d, J=5.9 Hz, 0.75 H), 7.20 (d, J=5.9 Hz, 0.25 H), 6.65 (m, 0.25 H), 6.35 (m, 0.25 H), 6.15 (br s, 0.75 H), 1.55 (d, J=7.0 Hz, 2.25 H), 1.35 (d, J=6.3 Hz, 0.75 H) ppm. LC/MS (M+1, found=374.0). Chiral SFC separation of the racemate afforded the individual enantiomers, (S)—N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine and (R)—N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=C([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])C(O)=O)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2].[C:31]([N:38]1[CH:42]=[CH:41]N=[CH:39]1)(N1C=CN=C1)=O.CNC.[O:46]1CCCC1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:41]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:42]([N:38]([CH3:31])[CH3:39])=[O:46])[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2]
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C(=O)O)cc1Oc1nc(Oc2cccc(C#N)c2)c(F)c(C)c1F
Agent: CNC
Product: COc1ccc(C(=O)N(C)C)cc1Oc1nc(Oc2cccc(C#N)c2)c(F)c(C)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-4-methoxybenzoic acid (0.47 g, 1.1 mmol) in tetrahydrofuran (12 mL) was added 1,1′-carbonyidiimidazole (0.22 g, 1.4 mmol) and stirred at ambient temperature for 3 hours. Then dimethylamine (aq, 0.077 g, 1.7 mmol) was added. After stirring for 12 hours the solution was partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/8) as eluent gave 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-N,N-dimethyl-4-methoxybenzamide; NMR (CDCl3) 6.9-7.4 (m, 7), 3.8 (s, 3), 3.0 (br, 6), 2.4 (s, 3) ppm.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[CH2:7]([C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH2:13][CH:14]=[CH2:15])[C:11]#[N:12])[CH:8]=[CH2:9]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:7]([C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH2:13][CH:14]=[CH2:15])[C:11]([NH2:1])=[NH:12])[CH:8]=[CH2:9]
Reactant: [NH4+]
Reactant: C=CCC(C#N)(CC=C)c1cccc(OC)c1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=CCC(CC=C)(C(=N)N)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of NH4Cl (13.5 9, 251 mmol) in 170 mL toluene at 0° C. was added a 2.0 M solution of AlMe3 (126 mL, 251 mmol) dropwise. The mixture was warmed to room temperature and stirred for 4 hours. 2-Allyl-2-(3-methoxy-phenyl)-pent-4-enenitrile (38.1 g, 167 mmol) in 30 mL toluene was added and the mixture was heated to 80° C. for 48 hours. The mixture was cooled to room temperature and poured into a stirring suspension of silica gel (50 g) in 150 mL chloroform (CHCl3). After stirring for 30 minutes, the suspension was filtered and the silica gel was washed with methanol (MeOH). The remaining solution was concentrated to an oil and 80 mL acetone was added. The resulting suspension was filtered, the solution was concentrated and the resulting residue was dissolved in 1N hydrochloric acid (HCl)/MeOH (200 mL). The solution was concentrated, 200 mL ethyl ether (Et2O) was added and the resulting precipitate was removed by filtration and dried yielding 22.4 9 (49% yield) of the desired product. 1HNMR (400 MHz, CD3OD) δ 8.73, 8.58 (2 brs, 3H, NH), 7.34 (t, 1H), 6.93-6.91 (comp, 2H), 6.90-6.83 (comp, 1H), 5.56-5.44 (comp, 2H), 5.18-5.14 (comp, 4H), 3.79 (s, 3H), 2.82-2.79 (comp, 4H); MS (M+1) 245.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([O:16][CH3:17])=O)[CH:13]=1.Br[C:26]1[C:27](=O)[N:28](C2C=CC=CC=2)[CH:29]=[C:30](C(OC)=O)[CH:31]=1.ClC1C=CC=CC=1B(O)O.C(Cl)(=O)C(Cl)=O.NC1C=CC=CC=1O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]2[O:16][C:17]3[CH:29]=[CH:30][CH:31]=[CH:26][C:27]=3[N:28]=2)[CH:13]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Agent: Nc1ccccc1O
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2Cl)cc(-c2nc3ccccc3o2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19 mg of carboxylate obtained by hydrolyzing the ester group of 3-(2-chlorophenyl)-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one (synthesized from 3-bromo-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one and 2-chlorophenylboronic acid in accordance with the method of Referential Example 3) was dissolved in 20 ml of dichloromethane. Under ice-cooling, a solution of 11 mg of oxalyl chloride in dichloromethane was added dropwise thereinto and a catalytic amount of dimethylformamide was added thereto, followed by stirring at room temperature in nitrogen atmosphere for 1 hour. The reaction solution was evaporeted, and the residue was dissolved in dichloromethane. The solution was added dropwise into a solution of 19 mg of 2-aminophenol in dichloromethane under ice-cooling. After heating to room temperature, dichlotomethane was evaporated. To the residue was added 1 ml of polyphosphoric acid, followed by stirring at 180° C. overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 3 mg of the title compound as white crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CN(C)C=O.[Br:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]3([C:13]([NH:32][C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([Br:25])[N:31]=4)=[O:15])[CH2:11][CH2:12]3)[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.2 g, 5.8 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (2.5 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir at 60° C. for 30 minutes. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 5 mL of anhydrous pyridine. This solution was then slowly added to a solution of 6-bromopyridin-2-amine (1.0 g, 5.8 mmol) suspended in 10 mL of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110° C. The mixture was then evaporated to dryness, suspended in 50 mL of dichloromethane, and washed with three 20 mL portions of 1N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified by silica gel column chromatography utilizing dichloromethane containing 2.5% triethylamine as the eluent to yield the pure product. ESI-MS m/z calc. 361.2, found 362.1 (M+1)+; Retention time 3.43 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.17 (m, 2H), 1.42-1.55 (m, 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.78 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[O:45][C:46](=[O:48])[CH3:47])[CH:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccnc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
3-Aminopyridine (0.424 g, 4.492 mmol), triethylamine (0.440 g, 4.342 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.735 g, 4.342 mmol) were added to a methylene chloride solution (200 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (1.120 g, 2.995 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.710 g, 1.576 mmol, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([C:23]([OH:24])([CH3:25])[CH3:22])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (60 mg, 1.0 eq) dissolved in THF (2.5 ml) at −78° C. was added 1.6M solution of n-butyllithium (0.20 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at −78° C. for 30 minutes. Acetone (0.07 ml, 4.0 eq) was added and reaction mixture was allowed to warm up to −40° C. and stirred for 1 h. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 2-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol 46. MS (Q1) 298 (M)+.
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6](=[O:42])[C@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:8][O:9][CH3:10])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[F:1][CH:2]1[CH2:3][N:4]([C:6](=[O:42])[C@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:8][O:9][CH3:10])[CH2:5]1
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
In a 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide (47 mg, 0.076 mmol) and TFA (1.2 ml, 15.6 mmol) were combined with dichloromethane (4 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (4 mL) and ethylenediamine (0.36 ml, 5.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 24 mg (64%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=486; 1H NMR (300 MHz, DMSO-d6) δ: 12.85 (br. s., 1H), 9.16 (s, 1H), 8.76 (dd, J=8.7, 5.3 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 5.23-5.58 (m, 1H), 4.97 (dt, J=8.1, 5.8 Hz, 1H), 4.56-4.82 (m, 1H), 4.21-4.56 (m, 2H), 4.18 (s, 3H), 3.87-4.10 (m, 1H), 3.68 (qd, J=9.8, 5.7 Hz, 2H), 3.28 (app. d, J=3.4 Hz, 3H).