Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[O:19][CH3:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2c(=O)n1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC)c2cc(Cl)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
A suspension of ethyl 6-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.41 g, 5 mmol), methyl iodide (0.47 ml, 7.5 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.11 g, 75.5%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To 0.5 g (3.9 mmol) of 6-chloro-pyridin-3-ylamine in 6 mL of 12M HCl at −20° C. were added a solution of 0.36 g (5.2 mmol, 1.3 eq) of sodium nitrite dissolved in 2 mL of H20. The reaction mixture was stirred for 15 min, and 4.4 g (19.5 mmol, 5 eq) of tin chloride dihydrate dissolved in 2 mL of 12M HCl were added. The reaction mixture was allowed to reach 0° C. within 40 min, and the white precipitate was recovered by filtration and washed with Et2O to yield 0.35 g (62%) of (6-chloro-pyridin-3-yl)-hydrazine hydrochloride as a white solid, MS: 144 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ncccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0321 g, 0.0672 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0152 g, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH3:16].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[CH2:15][CH3:16]
Reactant: CCCBr
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc2c(c1)CCCC2=O
Temperature: 122 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
6-Hydroxy-1-tetralone (2.0 g, 12.3 mmol), bromo-propane (2.24 mL, 24.7 mmol), potassium iodide (2.05 g, 12.3 mmol) and potassium carbonate (3.41 g, 24.7 mmol) were combined in ACN (50 mL) in a sealed vessel, and the reaction was stirred at 122° C. overnight. The reaction was cooled, filtered, and concentrated. Purification by silica gel chromatography (10-50% EtOAc/hexanes) gave 2.36 g (94%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 1.04 (3H, t, J=7.4 Hz), 1.79-1.85 (2H, m), 2.09-2.14 (2H, m), 2.60 (2H, t, J=6.3 Hz), 2.88-2.93 (2H, t, J=6.5 Hz), 3.97 (2H, t, J=6.5 Hz), 6.69 (1H, d, J=2.3 Hz), 6.81 (1H, dd, J=8.8, 4.1 Hz), 7.99 (1H, d, J=8.7 Hz). [M+H] calc'd for C13H16O2, 205. found 205.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:23][CH:25]3[O:27][CH2:26]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1cc(OCc2ccccc2)c2ccc(OCC3CO3)cc2o1

Procedure:
4-Benzyloxy-7-hydroxycoumarin (10.7 g, 0.041 mole) was dissolved in ethanol (200 ml) and a solution of potassium hydroxide (2.5 g) in water (10 ml) was added. Epichlorhydrin (40 ml) was added and the stirred mixture heated to reflux for 21/2 hr. After cooling, the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. Evaporation of the dried (MgSO4) organic phase gave the product as a white crystalline solid. Recrystallization from ethanol gave 11.1 g (83%) of material of m.p. 128°-129° C.; (Found; C, 70.48; H, 4.92; C19H16O5 requires; C, 70.36; H, 4.97%).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:7]=[CH:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>C(Cl)(Cl)Cl>[N:6]1[CH:7]=[C:8]([S:2]([OH:5])(=[O:4])=[O:3])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: O=S(=O)(O)Cl
Reactant: c1ccn2ccnc2c1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cnc2ccccn12
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Chlorosulfonic acid (0.170 mL, 2.55 mmol) was dissolved in chloroform (1 mL) and this solution was added dropwise to imidazo[1,2-a]-pyridine (0.100 g, 0.85 mmol) in chloroform (4 mL) over 10 min. The reaction mixture was heated to reflux for 24 h, then allowed to cool to RT and concentrated to dryness under vacuum. The crude oily product was treated with diethyl ether (10 mL) and ethanol (5 mL) resulting in a white precipitate. The solid was collected by filtration, washed with EtOH and dried to yield imidazo[1,2-a]-pyridine-3-sulfonic acid (0.128 mg). MS (ESI−) for m/z 131 (M−H)−.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:33])[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:33][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H](CN1CCC1)c1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(C(F)(F)F)cc3)ncnc12

Procedure:
Compound 27 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethylamine dihydrochloride to give the title compound as a white solid. LC/MS [417 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J=3.4 Hz, 1H), 9.11 (d, J=7.9 Hz, 1H), 9.01 (dd, J=4.5, 1.0 Hz, 1H), 8.53 (s, 1H), 8.38 (dd, J=4.5, 1.0 Hz, 1H), 8.16 (d, J=3.4 Hz, 1H), 7.83-7.50 (m, 3H), 5.36 (q, J=7.2 Hz, 1H), 3.21-2.99 (m, 4H), 2.84 (dd, J=12.0, 5.6 Hz, 1H), 1.92 (p, J=6.9 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16].[H-].[Na+]>CN(C=O)C.CO>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(C#N)cc21
Temperature: 180 °C

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (45 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (61.5 s15 mg) and NaH (9.0 mg) in DMF (1 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (11 mg) as white crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([OH:23])=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1.Cl>N1C=CC=CC=1>[C:20]([C:8]1[C:7]2[O:23][C:1](=[O:2])[NH:5][C:6]=2[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(=[O:22])[CH3:21]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12
Temperature: 50 °C

Procedure:
At 20 to 40° C. 52 g (0.53 mol) phosgene are piped into a solution of 121 g (0.47 mol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 800 mL pyridine. The reaction mixture is heated to 50° C. for 2 hours, then poured onto ice and acidified with conc. hydrochloric acid. A reddish-brown solid is isolated which is repeatedly recrystallised from ethanol with the addition of activated charcoal.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].N(C1C=CC(O)=CC=1)[C:18]([CH3:20])=[O:19].CC(C)=O.C(Cl)(Cl)Cl>>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)[C:18]([CH3:20])=[O:19]
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
FIG. 2A illustrates a reaction scheme for preparing 2-(4-aminophenoxy)-2-methyl propionic acid, a compound that is useful as a precursor in the preparation of Group I compounds. In accordance with the scheme of FIG. 2A, 8 grams (g) (0.2 mol) of pulverized sodium hydroxide is added to a suspension of 5.28 g (0.035 mol) of p-acetaminophenol in 23 g (0.4 mol) of acetone. The reaction mixture is stirred at room temperature for 1/2 hour. Subsequently, 3.58 g (0.03 mol) of chloroform is added dropwise over the course of 30 minutes. The reaction mixture is stirred overnight at room temperature and acetone is removed under vacuum. The residue is dissolved in water (10 ml), followed by acidification with 37% hydrochloric acid (HCl) to produce a pale yellow precipitate of 2-(4-acetaminophenoxy)-2-methyl propionic acid (5 g, 60% yield), crystallized from methanol, mp 69°-71° C.
Reaction SMILES: [I-].[Na+].[CH2:3]1[CH:7]2[CH2:8][NH:9][CH2:10][CH:6]2[CH2:5][N:4]1[CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=1>COCCOC>[N:26]1[N:25]=[CH:24][N:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:13][CH2:12][CH2:11][N:4]2[CH2:5][C@@H:6]3[CH2:10][N:9]([CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=4)[CH2:8][C@@H:7]3[CH2:3]2)[CH:27]=1
Reactant: c1cc2[nH]cc(CCCN3CC4CNCC4C3)c2cc1-n1cnnc1
Reactant: CC(=O)Nc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)Nc1ccc(CCN2C[C@H]3CN(CCCc4c[nH]c5ccc(-n6cnnc6)cc45)C[C@H]3C2)cc1
Yield: 30 %

Procedure:
Sodium iodide (98 mg, 0.65 mmol) was added to a mixture of 3-(3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)propyl)-5-(1,2,4-triazol-4-yl)-1H-indole (200 mg, 0.59 mmol), sodium carbonate (95 mg, 0.90 mmol) and N-(4-(2-bromoethyl)phenyl)acetamide (158 mg, 0.65 mmol) in dry 1,2-dimethoxyethane (5 ml) at room temperature under nitrogen. The mixture was then stirred and heated to reflux, protected from light, for 16 h. Upon cooling, the volatiles were removed in vacuo and the residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (60:8:1→50:8:1) to give the title indole (88 mg, 30%) as a foam. The bis hydrogen oxalate. 0.75 hydrate was prepared (Et2O/MeOH): mp 151-155° C. (Found: C, 57.43; H, 6.26; N, 14.35. C29H35N7O.2(C2H2O4).0.75(H2O) requires C, 57.34; H, 5.91; N, 14.18%). δ (360 MHz, d6 -DMSO) 1.94-2.02 (5H, m, includes NC(O)CH3), 2.7-3.3 (18H, m), 7.16 (2H, d, J=8.5 Hz, Ar--H), 7.30-7.36 (2H, m, Ar--H), 7.48-7.52 (3H, m, Ar--H), 7.81 (1H, s, Ar--H), 9.03 (2H, s, Triazole-H), 9.89 (1H, s, N--H), 11.17 (1H, s, N--H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C3CCCCO3)[CH:26]=2)[S:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])(=[O:14])=[O:13])=[CH:7][CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1.C(OCC)(=O)C>[OH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:10][CH:9]=1)[S:12]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])(=[O:14])=[O:13]
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCCBr)cc2)c(C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(OCCN3CCCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
To a solution of N-[4-(2-bromo-ethoxy)-phenyl]-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.070 g, 0.12 mmol) in 2 mL tetrahydrofuran was added piperidine (0.12 mL, 1.21 mmol). The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted to a volume of 30 mL with ethyl acetate and was washed with saturated aqueous sodium bicarbonate (2×15 mL) and saturated aqueous sodium chloride (1×15 mL). The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (5% methanol/methylene chloride) afforded 0.010 g of an oil. The oil was further purified by preparative TLC (0.5 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford 0.003 g of the title compound. MS 509.2 (M+1)+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=[N:6]1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[N:6]1
Reactant: CCOC(=O)c1ccnn1CCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCn1nccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Ethyl 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylate (Preparation 28, 710 mg, 3.6 mmol) was dissolved in ethanol (10 ml), a solution of sodium hydroxide (160 mg, 4.0 mmol) in water (5 ml) was added and the solution was stirred at room temperature for 2 hours. The ethanol was removed in vacuo and the residue was acidified with 2M HCl (approximately 2 ml) and extracted with dichloromethane (40 ml). The organic layers were dried over anhydrous Na2SO4, filtered and the dichloromethane removed in vacuo to give 590 mg of a pale yellow foam.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.[O:12]=[CH:13][CH2:14][C@@:15]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16]1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:12][CH:13]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)[CH2:14][C@@:15]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16]1
Reactant: Cn1cccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC=O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nccc1C(O)C[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of 1-methylpyrazole (0.165 mmol, 1.98 mmol, 3 eq) in THF (8 mL) at −78° C. under Ar was added n-BuLi (0.77 mL of a 2.5 M solution in hexane, 1.92 mmol, 2.9 eq) and the solution stirred 1 hr. Then a solution of the product of Example 10, Step A (300 mg, 0.66 mmol, 1 eq) in THF (8 mL) was added over 5 min. After 1 hr, saturated NH4Cl was added, the solution extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (12 g column) eluting with 50 to 100% EtOAc/heptane to 5 to 10% methanol/DCM afforded the title compound of Step A as a mix of diastereomers. 1H NMR (CHLOROFORM-d) δ: 8.70 (s, 1H), 7.62-7.80 (m, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.19-6.49 (m, 1H), 6.09 (br. s., 1H), 5.87 (dd, J=17.9, 5.6 Hz, 1H), 4.54-5.03 (m, 5H), 3.74-3.96 (m, 4H), 3.48 (s, 1H), 2.90-3.23 (m, 2H), 2.46-2.87 (m, 2H), 2.06-2.39 (m, 2H), 1.73-1.98 (m, 1H), 1.43 (br. s., 9H). Calculated for C27H34F3N5O4: 558.2 (M+23). found: 558.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][CH2:41]Cl)(=[O:39])[CH2:37][CH3:38]>CN(C=O)C>[C:36]([O:40][CH2:41][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:39])[CH2:37][CH3:38]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCC(=O)OCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)CC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 41.3 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.23 mmol) and a solution of chloromethyl propionate (75 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1), and recrystallized in methanol to afford the title compound as a white solid (145 mg, 41.4%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH2:22][CH2:21]1>>[O:25]=[C:23]1[CH2:22][CH2:21][C:20](=[O:26])[N:24]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: O=C1CCC(=O)N1
Product: CN(C(=O)Oc1ccc(CN2C(=O)CCC2=O)cc1)c1ccccc1
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield as beige crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and succinimide. 1H NMR (400 MHz; CDCl3): δ 2.68 (s, 4H), 3.41 (br s, 3H), 4.60 (s, 2H), 7.04 (br d, 2H), 7.23-7.41 (m, 7H); HPLC-MS: m/z=339.1 (M+1); Rt=3.40 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Product: Clc1cccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-[(3-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[OH-:9].[Na+].C>O>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:9])=[O:8])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCP(=O)(O)CCO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CC(=O)O
Temperature: 70 °C
Yield: 92 %

Procedure:
13.8 g (0.1 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 7) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Pt and 1% Bi is added, the suspension is heated to 70° C. and air is passed through the suspension at a rate of 10 l/h. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction has ended, the reaction solution is filtered to remove the catalyst, which is washed, the filtrate is made acidic with hydrochloric acid and the water is distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off to leave 14.0 g (92% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:19])[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]
Reactant: Brc1ccccn1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccn2)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.76 ml of 2-bromopyridine dissolved in 30 ml of absolute tetrahydrofuran are treated -60° within 30 minutes with 19.2 ml of 1.6M n-butyl lithium solution (in hexane), whereupon the mixture is stirred at -60° for 30 minutes. 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 50 ml of tetrahydrofuran are then added dropwise thereto at -40° within 30 minutes. The reaction mixture is warmed to 0° within 2 hours, poured into ice-water and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 200 g of silica gel with ethyl acetate. There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol as a brown oil.