Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][CH2:15][CH2:14][OH:18])=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C#CCCO
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Product: C[Si](C)(C)C#Cc1ccc(C#CCCO)cc1

Procedure:
4-(4-((trimethylsilyl)ethynyl)phenyl)but-3-yn-1-ol was prepared from ((4-bromophenyl)ethynyl)trimethylsilane (commercially available) and but-3-yn-1-ol (commercially available) following the procedures described for Example 44/Step 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)[CH3:5].[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH:17]=[O:19])[CH:13]=[CH:12]2)[CH3:5]
Reactant: O=[Se]=O
Reactant: COC[C@@H](C)Oc1cccc2ccc(C)nc12
Solvent: C1COCCO1
Solvent: O
Product: COC[C@@H](C)Oc1cccc2ccc(C=O)nc12
Yield: 90.1 %

Procedure:
To a solution of (R)-8-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.45 g, 1.9 mmol) in dioxane (35 mL) and water (0.35 mL) was added selenium dioxide (0.26 g, 2.3 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.42 g, 88%).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])O[C:5]1=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>CO>[OH:14][CH2:13][CH2:15][N:16]1[C:3](=[O:12])[CH:2]2[CH:6]([CH:7]3[O:10][CH:1]2[CH:9]=[CH:8]3)[C:5]1=[O:11]
Reactant: NCCO
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Solvent: CO
Product: O=C1C2C3C=CC(O3)C2C(=O)N1CCO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
The anhydride, 4,10-dioxa-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione, (2.00 g, 12.0×10−3 mol) was suspended in 50 mL of MeOH and the mixture cooled to 0° C. A solution of ethanolamine (0.72 mL, 12.0×10−3 mol) in 20 mL of MeOH was added dropwise (10 min) and the resulting solution was stirred for 5 min at 0° C., then 30 min at room temperature and finally refluxed for 4 h. After cooling to room temperature the solvent was removed under reduced pressure, the white residue was dissolved in 150 mL of CH2Cl2 and washed with 3×100 mL of water. The organic layer was dried over MgSO4 and filtered. Removal of the solvent under reduced pressure furnished the desired product (1.04 g 5.0×10−3 mol, 42% yield) as white solid that was used for the next step without further purifications. An analytical sample was obtained by flash chromatography (CC, SiO2, 100% ethyl acetate, Rf(6)=0.26). m.p. 139-141° C. (dec). IR (neat): 3472, 1681, 1435, 1405, 1335, 1269, 1168, 1100, 1053, 1013, 959, 916, 875, 850, 807, 722, 705, 654 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=1.90 (bs, 1H, OH); 2.90 (s, 2H, CH), 3.69-3.72 (m, 2H, CH2), 3.76-3.78 (m, 2H, CH2), 5.28 (t, J=0.9 Hz, 2H, CH), 6.52 (t, J=0.9 Hz, 2H, CHvinyl). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=41.77 (2C, NCH2), 60.18 (2C, OCH2), 47.50 (2C, CH), 81.04 (2C, CH), 136.60 (2C, CHvinyl), 176.97 (2C, C). Anal. Calcd. for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found C, 57.16; H, 5.37; N, 6.62.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][C:6]([OH:8])=O.[Cl-].[NH4+]>C(OCC)C>[CH3:3][CH:4]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][C:6](=[O:8])[CH3:1]
Reactant: [Li]C
Reactant: CC(CC(=O)O)CC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CC(C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
250 ml. of a ca. 2-M ethereal methyl lithium solution are added dropwise to 39.5 g. of 3,5,5-trimethylhexanoic acid in 250 ml. of absolute diethyl ether at such a rate that a slight reflux is maintained. After completion of the addition, the mixture is stirred at room temperature for 1.5 hours, then cooled in an ice bath and 100 ml. of saturated aqueous ammonium chloride solution are cautiously added dropwise with stirring. The mixture is filtered through diatomaceous earth and the two phases of the filtrate are separated. The aqueous phase is back-extracted once with diethyl ether and the ether solutions are washed successively with ammonium chloride solution, water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By distillation there is obtained pure 4,6,6-trimethyl-2-heptanone of boiling point 64°-67° C./12 mmHg; nD20 = 1.4258.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4′-Bromo-2,2,2-trifluoroacetophenone (3.00 mL, 19.8 mmol) was stirred in MeOH (66 mL) at 0° C. Sodium borohydride (0.748 g, 19.8 mmol) was added and the mixture was allowed to warm to ambient temperature. The mixture was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was then washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (eluting with 5% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford a racemic mixture of the title compounds. The racemic residue was resolved by Chiral SFC purification (Chiral Technology OJ-H 2.1×25 cm, 5 uM Column; eluting with 5% isopropyl alcohol/CO2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1I.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]2[CH:31]=[C:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:4]=2[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(I)c2O)c1=O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(-c4ccccc4)oc23)c1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 23.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 1.5 grams (0.003 mole) of 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.41 gram (0.004 mole) of phenylacetylene, and 0.71 gram (0.007 mole) of triethylamine in 25 mL of DMF was stirred. To this was added 0.09 gram (0.00013 mole) of dichlorobis(triphenylphosphine)pallidium (II) and 0.05 gram (0.00026 mole) of copper (I) iodide. Upon completion of addition, the reaction mixture was heated to 70° C. where it stirred for 2.5 hours. After this time, the reaction mixture was cooled to ambient temperature and then poured into 150 mL of an aqueous 10% ammonium chloride solution. The resulting precipitate was collected by filtration and washed with water. The precipitate was taken up in 120 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a brown solid. The solid was recrystallized using 1:1 chloroform and petroleum ether, yielding 0.31 gram of Compound 280. The mother liquor was concentrated to a residue. The residue was recrystallized using petroleum ether to yield an additional 0.21 gram of Compound 280, m.p. 215-216° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[C:20]([F:26])([F:25])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:20]([F:26])[O:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(OC(F)F)c2)C1
Temperature: 120 °C
Yield: 69.5 %

Procedure:
(3-Hydroxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 115, 300 mg, 1.19 mmol) and methyl 2-chloro-2,2-difluoroacetate (258 mg, 1.78 mmol) were dissolved in dry DMF (2 mL). Potassium carbonate (328 mg, 2.38 mmol) was added and the reaction was heated to 120° C. under microwave irradiation for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 20% hexanes in ethyl acetate to 100% ethyl acetate to afford the title compound as a yellow oil (250 mg, 67.3%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]12[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]1)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][CH2:11]2>C(=S)=S>[CH3:9][C:10]12[C:22]3[C:14](=[CH:15][CH:16]=[C:17]([C:5](=[O:7])[CH3:6])[C:18]=3[CH2:19][CH2:20][CH2:21]1)[CH2:13][CH2:12][CH2:11]2
Reactant: CC12CCCc3cccc(c31)CCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c3c1CCCC3(C)CCC2
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A suspension of aluminum chloride (1.62 g) in carbon disulfide (25 ml) was added with acetyl chloride (1.00 ml) at −10° C. The mixture was stirred at −10° C. for 20 minutes, and then slowly added with 3a-methyl-2,3,3a,4,5,6-hexahydro-1H-phenalene (1.74 g) dissolved in carbon disulfide (15 ml), and the temperature of the mixture was gradually elevated to room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:500) to obtain 1-(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-1-phenalenyl)ethanone (1.63 g, yield: 77%) and the title compound (0.465 g, yield: 22%). The compound was recrystallized from n-hexane to obtain colorless prisms (melting point: 100-101.5° C.).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].S(Cl)([Cl:13])=O>>[ClH:13].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](O)CCN
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (521.6 mg; 409.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 1.8 mL of thionyl chloride. The mixture was stirred at room temperature for 3 hours and then at 50° C. for 4 hours. Thereafter, the solvent was distilled off under reduced pressure to give 576.2 mg of methyl (R)-4-amino-2-chlorobutyrate hydrochloride (yield quantitative, optical purity 96.9% ee). The analysis of the optical purity was carried out by derivatizing into (R)-3-chloro-2-pyrrolidinone with sodium hydrogen carbonate, followed by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>COCCOC>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
To a slurry of sodium hydride (0.4 g,17 mmol) in 20 ml ethylene glycol dimethyl ether cooled with an ice bath under an atmosphere of nitrogen, a solution of 2-benzyloxyethanol (2.1 ml,15 mmol) and p-toluene sulfonyl chloride (2.9 g,15 mmol) in ethylene glycol dimethyl ether was added dropwise. When the addition was complete, the ice bath was removed and the solution stirred at room temperature for 18 hours. After dilution with diethyl ether, the resulting slurry was filtered through anhydrous magnesium sulfate and concentrated under vacuum to yield 3.6 g of crude 2-benzyloxyethyl p-toluenesulfonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[C:21]([N+:28]([O-:30])=[O:29])=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[C:21]([N+:28]([O-:30])=[O:29])=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (48 mg, 0.185 mmol) and 5-methoxy-2-methyl-4-nitroaniline (35 mg, 0.192 mmol) similar to Example 166 and was isolated as a white solid (mp 128-132° C., 11 mg, 0.027 mmol, 15%). 1H NMR (CDCl3): 9.62 (s, 1H), 8.68 (m, 2H), 7.79 (s, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.01 (s, 1H), 4.02 (s, 3H), 2.63 (s, 1H).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH3:13][C:12]1[CH:11]=[CH:10][C:8]([NH:9][C:16](=[O:15])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:21][CH:22]=2)=[CH:7][C:6]=1[Br:5]
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylaluminium (2M in toluene, 15.0 ml) is added over a period of 30 min to a solution of 3-bromo-4-methyl-aniline(2.15 g, 11.5 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (2.87 g, 11.5 mmol) in toluene (20 ml) at 40° C. under an atmosphere of argon. After gas evolution ceases, the reaction mixture is stirred 30 min before being cooled to 0° C. and partitioned between cold aqueous 1N NaOH (100 ml) and toluene (100 ml). The organic layer is extracted with aqueous saturated NH4Cl (100 ml) and aqueous saturated NaCl (100 ml) The organic layer is concentrated in vacuo to give 4.69 g (97 area % by HPLC) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[CH:4]=1.[H-].[Na+].[CH3:12][O:13][C:14](=[O:23])[CH:15](Br)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH3:12][O:13][C:14](=[O:23])[CH:15]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[N:7]1)[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: COc1cn[nH]c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CC1CCCC1)n1ncc(OC)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A solution of 5-methoxy-2H-pyridazin-3-one (500 mg, 3.96 mmol) in tetrahydrofuran (19.8 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (190 mg, 4.75 mmol). The reaction was stirred at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.02 g, 4.36 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., was poured into water (100 mL) and was extracted into ethyl acetate (3×75 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (488 mg, 43%) as a clear oil; ES+-HRMS m/e calcd for C14H20N2O4 [M+H+] 281.1496 found 289.1495. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-1.16 (m, 2H), 1.33-1.64 (m, 6H), 1.63-1.78 (m, 1H), 1.89-2.03 (m, 1H), 2.16 (ddd, J=13.9, 10.9, 5.4 Hz, 1H), 3.61 (s, 3H), 3.82 (s, 3H), 5.39 (dd, J=10.7, 4.4 Hz, 1H), 6.32 (d, J=2.7 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1)#[CH:2]
Reactant: O=C1CCCC(=O)O1
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Product: C#Cc1ccc(NC(=O)CCCC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-ethynylaniline (0.99 g, 8.5 mmol) in CH2Cl2 (100 ml) is added glutaric anhydride (1.06 g, 9.30 mmol). After 1 h, the resulting slurry is concentrated by rotary evaporation and the crude mixture is purified by silica column chromatography (10% methanol/5% TEA/CH2Cl2).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[C:18]=1[CH2:27][CH2:28][CH3:29]>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14]2[CH:13]=[C:12]([NH:11][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[CH:32]=[CH:31][CH:30]=2)=[C:18]([CH2:27][CH2:28][CH3:29])[C:19]=1[OH:26])(=[O:25])[CH3:24]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccc(Nc3ncccc3C(=O)O)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.1 %

Procedure:
Heat a mixture of 2-chloro-nicotinic acid (132 mg, 0.835 mmol) and 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (250 mg, 0.835 mmol) to 130° C. After 18 hours, cool to ambient temperature and purify via flash chromatography (ethyl acetate:hexanes) to give a residue which was further purified by reverse phase chromatography (methanol:acetic acid:water) to yield the title product as a yellow solid (32 mg, 9%): 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.51 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 5.27 (s, 2H), 6.73 (d, 1H), 6.87 (dd, 1H), 7.06 (d, 1H), 7.34 (t, 1H), 7.67 (d, 1H), 7.81 (d, 1H), 7.88 (s, 1H), 8.26 (dd, 1H), 8.36 (dd, 1H), 10.66 (bs, 1H), 12.85 (s, 1H), 13.63 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH:20]=[C:13]3[C:14](Cl)=[N:15][CH:16]=[C:17]([F:18])[C:12]3=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:21][Si](C)(C)C>C(#N)CC>[Br:21][C:14]1[C:13]2=[CH:20][N:10]([C:3]3[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:4]=3[C:5]#[N:6])[N:11]=[C:12]2[C:17]([F:18])=[CH:16][N:15]=1
Reactant: N#Cc1cccc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: N#Cc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 110 °C
Yield: 96.1 %

Procedure:
3-Chloro-2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-benzonitrile (890 mg, 2.9 mmol) was suspended in propionitrile (30 mL), under an atmosphere of nitrogen and bromotrimethylsilane (2.0 mL, 15 mmol) was added. The reaction mixture was heated at 110° C. for 3.5 hours. The resultant mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford the title compound as a yellow solid (980 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=2.5 Hz, 1H), 8.25-8.21 (m, 3H), 7.94 (t, J=8.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)[C:5](=[O:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CN4CCCC4)c3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1nc(N)c2c(n1)n(Cc1cccc(CN3CCCC3)c1)c(=O)n2Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (31 mg, 0.078 mmol) was dissolved in DMF (2 mL). Anhydrous potassium carbonate (50 mg) was added followed by p-methoxybenzyl chloride (13.7 μL, 0.101 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried with Na2SO4 and evaporated under vacuum. Purification by preparative HPLC (5-60% acetonitrile/40 mM aqueous HCl) gave 6-amino-7-(4-methoxy-benzyl)-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-7,9-dihydro-purin-8-one (Example P) (6 mg) as the HCl salt.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To 3-(6-Isopropyl-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (39, 35.0 mg, 0.086 mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (29 mg, 0.11 mmol). The reaction was stirred at 20° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0019, 18.0 mg, 81.9%). MS (ESI) [M+H+]+=252.