Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)O1.[OH-].[Na+].[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[CH:38]=[CH:37][C:36](Br)=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:18].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[CH:38]=[CH:37][C:36]([C:9]4[CH:14]=[N:13][CH:12]=[N:11][CH:10]=4)=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(-c3cncnc3)ccc2o1
Temperature: 90 °C

Procedure:
177 mg (0.86 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine and 2.15 ml of 1N sodium hydroxide solution are added to a mixture of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 ml of DMF. The reaction mixture is heated at 90° C. overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered through kieselguhr. Purification takes place by preparative HPLC. The product is dissolved in methanol, and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. Recrystallization of the residue from isopropanol and drying under high vacuum results in 28 mg (10% of theory) of the title compound.
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O.CN(C)C=O>[C:28]([C@@:2]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 250 mL flask was added 2'-deoxyguanosine monohydrate (5.0 g, 17.5 mmol), triethylamine (3.13 ml, 22.4 mmol) and N,N-dimethyl-4-aminopyridine (0.046 g, 0.37 mmol). N,N-dimethylformamide (130 mL) was added via cannula with stirring and the flask was purged with argon gas. The slurry was allowed to cool 10 minutes in an ice/NaCl bath and palmitoyl chloride (6.3 mL, 20.6 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25 degrees C. After 72 h, the mixture was poured with stirring into 400 mL of a 1:1 mixture of water and saturated aqueous sodium bicarbonate solution, which mixture had been warmed to about 60 degrees C. The resulting white solid was isolated by suction filtration, washed with water, and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:26])=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[C:3]=2[CH3:26])=[O:45])=[CH:47][CH:48]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: Cc1c(N)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of 4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile (380 mg; 1.12 mmol) and diisopropylethylamine (187 mg; 1.45 mmol) in anhydrous THF (25 mL) is stirred under nitrogen at rt. A solution of 4-tert-Butyl-benzoyl chloride (230 mg; 1.17 mmol) in 5 mL anhydrous THF is then added dropwise to the stirring reaction solution. After 30 minutes, the mixture is partitioned between ethyl acetate (75 mL) and water (75 mL) and the water layer extracted with ethyl acetate (2×50 mL). The organic layers are pooled, washed with brine and dried over anhydrous sodium sulfate. The filtrate is then concentrated in vacuo and the crude oil dissolved in a minimum volume of CH2Cl2. Diethyl ether is added and the resulting precipitate is filtered and washed with diethyl ether to provide 4-tert-butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamide as a light orange solid (450 mg)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:30]=[CH:29][C:16]=2[C:17]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)[CH:30]=[CH:29][C:16]=2[C:17]2[O:18][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccccc2C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccccc3c(=O)o2)CC1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzoic acid (about 11.23 mmol) was diluted with methylene chloride (115 mL). DMF (4 drops) and pyridine (1.1 mL, 13.6 mmol) were added, followed by oxalyl chloride (1.1 mL, 12.6 mmol). A precipitate formed immediately. After 2 hours, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue from the filtrate concentration was purified by flash column chromatography (5% EtOAc/CH2Cl2) to give the desired product (4.83 g, 9.82 mmol, 87%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:9]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(C2CC2)ccn1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 4-chloropyridin-2-amine (2.6 g, 15 mmol), cyclopropylboronic acid (2.6 g, 30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.2 g, 1.5 mmol), and potassium carbonate (4.0 g, 30 mmol) in 1,4-dioxane (40 mL) and water (5 mL) was stirred at 80° C. for 15 hours. After allowing to cool to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=5:1) to give 4-cyclopropylpyridin-2-amine. MS ESI calcd. for C8H11N2 [M+H]+135, found 135. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=6.0 Hz, 1H), 6.31-6.29 (m, 1H), 6.23-6.22 (m, 1H), 4.99 (s, 2H), 1.79-1.72 (m, 1H), 1.06-1.01 (m, 2H), 0.78-0.74 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:38])C(=O)C1.O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:9][O:10][C:11]1[C:12]([Br:38])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)oc(=O)c1cnccc12)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@@H](COc1cc2oc(=O)c3cnccc3c2cc1Br)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 67.4 %

Procedure:
To a stirred solution of (S)-tert-butyl(4-methyl-1-((5-oxo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (0.100 g, 0.242 mmol) (prepared as described in Example 11, Part E) in anhydrous acetonitrile (2 mL) was added NBS (0.043 g, 0.242 mmol) and the mixture heated to 80° C. for 12 h. After completion of reaction, water (10 mL) was added and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford crude compound which was purified by preparative TLC to afford (S)-tert-butyl(1-((9-bromo-5-oxo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.163 mmol, 67% yield) as a pale yellow solid. LCMS (ESI) m/e 491.2 [(M+H)+, calcd for C23H28BrN2O5491.1] LC/MS retention time (method F): tR=1.12 min.
Reaction SMILES: [CH2:1]([C:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH2:1]([C:4]([C@:6]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@:8]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: c1ccncc1
Product: C=CCC(=O)[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@H](O)CO
Temperature: 25 °C
Yield: 28.7 %

Procedure:
1-allyl-D-arabinose 32 (75 g, 394 mmol) was dissolved in pyridine (800 mL) at 0° C., benzoyl chloride (101 mL, 867 mmol) was added over 2 h by addition funnel and the reaction was stirred while warming to room temperature for 16 h. The solvent was removed in vacuo, and the resulting residue was purified by silica gel flash chromatography (4:1 Hexanes:EtOAc to 3:2 Hexanes:EtOAc) to give 33 as a thick oil (45 g, 113 mmol, 29%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (1.46 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.10 g) at 0° C. and the mixture was stirred at room temperature for 3 hrs. Sodium sulfate decahydrate (0.87 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give (1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy)-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (1.30 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: COc1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(C=O)c(C)o2)cc1
Yield: 87.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 4-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.9 g, 91%) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1.C(O)C1OC=CC=1>O.CS(C)=O>[CH2:20]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1ccco1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCc1ccco1
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1ccco1
Reaction time: 18 h
Yield: 70 %

Procedure:
To a stirred mixture of N-hydroxyphthalimide (41 g.), anhydrous potassium carbonate (26.4 g.) and dry dimethyl sulphoxide (400 ml.) was added 2-chloromethylfuran (freshly prepared, but undistilled, from 46.2 g. furfuryl alcohol according to the method of W. R. Kirner JACS, 1928, 50, 1955). The mixture was stirred for 18 hr., then poured into water (1.51). The precipitated solid was filtered off, washed well with water, and recrystallised from ethanol to give N-furfuryloxyphthalimide (42.8 g., 70%), m.p. 145.3°-146.2° τ values (DMSO-d6) are 4.80 (CH2), 2.22, 3.30, 3.50 (furyl protons) 2.08 (phthalimide protons). (b) Furfuryloxamine Hydrochloride.
Reaction SMILES: [F:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>>[F:1][C:2]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])([F:6])[CH:3]([F:5])[F:4]
Reactant: CCNCC
Reactant: FC(F)=C(F)F
Product: CCN(CC)C(F)(F)C(F)F

Procedure:
1,1,2,2-tetrafluoroethyldiethylamine is prepared by the addition of tetrafluoroethylene at pressures of up to 700 kPa (100 psig) to an agitated solution of diethylamine. Equipment used for this preparation consists of a one liter bomb in a barricaded rocker arm, on account of the explosive nature of tetrafluoroethylene at elevated pressures. The reaction is carried out between 25 and 91° C. The obtained crude product is fractionated at 14 kPa of pressure (100 mm Hg) to yield a liquid product having a boiling point between 70 and 90° C.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@@:24]2([CH3:25])[C@H:22]([O:23]2)[CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Li+].[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([C@@H:22]1[CH2:21][CH2:20][C@@H:19]([O:18][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:24]1([CH3:25])[OH:23])=[N+:33]=[N-:34]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@H]2O[C@@]12C)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N=[N+]=[N-])[C@]1(C)O)(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
The title compound is prepared by essentially following the procedure as described in Preparation 41 using rel-tert-butyl-[[(1R,4S,5R)-5-methyl-6-oxabicyclo[3.1.0]hexan-4-yl]oxy]-diphenyl-silane (enantiomeric mixture), except that the reaction is heated to 90° C. for 48 h and the addition of lithium perchlorate and the second addition of sodium azide are omitted.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[C:40]3[CH:39]=[CH:38][C:37]([CH3:41])=[C:36]([NH2:42])[C:35]=3[CH:34]=[CH:33][N:32]=2)=[CH:26][CH:25]=1>CN(C=O)C>[N:16]1[C:8]([C:7]2[C:2]([NH:42][C:36]3[C:35]4[CH:34]=[CH:33][N:32]=[C:31]([NH:30][C:27]5[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=5)[C:40]=4[CH:39]=[CH:38][C:37]=3[CH3:41])=[N:3][CH:4]=[N:5][CH:6]=2)=[C:9]2[C:13]([NH:12][CH:11]=[N:10]2)=[N:14][CH:15]=1
Reactant: Clc1ncncc1-c1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1N
Solvent: CN(C)C=O
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1Nc1ncncc1-c1ncnc2[nH]cnc12
Temperature: 70 °C

Procedure:
In a 2 mL microwave reaction tube were added 6-(4-chloropyrimidin-5-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (31 mg, 98 mop and N1-(4-chlorophenyl)-6-methylisoquinoline-1,5-diamine (28 mg, 98 μmol) in DMF (0.6 mL). The mixture was thoroughly mixed and flushed with argon then sealed. It was stirred at 70° C. The temperature was raised to 90° C. after 2 hrs and allowed over night. The reaction mixture was partitioned in EtOAc and NaHCO3. The organic layer was washed with brine and dried over Na2SO4. The residue was treated with MeOH (3 mL) and conc HCl (0.2 mL). The mixture was stirred for 2 hrs, then partitioned between NaHCO3 and EtOAc (10 mL each). The organic layer was collected and purified by prep HPLC (MeCN/H2O=5-95% with 0.1% TFA). Desired fractions were combined and neutralized with NaHCO3 (sat., aq.) and extracted with DCM. The DCM layer was washed with brine then dried over Na2SO4, then dried over a stream of N2 to give a yellow solid N5-(5-(9H-purin-6-yl)pyrimidin-4-yl)-N1-(4-chlorophenyl)-6-methylisoquinoline-1,5-diamine. MS Found: (ESI pos. ion) m/z 480 (M+H+).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=1[C:29]1[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:36])=[N:33][CH:34]=1)=O.[Cl:45][C:46]1[CH:51]=[C:50]([NH2:52])[CH:49]=[CH:48][C:47]=1[C:53]1[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=1.CC(O)=O>C(Cl)Cl.ClCCCl>[Cl:45][C:46]1[CH:51]=[C:50]([NH:52][CH2:15][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:36])=[N:33][CH:34]=2)[CH:49]=[CH:48][C:47]=1[C:53]1[CH:58]=[CH:57][C:56]([C:59]([F:60])([F:61])[F:62])=[CH:55][CH:54]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cn1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (74 mg, 0.35 mmol) was added to a DCE solution (1 mL) of ethyl 3-(5-(2-formyl-3-methoxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate (98 mg, 0.23 mmol), 2-chloro-4′-(trifluoromethyl)-[1,1-biphenyl]-4-amine (63 mg, 0.23 mmol) and HOAc (0.01 mL, 0.23 mmol) the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17]([O:19]CC)=[O:18])[C:9](=[O:16])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:5])[CH3:2].C[Si](I)(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17]([OH:19])=[O:18])[C:9](=[O:16])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c2ccccn2c1=O
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)O)c(=O)n2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
To a solution of 1,3-diethoxycarbonyl-4H-quinolizin-4-one (1 g) in chloroform (20 ml) was added trimethylsilyl iodide (0.49 ml) at room temperature and the mixture was stirred for 4 hours and heated with reflux for 4 hours. After cooling to room temperature, the mixture was washed with water, aqueous sodium thiosulfate, and brine. Drying over magnesium sulfate and evaporation gave a crystalline residue, which was washed with isopropyl alcohol to give 1-ethoxycarbonyl4H-quinolizin-4-one-3-carboxylic acid (794 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:21]([CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C1(C)C=CC=CC=1>[C:47]([O:24][C@H:23]1[C@@H:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:21]([CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[O:20][C@@H:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:49])[CH3:48]
Reactant: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](OC(C)=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 17 (10 mg, 18.0 μmol) was dissolved by addition of pyridine (1 mL). Acetic anhydride (0.5 mL) was added to the solution, and the mixture was stirred at the room temperature for 2 hours. The solvent was subjected to azeotropy with toluene, and the residue was purified with Sephadex LH-20 (CHCl3:MeOH=1:2) to obtain Compound 18 (11 mg, qu.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:13].[CH3:15][CH:16](O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH:16]([CH3:17])[CH3:15]
Reactant: CC(C)O
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 25.8 mmol methyl-5-acetyl-2-hydroxybenzoate, 28.3 mmol 2-propanol and 29.6 mmol triphenylphosphine in 100 ml THF was added 28.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 237.1 (M+H+, 100%)