Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([O-])=[O:23])[CH2:13][CH:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O-:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:40]([O:44][C:45](=[O:52])[C@H:46]([CH2:48][C:49](=[O:51])[NH2:50])[NH2:47])([CH3:43])([CH3:42])[CH3:41]>C1COCC1.CO.CC(O)=O.C(Cl)(Cl)Cl.CCOCC.CN(C=O)C>[C:40]([O:44][C:45](=[O:52])[C@H:46]([CH2:48][C:49](=[O:51])[NH2:50])[NH:47][C:22](=[O:23])[C@H:12]([CH2:13][CH:14]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:15](=[O:16])[OH:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.03 h

Procedure:
N-Benzyloxycarbonyl-γ-t-butyl-L-glutamate (50.7 g, 0.15 mol) in 300 ml freshly distilled THF was placed in a 2-liter 3-neck round bottom flask fitted with a thermometer, mechanical stirrer and dropping funnel and immersed in a dry ice-alcohol bath at -15°. N-Methylmorpholine (16.8 ml, 0.15 mol) was added dropwise. The temperature was maintained at -15° and isobutyl chloroformate (19.7 ml, 0.15 mol) was added dropwise over a 2-minute period. The reaction mixture was stirred an additional 2 minutes at -15° and a precooled solution of L-asparagine t-butyl ester (25.6 g, 0.136 mol) dissolved in 270 ml THF and 30 ml DMF was added dropwise over a 4-minute period while the temperature was maintained at -15°. The reaction mixture was stirred at -15° for 30 minutes and at 25° for 2.5 hours, evaporated in vacuo and the residue dissolved in EtOAc and washed with 10% NaHCO3 (2×300 ml), saturated NaCl solution (30 ml), 1 M citric acid (2×300 ml) and saturated NaCl solution (300 ml). The organic layer was dried over MgSO4, filtered and evaporated in vacuo to yield a thick oil. The oil was crystallized from EtOAc-ether to yield 34.5 g. Trituration of the mother liquid with ether gave an additional 31.1 g. Total yield 65.6 g (95%); mp 139° dec; Rf 0.22 (CHCl3 :CH3OH:AcOH:80-2-0.4). The analytical sample was prepared by recrystallization from methanol-ether; mp 142°-144.5°; [α]D25 -19.14° (c 1, CH3OH). Anal. calcd. for C25H37N3O8 (507.6): C, 59.16; H, 7.35; N, 8.28. Found: C, 59.24; H, 7.34; N, 8.40.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]2[S:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:10]=12)C1C=CC=CC=1.CC(C)=O.CCCCCC>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]2[S:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:10]=12
Reactant: COC(=O)c1cc2c(OCc3ccccc3)cncc2s1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc2c(O)cncc2s1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a suspension of 10 wt % Pd on activated carbon (38 mg, 10% w/w) in absolute ethanol (3 mL) was added a cold solution of Example 236C (380 mg, 1.3 mmol) in ethanol (82 mL) under nitrogen atmosphere. Then the reaction mixture was degassed and stirred at room temperature under hydrogen atmosphere. After one over night reaction mixture was treated with additional 10 wt % Pd on activated carbon (190 mg, 50% w/w) and stirred under hydrogen atmosphere. Additional catalyst (100 mg, 26% w/w) was added to the reaction mixture after 48 hours. The reaction mixture was stirred under hydrogen atmosphere for further 24 hours and filtered through Celite®. The filtrate was evaporated to dryness under reduced pressure to obtain the crude product (320 mg). The title compound Example 236E was obtained in 75% yield (200 mg) by flash chromatography on silica gel eluting with 5% acetone-hexane followed by 40% acetone-hexane.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:29])([CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:27])=[O:26])[C:10]=1/[CH:30]=[CH:31]/NC1C=CC=CC=1)([OH:3])=[O:2].[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][N+:49]1[C:57]2[C:52](=[CH:53][C:54]([S:58]([OH:61])(=[O:60])=[O:59])=[CH:55][CH:56]=2)[C:51]([CH3:69])([CH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])[C:50]=1[CH3:70].C([O-])(=O)C.[Na+:75].COCCOCC[N+]1C2C(=CC(S(O)(=O)=O)=CC=2)C(C)(CCCS(O)(=O)=O)C=1C>C(O)(=O)C.C(OC(=O)C)(=O)C.C(OCC)C>[Na+:75].[Na+:75].[Na+:75].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:29])([CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:26])=[O:27])/[C:10]/1=[CH:30]\[CH:31]=[CH:70]\[C:50]1[C:51]([CH3:69])([CH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])[C:52]2[C:57](=[CH:56][CH:55]=[C:54]([S:58]([OH:61])(=[O:59])=[O:60])[CH:53]=2)[N+:49]=1[CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH3:39])([OH:3])=[O:2]
Reactant: CC1(CCCS(=O)(=O)O)C(/C=C/Nc2ccccc2)=[N+](CCCCCC(=O)O)c2ccc(S(=O)(=O)O)cc21
Reactant: COCCOCCOCC[N+]1=C(C)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Agent: CC(=O)[O-]
Agent: COCCOCC[N+]1=C(C)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COCCOCCOCC[N+]1=C(/C=C/C=C2/N(CCCCCC(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCS(=O)(=O)O)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Temperature: 25 °C

Procedure:
One mmol 1-(5-carboxypentyl)-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and 1 mmol 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium were dissolved in 20 ml acetic acid/acetic anhydride (1/1) followed by the addition of 200 mg sodium acetate. The solution was stirred under reflux for 15 min. After cooling to room temperature, 20 ml diethylether was added. The resulting precipitate (mixture of the diastereomers 550-1 compound 2 and 550-2 compound 2) was extracted by suction, washed with ether and dried.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)=[O:11])[CH3:1]
Reactant: Nc1cccnc1
Reactant: CC(C)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-(1-methylethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 3; 300 mg, 1.11 mmol), pyridin-3-amine (157 mg, 1.67 mmol), EDC (319 mg, 1.67 mmol) and HOBT (255 mg, 1.665 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml), filtered and the solid was washed with water and dried to yield a white solid. The crude product was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate (3:1) to yield the title compound as a white solid. 140 mg.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:20]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cccc2ccccc12
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixture of 1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate (0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12 mL). The resultant solution was purged with nitrogen for 10 minutes before tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) was added. The reaction mixture was heated to reflux for 65 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL with water/ethyl acetate (1:1). The aqueous layer was extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield the title compound as a gold oil (1.09 g). This material was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1cc(Cl)cn[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2cn[nH]c(=O)c2)cc1
Temperature: 25 °C
Yield: 465 %

Procedure:
Five reaction tubes each containing 5-chloropyridazin-3(2H)-one (100 mg, 0.77 mmol), 4-methoxyphenylboronic acid (230 mg, 1.53 mmol), dioxane (3 ml), 2M aqueous sodium carbonate solution (1 ml) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (20 mg) were irradiated in a microwave reactor at 150° C. for 10 minutes. After cooling to room temperature the mixtures were combined and filtered. The collected solid was washed with water (3 ml), ethyl acetate (5 ml) and ether (5 ml), then dried to give the title compound (724 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([Br:13])=[C:10]([C:11]#[N:12])[C:3]=12.C(O[CH:18]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:24]([CH3:37])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[C:9]([Br:13])[N:8]([C@@H:18]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:24]([CH3:37])[C@H:19]3[O:20][C:21](=[O:23])[CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1c(Br)nc2[nH]cnc(N)c1-2
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](C)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(Br)c(C#N)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
BSA (0.29 mL, 2.0 mmol) was added into a stirred suspension of 4-amino-6-bromo-5-cyano-1H-pyrrolo[2,3-d]pyrimidine (0.24 g, 1 mmol; prepared according to Nucleic Acid Chemistry, Part N, Townsend, L. B. and Tipson, R. S.; Ed.; Wiley-Interscience: New York, 1991, pp. 16-17 and Synthetic Commun. 1998, 28, 3835) in dry acetonitrile (10 mL) at room temperature under argon. After 15 min, 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-methyl-D-ribofuranose (J. Med. Chem. (1976), 19, 1265) (0.36 g, 1.0 mmol) was added along with TMSOTf (0.54 g, 3 mmol). The mixture was stirred at room temperature for 5 min and then at 80° C. for 0.5 h. The solution was cooled, diluted with ethyl acetate (50 mL) and poured into ice-cold saturated aqueous NaHCO3 (15 mL). The layers were separated. The organic layer was washed with brine (15 mL), dried (Na2SO4) and then evaporated. The residue was purified on silica gel column using a solvent system of hexanes/EtOAc: 3/1. Appropriate fractions were collected and evaporated to provide the title compound as colorless foam (0.21 g).
Reaction SMILES: CC(C1C(OC)=C(C(C)(C)C)C=C(P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)[C:18]2[CH:23]=[CH:22][C:21]3OCO[C:20]=3[C:19]=2[C:27]2C3OCOC=3C=[CH:29][C:28]=2P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C=1)(C)C.C(=[O:92])C1C=CC=CC=1.C([Si](OC)(OC)OC)=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.O.CO>[C:19]1([CH:27]([OH:92])[CH:28]=[CH2:29])[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccc3c(c2-c2c(P(c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)ccc4c2OCO4)OCO3)cc1C(C)(C)C
Reactant: O=Cc1ccccc1
Agent: C=C[Si](OC)(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(O)c1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
CuF2.2H2O (3 mg, 0.020 mmol) and (R)-DTBM-SEGPHOS (47 mg. 0.04 mmol) were added to methanol (0.7 mL) under an argon atmosphere, and the mixture was refluxed for 2 hours. Thereafter, the reaction mixture was allowed to stand for cooling to room temperature, and the volatile matter was removed in vacuo. Toluene (0.5 mL) was added to the resulting residue, and the operation for removal of the volatile matter was again carried out twice in vacuo (this catalyst preparation method is designated as “B”; hereinafter the same). The resulting CuF-phosphine complex was dissolved in DMF (1 mL), to which were then added benzaldehyde (67 μL, 0.67 mmol) and vinyltrimethoxysilane (206 μL, 1.34 mmol) at room temperature, and the mixture was stirred at 40° C. for 30 minutes. The reaction mixture was allowed to stand for cooling to room temperature, to which was then added tetrabutylammonium fluoride (TBAF) (1M/THF, 0.5 mL), and the mixture was stirred for 10 minutes. After adding water, the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane: 1/9 to 1/4), thereby obtaining desired 1-phenyl-2-propen-1-ol in a yield of 99%. Its optical purity was measured by HPLC and found to be 94% ee. Furthermore, its absolute configuration was determined in terms of an angle of rotation by comparison with an already reported value. As a result, the product was found to be an (S)-form.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([F:27])[CH:20]=[C:19]([F:28])[C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([C:23]([F:24])([F:26])[F:25])=[C:21]([F:27])[CH:20]=[C:19]([F:28])[C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1c(F)cc(F)c(C(F)(F)F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(F)c(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.58 g (0.024 mol) of magnesium filings are introduced into 1.3 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 3.4 g (0,019 mol) of diethyl malonate in 2.4 ml of ethanol and 9 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50° and 60° C. Stirring is then continued for one hour at 60° C. A solution of 5.8 g (0,027 mol) of 2,4,6-trifluoro-3-trifluoromethylbenzoylchloride in 2.5 ml of toluene is added dropwise at -10 to -5° C., and stirring is continued for one hour at 0° C. and subsequently while the mixture comes to room temperature. The batch is poured into 10 ml of ice-water, treated with 1.5 ml of concentrated sulphuric acid, and the mixture is extracted using toluene. The toluene phase is washed using saturated sodium chloride solution, and the solvent is removed in vacuo.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>CCCCCC>[C:9]1([NH:8][C:5](=[O:7])[CH3:6])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCCC2
Solvent: CCCCCC
Product: CC(=O)Nc1cccc2c1CCCC2
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Acetic anhydride (100 ml, 1.06 mole) was added rapidly to neat 1-amino-5,6,7,8-tetrahydronaphthalene (25 g, 0.17 mole) (Aldrich) with stirring. The mixture quickly solidified and was allowed to stand overnight. The broken mass was suspended in hexane (200 ml), filtered, then resuspended in methylene chloride (150 ml). After stirring 10 minutes, the suspension was diluted with an equal volume of hexane, filtered, and the solid dried at 95° C. under reduced pressure to give N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (23 g). 1H NMR (CDCl3, 200 MHz) δ: 1.68-1.90 (m, 4H CH2 's) 2.20 (s 3H, CH3), 2.52-2.68 (m, 2H, ArCH2), 2.70-2.84 (m, 2H, ArCH2), 3.94 (br s, 1H, NH), 6.92 (d, J=8 Hz, 1H, Ar), 7.10 (t, J=8 Hz, 1H, Ar), 7.53 (d, J=8 Hz, 1H, Ar). Anal. Calculated for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.13; H, 8.04; N, 7.40.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH3:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([C:44](Cl)=[O:45])[S:43][C:36]=12>C(Cl)Cl.[Pd].CCO>[Cl:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([C:44]([N:14]3[CH2:17][CH:16]([O:18][CH3:19])[CH2:15]3)=[O:45])[S:43][C:36]=12
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Reactant: COC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COC1CN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A 100 ml round bottom flask was charged with 1-benzhydryl-3-methoxy-azetidine 78a (447 mg, 1.77 mmole), 10% Pd/C (300 mg), trifluoroacetic acid (0.15 ml, 1.94 mmole) and EtOH (30 ml) and placed under 1 atm H2 and vigorously stirred at rt. After 2 hr, the catalyst was removed and washed with MeOH. The filtrate was concentrated under reduced pressure to give the crude azetidine which was dissolved in CH2Cl2. To this solution were added triethylamine (0.6 ml, 4.41 mmole) and 7-chloro-thieno[3,2-b]pyridine-2-carbonyl chloride, prepared as previously described in example 25a. After stirring at ambient temperature overnight, the reaction mixture was diluted with more CH2Cl2, then washed sequentially with 0.5N HCl, satd. NaHCO3 (aq), and brine. The organic layer was dried (MgSO4) and concentrated to near dryness under reduced pressure, then triturated with hexanes to give 278 mg (56%) of the desired product as a light yellow solid. 1H NMR (DMSO-d6) δ 8.73(1H, d, J=5.1 Hz), 8.00 (1H, s), 7.70 (1H, d, J=5.1 Hz), 4.77 (1H, m), 4.49 (1H, m), 4.31 (2H, m), 3.90 (1H, m), 3.24 (3H, s). APCl m/z 283/285 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:20][CH2:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[N:23]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 2,6-dichloropurine (0.062 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (5 mL). 2-Chloro-N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ C50=615 nM] was obtained after purification as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (1H, s), 8.15 (1H, s), 8.04 (1H, dd, J=8.5, 1.2 Hz), 7.96 (1H, d, J=6.7 Hz), 7.60 (1H, d, J=7.3 Hz), 7.61 (1H, t, J=7.9 Hz), 7.54 (1H, d, J=6.7 Hz), 7.50 (1H, t, J=6.7 Hz), 7.44 (1H, t, J=7.3 Hz), 4.62 (2H, d, J=26.9 Hz) Mass Spectrum (ESI) m/e=455.0 and 457.0 (M+1)
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH2:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[NH2:2].O.[ClH:38]>O1CCCC1.B#B>[ClH:38].[ClH:38].[NH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH2:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:18])=[CH:12][CH:11]=2)=[CH:35][CH:36]=1
Reactant: CC(Cc1ccc(OCc2ccc(C(N)=O)cc2)cc1)NCCC(c1ccccc1)c1ccccc1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc(OCc2ccc(CN)cc2)cc1)NCCC(c1ccccc1)c1ccccc1

Procedure:
To the suspension of 5.0 g of racemic 1-[4-(4-carbamoylbenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane (Example 10/7) in 75 ml of tetrahydrofuran, 70 ml of 1-molar diborane in tetrahydrofuran are added dropwise while stirring under nitrogen at 0°. It is refluxed for 18 hours, cooled to 0° again and 30 ml of water are added dropwise, followed by 15 ml of concentrated hydrochloric acid. The mixture is evaporated, warmed with 50 ml of methanol, evaporated again and the residue is recrystallized from ethanol, to yield the 1-(4-(4-aminomethylbenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane dihydrochloride melting at 259°-262°.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@H:38]([C:49](O)=[O:50])[CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:49]([C@@H:38]([NH:37][S:34]([C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)(=[O:35])=[O:36])[CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)=[O:50])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-(4-nitrobenzenesulfonyl)-L-tryptophan (120 mg, 0.3 mmol) which was prepared in step A of example 5. The final product was purified by HPLC to give 66 mg (36%) of pure adduct.