Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C@@H:9]([CH3:10])[CH2:11][OH:12])[CH3:14])([CH3:7])([CH3:5])[CH3:6]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
20.3 g Boc-MeAla-OH (100 mmol; Fluka) were dissolved in 80 ml THF and cooled to 0° C. 150 ml 1M BH3-THF (150 mmol; Fluka) were added at 0° C. over 1 h and after additional stirring at 0° C. for 1 h, 65 ml deionized water were added carefully at 0-5° C. After warming up to RT 160 ml 10% Na2CO3 were added and stirring continued for 1 h. The reaction mixture was extracted with 500 ml and 400 ml ethyl acetate and the organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 18.5 g (98%) product as a colorless oil, [α]D=−6.1 (CHCl3; c=1). 1H-NMR:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:17])/[CH:14]=[CH:15]/[CH3:16].Cl>O.C(=S)=S>[CH:14]([C:13]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:17])=[CH:15][CH3:16]
Reactant: C/C=C/C(=O)Cl
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CC=CC(=O)c1ccc(OC)cc1

Procedure:
Into a round bottom three-necked flask equipped with a stirrer, a reflux condenser, and a dropping funnel were placed 583 g. of anisole, 720 g. of aluminum chloride, and 2.37 liters of carbon disulfide. The reaction solution was stirred and 565 g. of crotonyl chloride were added by dropwise addition at such a rate as to maintain a continuous reflux. As the reaction mixture thickened, an additional 2.37 liters of carbon disulfide were added. The resulting reaction mixture which had the consistency of a slurry was refluxed for 4 hours and thereafter was poured into a mixture of 9 kg. of ice, 2 liters of water and 900 ml. of concentrated hydrochloric acid. The carbon disulfide was removed from the dilute acidified reaction mixture under vacuum. The aqueous residue was then extensively extracted with dichloromethane. The extract was washed with water and dried and was then evaporated in vacuo to yield the condensation product, p-methoxyphenyl propenyl ketone as an oil having a boiling point of about 135° C. (0.5 mm).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C(Cl)Cl>[OH:18][CH2:17][CH2:1][NH:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCO
Yield: 67 %

Procedure:
The hydrochloride salt of L-tryptophan 2-hydroxyethylamide was prepared and coupled with 3 as described for the hydrochloride salt of L-tryptophan methylamide in Example 1 except that 3 was activated with 1,1'-carbonyldiimidazole for 20 minutes in methylene chloride at room temperature. The crude product was a mixture of 0.7 g (67% yield) of the diastereoisomers 12A,B: Rf (C) 12A 0.38, Rf (C) 12B 0.19.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=2)[O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][OH:15])=[CH:2]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][S:23]([O:15][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([CH2:10][O:9][C:8]2[CH:19]=[CH:20][CH:21]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)[CH:12]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(COc2cccc(-c3ccsc3)c2)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1cccc(COc2cccc(-c3ccsc3)c2)c1

Procedure:
104 mg of 3-[3-(3-thienyl)phenoxymethyl]benzyl alcohol was dissolved in 1 ml of ethyl acetate, and 45 microliters of methanesulfonyl chloride and 88 microliters of triethylamine were added with ice cooling and stirring. The reaction mixture was stirred for 1 hour. The precipitate was removed by filtration, and the organic layer was separated, then dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated to give 3-[3-(3-thienyl)phenoxymethyl)benzyl methanesulfonate as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:25][CH3:26])[C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:25][CH3:26])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1N
Reaction time: 1 h

Procedure:
1-Benzyl-4-[(N-ethyl-N-(3-nitro-2-pyridinyl)amino)methyl]piperidine (EXAMPLE 262, 4.70 g) is dissolved in 40 ml of THF and 1.7 g of platinum oxide is added and the reaction is placed on a Parr hydrogenator at 10 psi for 1 hr. Then a further 800 mg of platinum oxide is added and the reaction hydrogenated another hour. Then it is filtered through celite and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[CH:3]12[CH2:4][CH:5]([CH:1]=[CH:2]1)[CH:7]1[C:6]([O:11][C:9](=[O:10])[CH:8]21)=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCC=C1
Product: O=C1OC(=O)C2C3C=CC(C3)C12

Procedure:
Using the procedure of Example 1, cyclopentadiene was reacted with maleic anhydride to provide 5-norbomene-2,3-dicarboxylic anhydride, which was then slowly added to a 10% NaOH aqueous solution. The resulting mixture was heated to about 85° C. for about 90 minutes and slowly cooled to room temperature. The resulting solution was neutralized by adding 10% sulfuric acid drop-wise. The reaction mixture was extracted using ethyl acetate. The organic phase was separated, dried over anhydrous MgSO4, filtered, and concentrated to yield 5-norbornene-2,3-dicarboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[C:10]([O:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:5](OC)=[O:6].[CH3:28][NH2:29].CCCCC.O>O1CCCC1>[CH3:28][NH:29][C:5](=[O:6])[C:4](=[N:3][O:2][CH3:1])[C:9]1[C:10]([O:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CON=C(C(=O)OC)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CNC(=O)C(=NOC)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Yield: 84 %

Procedure:
A mixture of 0.65 g (1.7 mmol) of methyl methoxyimino-[2-(1-(4-chlorophenyl)-3-pyrazolyloxy)pyridin-3-yl]acetate (Example 1.b) and 3.2 g of 40% strength aqueous methylamine solution in 2 ml of tetrahydrofuran were heated under reflux for 0.5 hours. The reaction mixture was freed from the solvent under reduced pressure. The residue was stirred with pentane/water, and the solid was separated off, washed with water and dried under reduced pressure. 0.55 g (84%) of the title compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[CH2:25][CH2:24]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(-c2ccc(CC(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(-c2ccc(CC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)cc2)cc1
Reaction time: 12 h
Yield: 67 %

Procedure:
[4-(4-Acetylphenyl)phenyl]acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (2.5 g) were suspended in DMF (50 mL), and triethylamine (2.1 mL), EDC hydrochloride (1.6 g) and HOBt (1.3 g) were added-to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (2.5 g) as a white solid. melting point: 184° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:20][C:21]1[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:20][C:21]3[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:31])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: Cc1cccc2cc(CCl)c(-c3ccccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3ccc(=O)c4c(N)ncnc43)c(-c3ccccc3Cl)nc12
Temperature: 140 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 3-(chloromethyl)-2-(2-chlorophenyl)-8-methyl-quinoline (0.2049 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 140° C. for 2.5 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to provide 4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as white solid. The white solid was triturated with EtOAc-Hexane (1:1) and filtered to provide 4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=58 nM] as white solid. 1H NMR (DMSO-d6) δ ppm 9.53 (1 H, d, J=4.7 Hz), 8.13 (1 H, s), 8.04-8.11 (2 H, m), 7.84 (1 H, d, J=7.8 Hz), 7.78 (1 H, d, J=7.8 Hz), 7.64 (1 H, d, J=7.0 Hz), 7.38-7.59 (5 H, m), 6.12 (1H, d, J=7.8 Hz), 5.40 (2 H, d, J=6.3 Hz), 2.64 (3 H, s). Mass Spectrum (ESI) m/e=428.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([O:17][CH3:18])[CH:3]=1.Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[N:24]3[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:30])[CH3:31])=[N:28][C:23]3=[N:22][CH:21]=2)=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: COc1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(F)ccc1-c1cnc2nc(C(C)(C)O)cnn12
Yield: 91 %

Procedure:
2-(4-Fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (from Example 1, step d) under the conditions described in Example 1, step e. The residue was purified by flash column chromatography (silica gel, EtOAc) to give the title compound in 91% yield: 1H NMR (400 MHz, CDCl3) δ 1.70 (6H, s), 3.57 (1H, s), 3.87 (3H, s), 6.78–6.83 (2H, m), 7.87 (1H, dd, J 1.6, 6.6), 8.23 (1H, s), 8.69 (1H, s); MS (ES+) m/z 303 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:29][C:30]1[C:35](Cl)=[N:34][CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[C:35]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)=[N:34][CH:33]=[CH:32][N:31]=1
Reactant: Clc1nccnc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3Cl)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.58 g, 14.5 mmol, 60% dispersion in mineral oil) was added to a solution of trans-4-(bis(4-methoxybenzyl)amino)cyclohexanol (4.30 g, 12.1 mmol) in DMF (50 mL). The mixture was stirred for 30 min at RT before 2,3-dichloropyrazine (1.89 mL, 12.7 mmol) was added dropwise via syringe. The reaction mixture was warmed to 60° C. and stirred overnight. The mixture was diluted with water and extracted with EtOAc (3×). The extracts were combined, washed with water (3×), washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude oil was purified by silica gel chromatography to give trans-4-(3-chloropyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[C:14]([CH:15]=O)=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[C:14](/[CH:15]=[CH:24]/[C:23]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(OCc2ccccc2)cc(OC)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(OC)cc(OCc2ccccc2)cc1OC
Yield: 64 %

Procedure:
To a solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.0 g, 5.49 mmol), benzyl alcohol (0.65 g, 6.01 mmol) and tributylphosphine (1.5 g, 7.41 mmol) in tetrahydrofuran (120 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.8 g, 7.13 mmol) by small portions, and the mixture was stirred at room temperature for 18 hrs. Diethyl ether (120 ml) was added to the reaction mixture, the precipitated insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-1:1) to give 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) as pale-yellow crystals. Separately, a solution of ethyl diethylphosphono acetate (1.1 g, 4.91 mmol) and 60% sodium hydride (0.17 g, 4.25 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. A solution of 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) was added, and the mixture was stirred while elevating the temperature to room temperature for 5 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether-hexane to give the title compound (1.2 g) as colorless crystals. yield 64%. MS 343.1 (MH+).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH-].[Na+].[CH2:8]([O:14][C:15](Cl)=[O:16])[CH2:9][CH:10]=[CH:11][CH2:12][CH3:13]>C(OCC)C>[CH2:8]([O:14][C:15](=[O:16])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:9][CH:10]=[CH:11][CH2:12][CH3:13]
Reactant: CCNCC
Reactant: CCC=CCCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCC=CCCOC(=O)N(CC)CC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
Diethylamine (9.1 g, 125 mmol, 1.25 equiv.) was added to a 2%-aqueous NaOH-solution (200 ml) and the resulting mixture was cooled to 0° C. (icebath). At this temperature chloroformic acid hex-3-enyl ester (16.2 g, 100 mmol) in diethyl ether (200 ml) was added over a period of 35 min. After complete addition, the cooling bath was removed and stirring was continued for 1.5 h. The mixture was acidified with 2N aqueous HCl-solution, the phases separated and the organic phase was washed with brine and dried over MgSO4. The crude product was purified via fractionated distillation (74-76° C./0.05 mbar) to yield 18.2 g (92%) of product.
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][CH3:74])[CH:68]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[CH:68]=[C:69]([NH:73][CH3:74])[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CNc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 144 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloro-N-methylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (s, 1H), 6.48 (d, J=1.51 Hz, 2H), 5.69 (s, 1H), 3.91 (dd, J=3.78, 7.55 Hz, 3H), 3.74 (s, 2H), 3.50-3.67 (m, 2H), 2.90 (s, 3H), 1.96 (dt, J=4.53, 9.06 Hz, 1H), 1.73-1.88 (m, 2H), 1.57-1.73 (m, 1H). EIMS (m/z): calcd. for C18H22Cl2N6O (M+1H) 409. found 409.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].[Na].[CH:8]([C:11]1([CH3:25])[N:15]2[C:16](=[O:23])[C:17]3[C:22]([C:14]2=[N:13][C:12]1=[O:24])=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH3:10])[CH3:9].Cl>C(Cl)Cl>[CH:8]([C:11]1([CH3:25])[NH:15][C:14]([C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]([O:4][CH2:1][C:2]#[CH:3])=[O:23])=[N:13][C:12]1=[O:24])([CH3:10])[CH3:9]
Reactant: C#CCO
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1
Temperature: 5 °C

Procedure:
To 12.5 ml of propargyl alcohol is added 0.1 g of a 50% suspension of sodium hydride in mineral oil. The addition is made under a blanket of nitrogen while the mixture is stirred and the temperature thereof maintained at from 20° C. to 25° C. by means of external cooling. The formation of the sodium salt of propargyl alcohol is complete in about 1 to 2 hours. To this solution is added 5.0 g of 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione and the mixture stirred at room temperature overnight under a blanket of nitrogen. Thin layer chromatography indicates incomplete reaction and an additional 50 mg of a 50% suspension of sodium hydride in oil is added to the reaction mixture. After stirring overnight, the mixture is cooled to 5° C. and 0.7 ml of 3N hydrochloric acid is added. The mixture is then diluted with methylene chloride, washed with water and the organic phase dried and concentrated in vacuo. The crystalline residue is transferred to a filter funnel with hexane and air dried to give 6.02 g of 2-propynyl o-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)benzoate, melting point 131°-144° C. Material from a similar reaction was recrystallized from acetonehexane to give pure product melting point 145°-147° C.
Reaction SMILES: [C:1]([C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH2:14])[N:6]=1)(=[O:4])[CH:2]=[CH2:3].[C:15](Cl)(=O)C(C)=C>>[C:1]([C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH2:14])[N:6]=1)(=[O:4])[C:2]([CH3:15])=[CH2:3]
Reactant: C=CC(=O)c1nc(N)c2[nH]cnc2n1
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)c1nc(N)c2[nH]cnc2n1

Procedure:
All procedural steps and molar ratios were the same as those for the preparation of acryloyladenine, except that methacryloyl chloride was used instead of acryloyl chloride. The yield of MAD was 85%. The IR spectra showed the same bands as the IR spectra of AAD.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]2[O:9][C:10](Br)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11](Br)[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[I-].[K+]>CC(C)=O>[C:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]2[O:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1(Br)Oc2ccc(OC(C)=O)cc2OC1Br
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=COc2cc(OC(C)=O)ccc2O1
Reaction time: 6 h

Procedure:
Under an inert atmosphere, 6 g of ethyl 6-acetoxy-2,3-dibromo- 1,4-benzodioxane-2-carboxylate in solution in 100 ml of acetone are mixed with 7.75 g of potassium iodide and stirred for 6 hours. After evaporation of the acetone under reduced pressure, the residue is diluted in ether and then washed with 20% sodium thiosulfate solution until the mixture is decolorized. The organic phase is then dried over magnesium sulfate and thereafter concentrated under vacuum. The compound is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 7:3).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[H-].[Na+].[Na].[CH:19](Br)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CO>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][O:4]1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(C(F)(F)F)OCC(COC(c2ccccc2)c2ccccc2)O1

Procedure:
A sample of 12 grams (0.05 mols) of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane in 50 ml toluene is treted with 1.93 grams sodium hydride - mineral oil (53.4%, 0.043 mols) at 25°-33° C. The sodium salt is stirred for 2 hours at 35° C. Benzhydryl bromide, 10.6 grams, (0.043 mols) is added at 37° C. and then the temperature is raised to 75°-95° C. for 3 hours. The mixture is filtered and the filtrate washed with water. Vacuum-stripping gives an oil which is dissolved in methanol and clarified by filtration through Super Cel. Yield of product is 17.0 grams at this point. A forerun is distilled in a 4" column filled with stainless steel packing, the remainder without packed column. The product obtained is distilled at 137° C. under 0.45 mm of mercury pressure to yield 2,2-bis(trifluoromethyl)-4-diphenylmethoxymethyl-1,3-dioxolane.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH2:30]([NH:37][CH2:38][CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]([N:37]([CH2:38][CH3:39])[C:27]([C:23]1[CH:22]=[C:21]([NH:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:4]2([C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[NH:11][C:3]2=[O:2])[CH2:19]3)[N:26]=[CH:25][N:24]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNCc1ccccc1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
100 mg (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 μL (0.33 mmol) benzyl-ethyl-amine, 0.10 mL (0.72 mmol) TEA and 85 mg (0.27 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.