Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[CH:27]([NH2:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH:27]([NH:30][CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][NH:5][CH:6]([CH3:19])[CH3:7])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4])([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Solvent: CN(C)C=O
Product: CC(C)NCC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CNC(C)C)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.6 ml, 6 mmole isopropylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into a little bit ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3o.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=2)=[CH:18][CH:17]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(Br)cc1
Solvent: O
Product: Cn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (2.0 g), 4-bromophenol (4.9 g) and TEA (4.0 ml) was stirred at 120° C. for 3 h. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with 1 M NaOH aqueous solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were recrystallized from AcOEt to give the title compound (1.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[NH4+:47].Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([NH2:47])=[O:27])[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2ccc(CC(=O)O)cc2OCc2ccccc2)cc1
Reactant: [NH4+]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(CC(N)=O)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a mixture of [3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetonitrile (0.41 g) in ethanol (5 mL) and water (10 mL) was added potassium hydroxide (0.68 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was acidified by adding 2 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g). To a solution of the obtained [3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetic acid (0.41 g) in tetrahydrofuran (10 mL) were added pyridine (0.19 mL), di-tert-butyl dicarbonate (0.50 g) and ammonium hydrogen carbonate (0.18 g), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetamide (0.38 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Cl[CH2:9][CH:10]=O.C(=O)(O)[O-].[Na+]>C(=O)([O-])[O-].[K+].[K+]>[N:7]1[CH:9]=[CH:10][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: Nc1cnccn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cn2ccnc2cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40% 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol). After stirring for 48 hours at 100° C., the reaction mixture was cooled to room temperature, added with 100 mL of a saturated potassium carbonate solution, and extracted with dichloromethane (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain imidazo[1,2-a]pyrazine 4b (3 g, yield 50.0%) as a brown solid.
Reaction SMILES: [C:1]1(B(O)O)C=CC=CC=1.[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[N:25]=[C:26]([C:30]3[CH:31]=N[C:33](OC)=[CH:34][CH:35]=3)[C:27](F)=[CH:28][C:15]=2[CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[N:25]=[C:26]([C:30]3[CH:31]=[CH:1][CH:33]=[CH:34][CH:35]=3)[CH:27]=[CH:28][C:15]=2[CH2:14]1)(=[O:12])[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2ccc(-c3ccccc3)nc2C=Cc2ccccc21
Yield: 87 %

Procedure:
The title compound (19.9 mg, 87%) was prepared from 13C (20.0 mg, 0.07 mmol) and phenylboronic acid (12.8 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.353 min; LCMS Found: (M+H)+=327.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1B(O)O>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][C:44]=2[Cl:46])[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)cc2Cl)c1

Procedure:
5-(tert-Butyl)-2′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 2,4-dichlorophenylboronic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@H:10]([CH2:39][OH:40])[N:11](O[Si](C(C)(C)C)(C)C)[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[C:12]([NH:11][CH:10]([CH2:9][OH:8])[CH2:39][OH:40])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CO)N(O[Si](C)(C)C(C)(C)C)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To dry ethyl ether (300 ml) is added with stirring lithium aluminum hydride (4.5 g; 0.12 mol) and cooled to 0° C. under nitrogen. The N-trityl-t-butyldimethylsilyloxy serine methyl ester (57 g; 0.12 mol) is added portionwise over 5 minutes as a solid. The reaction mixture is allowed to warm and stir for 30 minutes at 25° C. The mixture is quenched by slow addition of H2O (4.5 ml) at 0° C. followed by 15% NaOH (4.5 ml) and H2O (13.5 ml) at 25° C. After stirring for 3 hours, the mixture is filtered and the solid washed with THF. The combined filtrates are concentrated to which is added ether and petroleum ether to precipitate N-trityl-1,3-dihydroxy-2-propanamine which is used directly in Step D.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Br:18][C:19]1[CH:24]=[C:23]([O:25]C)[CH:22]=[C:21]([Br:27])[C:20]=1[N:28]=[C:29]=[S:30]>CN(C)C1C=CN=CC=1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:20]1[C:21]([Br:27])=[CH:22][C:23]([OH:25])=[CH:24][C:19]=1[Br:18]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1cc(Br)c(N=C=S)c(Br)c1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Br)cc(O)cc2Br)c1NCCCO
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 3.87 mmol), 1,3-dibromo-2-isothiocyanato-5-methoxybenzene (1.50 g, 4.64 mmol) and catalytic amount of 4-dimethylaminopyridine was stirred at 80° C. for 16 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown oil (560 mg, 0.963 mmol, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2cccc(Cl)c2C1=O

Procedure:
29.1 g (0.14 mol) of 6-chloroisatoic acid anhydride are stirred at 110° C. for 1 hour with 13.12 g (0.14 mol) of sarcosine in 150 ml of dimethyl sulphoxide. The solution obtained is concentrated and the residue is recrystallised from alcohol. There is obtained 6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 237°-238° C.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[Si:6]([O:13][CH2:14][CH2:15][NH2:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>CO>[Si:6]([O:13][CH2:14][CH2:15][NH:16][CH:3]1[CH2:2][O:1][CH2:4]1)([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: O=C1COC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNC1COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 249.3 %

Procedure:
To a stirred solution of oxetan-3-one (1 g, 13.87 mmol) in methanol (40 mL) was added 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (2.7 mg, 15.27 mmol). The mixture was stirred for 30 min at room temperature after cooling, Na(CN)BH3 was added portion-wise, followed by stirring at room temperature for 2 h. The reaction mixture was quenched with water, extracted with dichloromethane (3×30 mL). The organic part was concentrated, dried and purified by Combi-Flash column (eluted at 20-50% ethyl acetate in hexane) to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (8 g) (1.5 g, 46.71%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:12])[O:4][C:5]([CH2:10][CH3:11])([CH3:9])[CH2:6][C:7]=1[OH:8].[Cl:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]([CH:22]([CH3:24])[CH3:23])[C:19]([SH:21])=[N:20][C:16]=2[CH:15]=1>>[Cl:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]([CH:22]([CH3:24])[CH3:23])[C:19]([S:21][C:2]3[C:3](=[O:12])[O:4][C:5]([CH2:10][CH3:11])([CH3:9])[CH2:6][C:7]=3[OH:8])=[N:20][C:16]=2[CH:15]=1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: CCC1(C)CC(O)=C(Cl)C(=O)O1
Product: CCC1(C)CC(O)=C(Sc2nc3cc(Cl)ccc3n2C(C)C)C(=O)O1

Procedure:
The title compound was prepared from 3-Chloro-6-ethyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (from Step 1) and 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol using the coupling method described in Example C(4).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added pyrrolidine (24.1 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1—(4-nitrobenzyl)pyrrolidine (23.5 g) as orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([NH:14]C(=O)C(F)(F)F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH2:14])([CH2:21][NH2:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(NC(=O)C(F)(F)F)CC1
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)(CN)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminomethyl-4-(2,2,2-trifluoro-acetylamino)-piperidine-1-carboxylic acid tert-butyl ester in MeOH (70 ml) is added a 30% aqueous solution of ammonia (70 ml) and the reaction mixture is stirred at 80° C. overnight. The reaction mixture is concentrated in vacuo to 4-Amino-4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester as a brown oil that is used crude without further purification; [M+H]+ 230.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](Cl)=[O:45])=[CH:43][C:38]=2[CH2:37][CH2:36]1>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:44]([C:42]3[CH:41]=[CH:40][C:39]4[O:35][CH2:36][CH2:37][C:38]=4[CH:43]=3)=[O:45])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4c(c3)CCO4)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 2,3-dihydro-1-benzofuran-5-carbonyl chloride as a colorless oil (92%). 1H NMR (CDCl3, 300 MHz) δ 7.66 (d, J=2.7 Hz, 1H), 7.44 (m, 4H), 7.34 (brs, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.02 (m, 1H), 6.97 (dd, J=8.6, 2.7 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.52 (d, J=8.3 Hz, 1H), 5.12 (s, 2H), 4.55 (t, J=8.9 Hz, 2H), 3.12 (t, J=8.9 Hz, 2H), 2.62 (t, J=7.8 Hz, 2H), 1.69 (s, 6H), 1.61 (m, 2H), 1.36 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). M+ (ESI): 586.4. HPLC, Rt: 6.05 min (Purity: 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2ccc(Cl)nn2)c1
Reactant: NNC=O
Solvent: CCCCO
Product: Fc1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 3.6 g. of 3-chloro-6-(m-fluorophenyl)pyridazine and 2.06 g. of formylhydrazine in 50 ml. of n-butanol is refluxed for 48 hr. and worked up as in Example 35 to give the product as crystals, m.p. 159°-161° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:40][CH2:39][CH2:38][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[C:34](OC)=[O:35])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:40][CH2:39][CH2:38][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[C:34]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:35])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (6.09 g, 54.4 mmol) in dry THF (100 mL) was added a 2M solution of isopropylmagnesium chloride (27.2 mL, 54.4 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (5 g, 13.5 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (200 mL). The product was extracted with EtOAc (2×80 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a solid residue which was purified by column chromatography on silica gel using 2-2.5% MeOH-DCM system as eluent to afford 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide (2.85 g, 47% yield) as the racemate. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.56-0.72 (m, 2H), 0.82-0.94 (m, 2H), 1.70-1.82 (m, 1H), 2.00-2.20 (m, 4H), 2.21-2.38 (m, 2H), 2.70-2.77 (m, 2H), 2.78-2.82 (m, 2H), 3.58-3.78 (m, 1H), 3.79-3.81 (m, 1H), 4.70 (dd, 1H), 6.25 (s, 1H), 6.98 (dd, 1H), 7.95 (s, 1H), 8.18 (s, 1H). Separation by chiral HPLC provided enantiomers 2a and 2b.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([NH:12][CH:13]3[CH2:15][CH2:14]3)[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:2]1[C:3]2[N:11]=[C:10]([NH:12][CH:13]3[CH2:15][CH2:14]3)[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Oc1ncnc2cnc(NC3CC3)nc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2cnc(NC3CC3)nc12

Procedure:
1.7 g of 4-hydroxy-6-(cyclopropylamino)-pyrimido[5,4-d]pyrimidine are heated under reflux with 50 ml of thionyl chloride with the addition of 4 drops of dimethylformamide for 1.5 hours. The reaction mixture is concentrated, methylene chloride is added and the mixture is concentrated again. The residue is then partitioned between methylene chloride and an aqueous potassium carbonate solution. The aqueous phase is extracted twice more with methylene chloride and the combined organic phases are dried and concentrated. The product is reacted further without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C[Al](C)C.[NH:24](/[C:28](/[CH3:34])=[CH:29]\[C:30](OC)=[O:31])[C:25]([CH3:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:30](=[O:31])[CH:29]=[C:28]([CH3:34])[N:24]=[C:25]2[CH3:27])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(NCCCCN2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCCCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of 2-fluoro-N1-(4-morpholinobutyl)benzene-1,4-diamine (1.07 g, 4.00 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (14 mL, 28 mmol, 2 M in toluene) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.30 g, 8.27 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellowish solid (0.26 g, 17%). The compound was characterized by the following spectroscopic data:
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][N:20]1[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22](I)=[N:21]1)=[CH:7]2.[C:31](=[O:34])([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[NH2:29][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:20]([CH2:19][C:8]3[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[Cl:18])=[N:10][C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[Cl:1])[N:21]=[C:22]([C:11]3[CH:6]=[C:31]([OH:34])[CH:4]=[CH:3][CH:2]=3)[C:23]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure J using 1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.18 mmol), 3-(hydroxyphenyl)boronic acid (0.050 g, 0.37 mmol, 2 eq), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol, 0.1 eq) and 2M aq sodium carbonate (0.54 mL, 1.08 mmol, 6 eq) in DMF (1 mL). 3-(4-Amino-1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol [PI3Kδ IC50=14 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (1 H, s), 8.31 (1 H, s), 7.91-8.00 (2 H, m), 7.86 (1 H, dd, J=7.4, 1.2 Hz), 7.52 (1 H, t, J=7.8 Hz), 7.35 (1 H, d, J=8.2 Hz), 7.07-7.28 (3 H, m), 6.97-7.05 (1 H, m), 6.78-6.93 (2 H, m), 6.70 (1 H, dd, J=8.2, 1.6 Hz), 5.36-5.57 (2 H, m) Mass Spectrum (ESI) m/e=513.1 and 515.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:23][NH2:24])(=O)[CH2:19][CH2:20][CH3:21]>C(O)CCC>[CH2:19]([C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:24][N:23]=1)[CH2:20][CH3:21]
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCCC(=O)NN
Solvent: CCCCO
Product: CCCc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
A mixture of 5.0 g of 3-chloro-6-(α,α, α-trifluoro-p-tolyl)pyridazine, 3.94 g. of butyric acid hydrazide and 100 ml. of n-butanol is refluxed for 48 hr. The solvent is removed under vacuum and the residue dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate and the eluent concentrated to give 3.2 g. of product Recrystallization from CHCl3 -hexane gives crystals, m.p. 173°-175° C.