Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1.[H-].[Na+].[CH:25]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1
Reactant: BrC1CCCC1
Reactant: COc1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Reaction time: 1 h
Yield: 46.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-(3,4-dimethoxy-benzyl)-amine (799 mg, 2.5 mmol) was dissolved in dry DMF (10 mL). NaH (78 mg, 3.25 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (633 mg, 4.25 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (451 mg, 46.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:16])[CH2:6]2.[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:14][C:13](=[O:15])[CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:16]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc2c(c1)CC(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)CC(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 26.4 %

Procedure:
To a solution of 2-(5-methoxy-2-oxoindolin-1-yl)acetic acid (200 mg, 0.904 mmol) in DCM (30 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (380 mg, 0.904 mmol), EDC (520 mg, 2.71 mmol) and DMAP (55.2 mg, 0.452 mmol) were added, and the mixture was reacted at room temperature overnight. The solvent was evaporated, and the resulting crude was partitioned between DCM (20 ml) and a 1N HCl (20 ml), and the desired compound was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel (DCM:MeOH 98:2) recovering the title compound (149.2 mg, 0.239 mmol, 27% yield). MS/ESI+ 623.12 [MH]+; [αD]=+19.12 c=0.5 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92-6.98 (m, 2H), 7.07 (t, 1H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.02 (dd, 1H), 4.54 (d, 1H), 4.46 (d, 1H), 3.91 (d, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.03-1.41 (m, 1H), 0.50-0.70 (m, 2H), 0.21-0.50 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([N:16]2[C:20](=[O:21])[CH:19]=[C:18]([NH2:22])[N:17]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(#N)C.O>[C:10]1([N:16]2[C:20](=[O:21])[CH:19]=[C:18]([NH:22][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:17]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)n1c(N)cc(=O)n1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)n1c(NC(=O)c2ccccc2)cc(=O)n1-c1ccccc1

Procedure:
15.4 g (0.11 mole) of benzoyl chloride are added at room temperature to a solution of 24.7 g (0.1 mole) of 1-phenyl-2-ethoxycarbonyl-3-amino-3-pyrazolin-5-one (compound 2),3 ml of nitrobenzene, and 26.7 g (0.2 mole) of anhydrous aluminium chloride in 100 ml of acetonitrile. The solution is refluxed for 3 h and then poured out into water. The precipitate is filtered off, rinsed with water, dried, and recrystallized from acetonitrile.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([N:26]1[CH2:27][CH2:28][N:29]([CH2:2][C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:30][CH2:31]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.5 g) was dissolved in CH2Cl2 and added to N-Boc-piperazine (2.5 g) and NaHCO3 (1 g) and stirred at RT overnight. The mixture was diluted with CH2Cl2 (100 ml), washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexane, CH2Cl2:hexane 2:8) to give the compound as an yellow solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].[CH3:21]N(C)C=O.CI>O>[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Reactant: CN(C)C=O
Agent: [Na]
Solvent: CI
Solvent: O
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Reaction time: 2 h

Procedure:
A solution of 4.0 g. (0.014 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid in 100 ml. of dry dimethylformamide was treated with 8.0 g. (0.057 mole) of methyl iodide. After stirring for two hours the solution was poured into water and the aqueous solution extracted several times with ethyl ether. The combined extracts were washed with water, dried over sodium sulfate and concentrated under vacuum to a yellow oil. The oil was crystallized from a chilled methanol-water solution to give 3.5 gms. (90%) of a yellow solid which melted at 52°-54° C.
Reaction SMILES: [CH2:1]([CH:7]1[S:12]CCCS1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(=O)C1OC=CC=1.[CH2:20](S)[CH2:21][CH2:22][SH:23].C[Si](Cl)(C)C>C(Cl)(Cl)Cl>[CH2:1]([CH:7]1[CH2:20][CH2:21][CH2:22][S:23][S:12]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: c1coc(CC2SCCCS2)c1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: O=Cc1ccco1
Product: c1coc(CC2CCCSS2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Preparation of 2-furfuryl-1,3-dithiane—Furfural (40 mL, 0.4825 mol) was dissolved in CHCl3 (400 mL) and cooled to 0° C. (ice bath) with 1,3-propanedithiol (48.5 mL, 0.482 mol, 1 eq) and a catalytic amount of TMSCl (3 pipets full). The reaction mixture was allowed to warm gradually to room temperature overnight and then partitioned with aqueous 5% NaOH (200 mL) and separated. The aqueous layer was extracted with Et2O and the combined organics were dried (Na2SO4), filtered, and evaporated to afford crude furfuryl dithiane (85 g, 0.457 mol, 94.8% yield), which was taken on to the next step without further purification. 1H NMR: δ 7.38 (m, 1H), 6.40 (m, 1H), 6.35 (m, 1H), 5.23 (s, 1H, —SH), 2.97 (m, 4H), 2.19–2.10 (m, 1H), 2.05–1.94 (m, 1H). 13C NMR: δ 152.2, 142.7, 111.0, 108.3, 42.5, 30.7, 25.7.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[C:25]([O:31][CH2:32][CH:33]=[CH2:34])(=[O:30])[CH2:26][C:27]([CH3:29])=O>O1CCOCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:26]([C:25]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[C:27]([CH3:29])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:10](=[O:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: C=CCOC(=O)CC(C)=O
Solvent: C1COCCO1
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1

Procedure:
45.0 g ethyl polyphosphate are dissolved in 150 ml dioxane, 15.0 g (73.5 mmol) N-[3-(trifluoromethyl)phenyl]urea, 19.3 g (147 mmol) 4-cyanobenzaldehyde and 20.9 g (147 mmol) allyl aceto-acetate are added, and the mixture is stirred under reflux overnight. Volatiles are evaporated in vacuo, the remainder is dissolved in ethyl acetate and sequentially washed with saturated sodium hydrogencarbonate, sodium hydrogensulfite and sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude product is purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:32](=[O:35])[CH2:33][CH3:34])([CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(CC12CC1CCN(Cc1ccccc1)C2)c1ccccc1
Reaction time: 2 h

Procedure:
To the a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]hept-1-ylmethyl)-phenyl-amine (175) (250 mg, 0.86 mmol) in CH2Cl2 (2 ml) at 0° C. was added i-Pr2NEt (0.30 ml, 1.72 mmol)) and propionyl chloride (0.11 ml, 1.29 mmol). The mixture was stirred for 2 hrs. The mixture was diluted with CH2Cl2 (5 ml), washed with sat. NaHCO3 (2×5 ml), brine (5 ml) and water (5 ml) and dried with Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH in CH2Cl2) to give 176 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.41-7.20 (m, 10H), 4.20 (d, 1H), 3.42 (AB, 2H), 3.21 (d, 1H), 2.65 (q, 2H), 2.20-2.00 (m, 4H), 1.80-1.60 (m, 2H), 1.30 (m, 1H), 1.05 (t, 3H), 0.80-0.20 (m, 2H) ppm; LRMS (calculated for C23H28N2O) 348, found 348; IR (film) 3308, 3105, 3064, 2978, 2937, 2874, 2811, 1689m 1666, 1598, 1540, 1499, 1445, 1314, 1246, 1196, 1074, 757 cm−1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)cc1
Yield: 54.3 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]pentane-1,4-dione (3 g, 11.8 mmol), 4-bromoaniline (2.03 g, 11.8 mmol), and p-toluenesulfonic acid (150 mg) in toluene (250 mL) was heated at reflux temperature using Dean-Stark apparatus. After cooling down, volatiles were removed by evaporation. The residue was purified, by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/3) to give the subtitle compound (2.5 g, 54% yield).
Reaction SMILES: [OH-].[Na+:2].[C:3]12([NH:13][C:14]([C:16]#[C:17][C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[Cl:27])[NH:20][C:19]=3[C:29]([O:31]CC)=[O:30])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.O>C(O)(C)C>[Na+:2].[C:3]12([NH:13][C:14]([C:16]#[C:17][C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[Cl:27])[NH:20][C:19]=3[C:29]([O-:31])=[O:30])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C#CC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(C#Cc1c(C(=O)[O-])[nH]c2cc(Cl)cc(Cl)c12)NC12CC3CC(CC(C3)C1)C2
Temperature: 60 °C
Yield: 93.6 %

Procedure:
Sodium hydroxide (59 mg) was added to a solution of Example 18 (170 mg) in isopropyl alcohol (5.4 ml) and the reaction was heated at 60° C. for 3 h. After cooling, water (6 ml) was added and the resulting yellow precipitate was filtered and washed well with more water, then dried to furnish the title compound (157 mg,) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[O:15][CH3:17])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
Methyl 3-t-butyl-4-hydroxy-5-iodobenzoate (2.77 g) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (12.0 g) and dimethylsulfuric acid (4.1 mL) were added to the solution, and then the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.77 g) as a brown crystal.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:20]([O:22]C)=[O:21])=[CH:7][C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.O>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH3:18])[O:9][C:8]([C:20]([OH:22])=[O:21])=[CH:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC)=C[C@@H](N=[N+]=[N-])[C@H]1NC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@@H](N)[C@H]1NC(C)=O
Reaction time: 21 h
Yield: 38.4 %

Procedure:
To a stirred solution of (4R,5R,6R)-5-acetylamino-4-azido-6-(dipropylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (500 mg) in tetrahydrofuran (6 ml) under nitrogen was added triphenylphosphine (428 mg). After 3.5 hours at 23° C. water (1 ml) was added adn the solution was stirred for a further 21 hours. Triethylamine (1 ml) was added and stirring was continued for a further 7 hours after which the solvents were removed in vacuo. The resulting liquid was redissolved in ethyl acetate, was dried over anhydrous magnesium sulphate, and the solvent was evaporated in vacuo to leave a yellow solid. The solid was chromatographed over silica (Merck 9385, 45 g) using medium pressure (ca 4 psi) and chloroform/methanol (15:1, v/v) as eluant. Appropriate fractions were combined and the solvent was evaporated in vacuo to afford a white solid which was suspended in water (5 ml) containing triethylamine (2 ml) and was stirred at 50° C. for 1.5 hours. The solvents were removed in vacuo to afford the title compound as a white solid (171 mg). 1H NMR (250MHz, D6 -DMSO) 8.4 (1H, broad s), 5.7 (1H, d, J=1.5Hz), 5.1 (1H, d, J=4Hz), 4.4 (1H, broad s), 3.95 (1H, broad s), 2.95-3.86 (6H, m), 2.0 (3H, s), 1.6 (4H, m), 0.94+0.99 (6H, two t, J=7.5Hz). Mass spec. (low resolution): MH+ =328. Mass analysis: C15H25N3O5. 1.5 H2O Required: C, 50.79; H, 7.90; N, 11.85. Found: C, 50.87; H, 8.04; N, 11.54.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8]2)=[N:3]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)=[CH:6][C:7]([C:11]([F:13])([F:12])[F:14])=[CH:8]2)=[N:3]1
Reactant: [BH3-]C#N
Reactant: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c2n1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn(C)nc23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-methyl-7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-2H-indazole (58 mg, 0.144 mmol) and sodium cyanoborohydride (18 mg, 0.288 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (25%). 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 7.85 (s, 1H), 7.41 (m, 2H), 7.34 (m, 2H), 7.22 (m, 1H), 4.82 (s, 2H), 4.21 (s, 3H), 3.58 (s, 2H), 2.60 (m, 2H), 2.20-2.33 (m, 4H), 2.22 (s, 3H), 2.06 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 147.6, 135.1, 129.3, 128.3, 127.4, 126.1, 125.5, 124.9 (q, J=272 Hz), 124.2 (q, J=32 Hz), 120.7, 118.7, 117.5 (q, J=4.8 Hz), 79.9, 68.7, 52.1, 46.2, 40.9, 40.7, 32.4. Mass spec.: 418.15 (MH)+. Accurate mass spec.: m/z 418.2019 [MH]+, Δ=0.7 ppm.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:20])[CH2:16][N+:17]([O-:19])=[O:18]>N1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:20][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:16][N+:17]([O-:19])=[O:18]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(C[N+](=O)[O-])c1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Reaction time: 1 h

Procedure:
At RT, 219 μl (2.31 mmol) of ethanesulphonyl chloride were added to a solution of 295 mg (about 93% pure, 1.16 mmol) of the compound of Example 25A in 7.0 ml of pyridine, and the mixture was stirred for 1 h. The pyridine was then removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. This gave 230 mg (about 90% pure according to LC/MS, 61% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH2:19])[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccs1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(thiophen-2-yl)-quinolin-3-yl)ethanamine (0.078 g, 0.286 mmol), 6-chloropurine (0.053 g, 0.344 mmol, 1.2 eq) and DIEA (0.58 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(7-fluoro-2-(thiophen-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.62 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.00-8.07 (m, 1H), 7.62-7.73 (m, 3 H), 7.43-7.51 (m, 1H), 7.18 (m 1H), 1.78 (d, J=7.04 Hz, 3H), 1H), Mass Spectrum (ESI) m/e=391 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]([Cl:21])([O:13][C:14](=O)[O:15]C(Cl)(Cl)Cl)[Cl:12].C.C1(C)C=CC=CC=1>CCCCCC.CCOCC>[Cl:10][C:11]([O:13][C:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:15])([Cl:21])[Cl:12]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(OC(Cl)(Cl)Cl)n1nnc2ccccc21

Procedure:
A stirred mixture of benzotriazole (3 g), triphosgene (11.22 g), charcoal (1 g) and anhydrous toluene was refluxed overnight and filtered. Evaporation of the filtrate gave an oily solid which was suspended in a mixture of hexane and ether (1:1). Filtration and evaporation of the filtrate gave the titled compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:24][N:21]1[CH2:22][CH2:23][CH:18]([O:16][C:14](=[O:15])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH2:8])[CH2:19][CH2:20]1.[CH3:24][N:21]1[CH2:22][CH2:23][CH:18]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:10][CH2:11][S:12][CH3:13])[C:14]([O-:16])=[O:15])[CH2:19][CH2:20]1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSCCC(NC(=O)OC(C)(C)C)(C(=O)[O-])C1CCN(C)CC1
Product: CSCC[C@H](N)C(=O)OC1CCN(C)CC1

Procedure:
L-methionine (N-methylpiperidin-4-yl) ester was prepared as follows: A solution of tert-butoxycarbonyl-L-methionine (5 g; 20 mmol), 4-hydroxy-1-methylpiperidine (3.3 g; 20 mmol); DMAP (2.44 g; 20 mmol) and EDC (4.6 g; 2.4 mmol) in dichloromethane (200 ml) was stirred at ambient temperature overnight. The mixture was extracted with dichloromethane. The organic phase was evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (97/3) to give 1-methylpiperidin-4-yl-2-tert-butoxycarbonylamino-4-methylsulfanylbutyrate. Yield 56%.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].COC1C=C(C=CC=1OC)C(O)=O.S(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(CN)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(C(=O)NCc2ccc(OCCN(C)C)cc2)cc1OC

Procedure:
To a cooled solution of 20.0 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 60 ml of toluene was added a solution of 21.7 g of 3,4-dimethoxybenzoyl chloride (which was prepared with 19.7 g of 3,4-dimethoxybenzoic acid and 38.5 g of thionyl chloride in the usual manner) in 60 ml of toluene with stirring. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 120 ml of water and 1 ml of concentrated hydrochloric acid. The aqueous layer was separated, washed with 20 ml of toluene and made alkaline with 20% sodium hydroxide solution to give a precipitate, which was washed with isopropyl ether, of 37.0 g of pale brownish crystals. Recrystallization of the crystals from ethanol and isopropyl ether gave the title compound as colorless needles, m.p. 111°-112° C.