Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[S:15][CH2:16][C:17](O)([C:19]([F:22])([F:21])[F:20])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a mixture of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea (Intermediate 41, 2.2 g, 5.32 mmol) in DCM (30 mL), TFAA (1.128 mL, 7.99 mmol) followed by TEA (1.113 mL, 7.99 mmol) were added. The reaction mixture was allowed to stir overnight at room temperature, then another 150 uL of TEA and TFAA were added and the reaction mixture was stirred for additional 3 h. The reaction was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The layers were separated, and the organic layer was washed with sodium bicarbonate solution, water and brine, then dried over magnesium sulfate and concentrated under reduced pressure. The light yellow solid obtained was purified by normal phase (1% MeOH in dichloromethane to 3% MeOH in dichloromethane) to give 520 mg of the product. MS (ESP): 396 (M+1) for C12H10BrN3O; NMR: 1.07 (t, 3H); 3.11-3.17 (m, 2H); 7.24 (t, 1H); 8.35 (s, 1H); 8.50 (s, 1H); 8.77 (s, 1H); 9.34 (s, 1H)
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[C-:11]#[N:12].[K+]>CCO.O>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([I:9])[C:3]=1[CH2:2][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Clc1cccc(I)c1CBr
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(Cl)cccc1I
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 2-(bromomethyl)-1-chloro-3-iodobenzene (14 g, 42 mmol) in 100 mL EtOH was treated with a solution of potassium cyanide (3.6 mL, 84 mmol) in 40 mL water. The mixture was refluxed for 2.5 hours. The mixture was cooled to room temperature and then concentrated. The residue was diluted with 200 mL EtOAc, washed with water (2×50 mL), saturated NaCl (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexane) to give 10.18 g pale yellow solid. MS m/e: (M−1)− 276.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][NH:18][C:17]2=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[Cl:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
Phosphorus oxychloride (3.1 ml) was added to 6-(benzyloxy)-7-methoxy-3,4-dihydro-4-quinazolinone (3.5 g) and diisopropylethylamine (11.5 ml). The mixture was refluxed for 20 min. The reaction solution was cooled to room temperature, and a 10% aqueous sodium hydroxide solution was then added to the cooled reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate. The organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 2.9 g (yield 72%) of the title compound.
Reaction SMILES: [CH:1]1[N:5]=[C:4]([NH2:6])[NH:3][C:2]=1[C:7]1[C:14]2[C:15](Br)=[C:16]([Br:18])[NH:17][C:13]=2[C:11](=[O:12])[NH:10][CH2:9][CH:8]=1.Br>>[CH2:9]1[NH:10][C:11](=[O:12])[C:13]2[NH:17][C:16]([Br:18])=[CH:15][C:14]=2[C:7]([C:2]2[NH:3][C:4]([NH2:6])=[N:5][CH:1]=2)=[CH:8]1
Reactant: Nc1ncc(C2=CCNC(=O)c3[nH]c(Br)c(Br)c32)[nH]1
Agent: Br
Product: Nc1ncc(C2=CCNC(=O)c3[nH]c(Br)cc32)[nH]1
Temperature: 90 °C

Procedure:
With precursor 19 in hand, all that remained in the synthesis of stevensine (2) was the elimination of HBr. The direct removal of HBr involves a syn elimination event, a process that proved troublesome when tried under basic conditions. Therefore, an acid promoted elimination was attempted since the salts of AI heterocycles are generally quite stable. Heating 19 in methanesulfonic acid (90° C., sealed flask, 12 h) afforded products 3-debromostevensine (20) and 5-bromo-3-debromostevensine (21) in 14% and 47% yields, respectively (Scheme 3).19 The molecular skeleton of 20 and 21 was established by hydrogenation to 2,3-debromohymenin (15). The bromo substitution pattern in 20 and 21 was deduced from their 1H NMR spectra. The a-bromo substituted pyrrole showed b-pyrrole hydrogens at 6.42 (s) ppm and 6.10 (s) ppm for 20 and 21 in CD3OD, respectively.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[O:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:19][C:17]2[O:18][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: OCc1cccc(NO)c1
Product: O=[N+]([O-])c1ccc(C=[N+]([O-])c2cccc(CO)c2)o1
Yield: 70.6 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 5-nitro-2-furaldehyde (65) (1.41 g, 10 mmol) afforded, after workup, a yellow solid. The crude product was recrystallized from acetone/petroleum ether to obtain 1.85 g (7.06 mmol, 71%) of 96 as a yellow crystalline solid: mp 187°-188° C.; IR (CH2Cl2) 3310, 1550, 1520, 1340, 1140, 1025, 1002, 802 cm-1 ; 1H NMR (Me2SO-d6) δ 4.5 (d, J=5.6 Hz, 2H), 5.39 (t, J=5.6, 1H), 7.48-7.93 (m, 6H), 9.01 (s, 1H); 13C NMR (Me2SO-d6) δ 62.81, 115.39, 117.26, 119.49, 119.74, 123.41, 123.56, 129.22, 129.53, 144.88, 147.17, 150.15, 151.78. Anal. Calcd for C12H10N2O5 : C, 54.96; H, 3.81. Found: C, 55.35; H, 3.88.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[B:17](OC)([O:20]C)[O:18]C>O>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: OB(O)c1cccc(F)c1F
Temperature: 25 °C

Procedure:
10 g of trimeric 2,3-difluorophenylboronic anhydride are prepared according to Example 1 from 1,2-difluorobenzene, lithium diisopropylamide and trimethyl borate. The anhydride is dissolved in 200 ml of boiling water. The hot solution is filtered, and the filtrate is allowed to cool slowly to room temperature. The solid is separated off and dried to give 2,3-difluorophenylboronic acid having a melting point of 89° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:26]=[CH:25][C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.[F-].[Cs+].O>CS(C)=O>[C:19]1([N:18]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[C:17]2[CH:25]=[CH:26][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N(c2ccccc2)c2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
One hundred and twenty (120) ml of DMSO as a solvent was added to 10.0 g of N,N′-diphenylbenzidine (29.7 mmol), 8.38 g of p-fluoronitrobenzene (59.4 mmol), and 4.5 g of cesium fluoride (29.7 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 24 hours. Following reaction, the mixture was poured with stirring into 2500 ml of cold water to obtain crude crystals of N,N′-diphenyl-N-(4-nitrophenyl)-1,1′-biphenyl-4,4′-diamine (NTPD). Subsequently, the mixture was dried for 12 hours in a vacuum at 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 60 °C

Procedure:
To methyl 3-chloro-4-hydroxy-benzoate (3.0 g, 16.1 mmol) in DMF (19 mL) was added potassium carbonate (8.9 g, 64.3 mmol) followed by 2-iodopropane (5.5 g, 3.2 mL, 32.2 mmol). The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled, filtered and diluted with EtOAc and the solvent was concentrated in vacuo. The material was dissolved in EtOAc and washed with water (3×10 mL) and brine (1×10 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo to give methyl 3-chloro-4-isopropoxybenzoate. To the ester was added dioxane (47 mL) and sodium hydroxide (42.7 mL of 1 M, 42.7 mmol) and the reaction was heated at 80° C. for 15 minutes. The reaction was cooled and solvent was removed in vacuo. The resulting residue was dissolved in water and washed with EtOAc (3×10 mL) and the layers were separated. The aqueous layer was acidified to pH 1 and was extracted with EtOAc (3×10 mL). The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 3-chloro-4-isopropoxy-benzoic acid (2.86 g, 83%) as a white solid. ESI-MS m/z calc. 213.6. Found 215.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400.0 MHz, CDCl3) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd, J=8.8, 2.2H, 1H), 7.06 (d, J=8.8 Hz, 1H) and 3.90 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:14]([CH3:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4]
Reactant: COC(=O)c1nc2ccccc2cc1C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1Nc2ccccc2C[C@@H]1C
Yield: 78.2 %

Procedure:
2-Methoxycarbonyl-3-methylquinoline (30 g, 0.149 mol) in acetic acid (300 mL) was hydrogenated over platinum oxide (1 g) under atmospheric pressure of hydrogen at room temperature until the theoretical amount of hydrogen was consumed. The mixture was passed through celite and concentrated in vacuo. The residue was purified by silica gel column chromatography with 20:1 to 10:1 hexane/ethyl acetate to give 23.93 g of cis-2-methoxycarbonyl-3-methyltetrahydroquinoline (78%): 1H NMR (270 MHz, CDCl3) d 6.99 (m, 2H), 6.64 (t, 1H, J=7.9 Hz), 6.58 (d, 1H, J=7.9 Hz), 4.34 (s, 1H), 4.09 (t, 1H, J=2.5 Hz), 3.06 (dd, 1H, J =16.9, 5.8 Hz), 2.55 (m, 1H), 2.50 (dd, 1H, J=16.9, 3.3 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:30])[C@@H:10]([CH:11]=O)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=1[F:29])=[O:14].C(OP([CH:39]([Cl:42])[C:40]#[N:41])(=O)OCC)C>O1CCCC1>[Cl:42]/[C:39](/[C:40]#[N:41])=[CH:11]\[C@@H:10]1[C@@H:9]([C:13]([O:15][CH2:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=2[F:29])=[O:14])[C:8]1([CH3:7])[CH3:30]
Reactant: CCOP(=O)(OCC)C(Cl)C#N
Reactant: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@H](C=O)C2(C)C)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](/C=C(\Cl)C#N)C2(C)C)c(F)c1F
Yield: 32.3 %

Procedure:
A solution of 0.14 g of potassium tert-butoxide in 1 ml of tetrahydrofuran was added dropwise to a mixture of 0.35 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3S)-2,2-dimethyl-3-formylcyclopropanecarboxylate, 0.21 g of diethyl(chlorocyanomethyl)phosphonate and 5 ml of anhydrous tetrahydrofuran with ice-cooling under a nitrogen atmosphere. After stirring with ice-cooling for 15 minutes, the reaction mixture was poured into a saturated saline solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.13 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3S)-3-((Z)-2-chloro-2-cyanovinyl)-2,2-dimethylcyclopropanecarboxylate represented by the formula (1):
Reaction SMILES: Cl.C[O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][NH:7]1)=O.[NH3:12]>CO>[OH:11][C@@H:9]1[CH2:8][NH:7][C@H:6]([C:4]([NH2:12])=[O:3])[CH2:10]1
Reactant: N
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Agent: Cl
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](O)CN1
Reaction time: 4 h

Procedure:
A solution of (2S,4S)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1 g) in a 7M solution of ammonia in MeOH (10 ml) was stirred for 18 h then evaporated and triturated with Et2O. The residue was dissolved in the minimum volume of hot MeOH and stood at 4° C. for 4 h. The title compound was isolated by filtration as a white solid.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24].S(=O)(=O)(O)O>IC.O1CCCC1>[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:22]2[CH2:27][CH2:26][O:25][C:23]2=[O:24])([OH:8])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1OCCC1Br
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(O)(c2ccc(F)cc2)C2CCOC2=O)cc1

Procedure:
Magnesium turnings (3.5 g) are covered with anhydrous tetrahydrofuran, and a few drops of iodomethane are added. As soon as the reaction has started, a mixture of 24.6 g of 4-fluoro-4′-methanesulphonylbenzophenone and 8.1 ml of α-bromo-γ-butyrolactone in 250 ml of anhydrous tetrahydrofuran is run in dropwise so as to maintain a gentle reflux. When the addition is complete, the reaction medium is cooled and then run into a mixture of ice and 10% dilute sulphuric acid. The organic phase is extracted with tetrahydrofuran, washed with saturated sodium bicarbonate solution and then dried over magnesium sulphate. After evaporation of the solvent, the residue obtained is chromatographed on silica gel with a 9/1 dichloromethane/acetone mixture to give 7 g of 3-[1-(4-fluorophenyl)-1-hydroxy-1-(4-methanesulphonylphenyl)methyl]dihydrofuran-2-one in the form of an amorphous beige powder, which is used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH:24]([CH3:25])[CH:23]2[NH2:26])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[C@H:24]([CH3:25])[C@H:23]2[NH:26][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:20][CH:21]=1
Reactant: CC1C(N)C1c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@@H](NC(=O)c2ccccc2C(F)(F)F)[C@H]1c1ccc(Cl)cc1
Yield: 33.3 %

Procedure:
2-Trifluoromethyl-benzoyl chloride (0.028 ml, 39.4 mg, 0.17 mmol) was added to a solution of racemic (1R,2R,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanamine hydrochloride (37.2 mg, 0.17 mmol), and triethylamine (43.4 mg) in THF at 0° C. with stirring, and stirred for 18 hours. The white solid of Et3NHCl was filtered off and the filtrate concentrated and chromatographed with diethyl ether/hexane to yield 20 mg of pure racemic N-[(1R,2R,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropyl]-2-(trifluoromethyl)benzamide. M.p. 167-9
Reaction SMILES: [CH2:1]([C@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:24]([Mg]Br)[CH3:25].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[CH2:1]([C@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH2:24][CH3:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C=O)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C(O)CC)cc1
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)benzaldehyde (N) (16 mg, 0.05 mmol) in THF (0.2 mL) at 0° C. was added ethylmagnesium bromide (20 μL, 3M in THF) dropwise. After one hour, the reaction mixture was heated to refluxing temperature for an additional hour until TLC indicated completion of the reaction. Upon completion, saturated aqueous NH4Cl was added, and the mixture extracted with ether. The collected organic layers were washed with brine, dried with MgSO4, filtered and concentrated. Preparative thin layer chromatography (25% EtOAc/Hex, 250 μm, silica) yielded the title compound (6 mg, 0.017 mmol, 35%). 1H NMR (CDCl3, 300 MHz) δ 7.27 (2H, d, J=7.2 Hz), 7.21 (2H, d, J=8.1 Hz), 4.58 (1H, t, J=6.6 Hz), 3.88-3.81 (1H, m), 3.71-3.65 (1H, m), 2.92 (1H, dd, J=0.02, 18.6 Hz), 2.82 (1H, dd, J=0.02, 18.6 Hz), 1.86-1.68 (2H, m), 1.51-1.29 (12H, m), 1.37 (3H, s), 1.35 (3H, s), 0.92-0.85 (6H, m); HRMS (FAB+) calcd for C22H35O3 [M−H]: 347.2586; found 347.2575, C22H35O3.
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]=[C:14]([F:18])[CH:13]=1)[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[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]=[C:14]([F:18])[CH:13]=1)[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(3-fluorophenyl)quinolin-3-yl)methanamine (0.030 g, 0.11 mmol), 6-Chloropurine (0.019 g, 0.13 mmol, 1.2 eq) and DIEA in n-butanol (3 mL). N-((8-chloro-2-(3-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=74 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.41 (s, 1 H), 8.13 (s, 1 H), 7.88-8.02 (m, 4 H), 7.59 (dd, J=4.40, 2.20 Hz, 4 H), 4.80-4.98 (m, 2 H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:14][C@:13]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][O:11]C(=O)[N:9]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:1]([O:5][C:6]([C@@:8]1([NH:9][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C@@:13]1([CH2:12][OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)OC[C@@]2(c3ccccc3)C[C@@]12C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C[C@@]1(CO)c1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To the obtained solution of (1R*,6R*)-3-oxo-6-phenyl-4-oxa-2-aza-bicyclo[4.1.0]heptan-1,2-dicarboxylic acid di-t-butyl ester (2.1 g, 5.5 mmol) in methanol (42 mL) was added cesium carbonate (0.54 g, 1.7 mmol) at room temperature. After stirring for 30 min., the mixture was concentrated to about half the amount under reduced pressure, and then saturated aqueous sodium chloride solution (40 mL) was added to the obtained residue. The mixture was extracted three times with ethyl acetate (30 mL), washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), and dried over sodium sulfate. After filtration and evaporation, hexane (20 mL) was added to the obtained residue to allow precipitation of crystals. The crystals were filtrated and dried under reduced pressure to give the title compound (1.9 g, yield 74%) as a colorless amorphous form.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[C:16]([NH:17][C:18]4C=CC(S([O-])(=O)=O)=C(N)C=4)=[CH:15][C:14]([S:29]([O-:32])(=[O:31])=[O:30])=[C:13]([NH2:33])[C:10]=3[C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:8].[Na+:34].[Na+].[O-][Mn](=O)(=O)=O.[K+]>CC(O)=O.O>[CH3:18][NH:17][C:16]1[C:9]2[C:7]([C:5]3[C:4]([C:11](=[O:12])[C:10]=2[C:13]([NH2:33])=[C:14]([S:29]([O-:32])(=[O:31])=[O:30])[CH:15]=1)=[CH:3][CH:2]=[CH:1][CH:6]=3)=[O:8].[Na+:34]
Reactant: Nc1cc(Nc2cc(S(=O)(=O)[O-])c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1cc(S(=O)(=O)[O-])c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of AQ-1 (51.5 g, 343 mmol) in AcOH (500 mL) is added a solution of KMnO4 (59.7 g, 36.6 mmol) in H2O (500.0 mL) dropwise at 5° C. The reaction mixture is then stirred at rt for 1 h. The mixture is extracted with EtOAc, washed with aq. NaHCO3, dried (Na2SO4) and concentrated. The resultant residue is purified by recrystallization to yield AQ-2.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=O)(C)(C)C.[OH-].[Na+]>>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:18]2[CH2:17][CH2:16][CH2:15][N:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C(=O)CCCNC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2=NCCC2)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 91.7 %

Procedure:
Add trifluoroacetic acid (49.8 mL, 670 mmol) to [4-(3-methoxy-phenyl)-4-oxo-butyl]-carbamic acid tert-butyl ester (22.21 g, 67 mmol) with ice/water cooling. After stirring at 0° C. for 3.5 h, adjust the reaction to pH 10 with 50% sodium hydroxide. Extract the reaction mixture with ether (5×100 mL), dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain the crude product (15.43 g). Purify by flash chromatography [silica gel, 330 g, 0 to 30% gradient of (90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) in methylene chloride] to obtain the title compound (10.76 g, 88% for two steps). MS (APCI+): 176 [C11H13NO+H]+; 1H NMR (300 MHz, CDCl3): δ 7.46-7.45 (m, 1H), 7.37-7.27 (m, 2H), 6.99-6.95 (m, 1H), 4.09-4.03 (m, 2H), 3.84 (s, 3H), 2.96-2.89 (m, 2H), 2.08-1.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1CCCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclohexylamine according to conditions described in general procedure C. Mp: 135-136° C.; 1H NMR (400 MHz, CDCl3) δ 1.10-1.25 (m, 6 H), 1.58-1.64 (m, 4 H), 1.19 (bs, 1 H), 3.27 (s, 4H), 3.87-3.89 (m, 4 H), 4.90 (s, 1 H), 6.05 (s, 1 H), 6.78 (d, J=11.3 Hz, 1 H), 7.07 (d, J=7.8 Hz, 1 H), 7.26 (s, 1 H), 7.31-7.33 (m, 2 H), 7.51-7.61 (m, 2 H), 7.90 (d, J=8.6 Hz, 1 H), 7.97-8.00 (m, 2 H), 8.07 (s, 1 H), 8.12 (s, 1 H).