Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([N+:26]([O-])=O)=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1.CO.O.[Fe]>[NH2:26][C:10]1[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][C:13]([NH:15][C:16](=[O:24])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([CH3:25])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)cc1NC(=O)Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N)c(Sc2ccc(O)cc2)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
The product of Example 265B (0.282 g, 0.715 mmol), iron powder (0.160 g, 2.86 mmol, 4.0 eq), and ammonium chloride (0.0469 g, 0.858 mmol, 1.2 eq) in tetrahydrofuran (6 mL), methanol (6 mL) and water (2 mL) was heated under reflux for 1.5 h and then cooled to room temperature. The reaction mixture was then filtered through Celite and the Celite pad rinsed with methanol (50 mL). The filtrate was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to provide an orange oil that was triturated with dichloromethane to provide the title compound as a yellow powder (0.246 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=O)=[CH:11][CH:10]=1.CN(C(ON1N=[N:46][C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl.CN(C=O)C>[CH:41]([NH:46][C:18]([C@@H:16]1[CH2:17][C@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]2[S:5][C:4]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)=[N:3][C:2]=2[CH3:1])=[CH:10][CH:11]=1)=[O:20])([CH3:42])[CH3:40]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)NC(C)C)cc1
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (I-2m) (0.10 g, 0.231 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.13 g, 0.346 mmol). The mixture was stirred for 15 mins followed by addition of isopropylamine (0.04 g, 0.693 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a yellow ppt which was filtered and dried under high vacuum to give the title compound as a yellow powder (0.062 g, 60%). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 5.29 (d, J=7.8 Hz, 1H), 4.45 (s, 2H), 4.15-4.08 (m, 1H), 4.06 (s, 1H), 2.49 (s, 3H), 2.42-2.34 (m, 1H), 1.54-1.51 (m, 1H), 1.44-1.39 (m, 1H), 1.53-1.10 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=2[N:34]=1.C(N(C(C)C)CC)(C)C>CCO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=3[N:34]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: Cc1ccc2oc(Cl)nc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)c2nc3cc(C)ccc3o2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.300 g, 0.76 mmol), chloro-5-methyl-benzooxazole (0.135 g, 0.81 mmol), and diisopropylethylamine (0.5 mL, 2.87 mmol) were combined in EtOH (2 mL) in a sealed tube, and the reaction was stirred at 80° C. for 8 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.[OH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[C:4]1[N:3]=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C@H:22]([OH:21])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:29]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (300 mg, 1.04 mmol) in CH2Cl2 (5 mL) was cooled using an ice water batch. To this stirring solution was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (312 mg, 1.56 mmol), followed by triethylamine (210 mg, 291 μL, 2.08 mmol). After letting the reaction warm to room temperature, it was stirred overnight. The mixture was partitioned between water and CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a viscous yellow oil. Purification via silica gel chromatography using 0-30% EtOAc in CH2Cl2/hexanes (2:1) gave (R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a bright yellow foam/solid. (413 mg, 88%). LC/MS: m/z 453.1 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.40-4.35 (m, 1H), 4.02-3.65 (m, 8H), 2.52 (s, 3H), 1.82-1.73 (m, 1H), 1.47-1.34 (m, 2H), 0.91 (dd, J=6.5, 4.1 Hz, 6H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][C:34]2=[O:40])=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:38]=[CH:37][C:36]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[CH:35][C:34]2=[O:40])=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Product: Cc1nc(-n2ccc(OCC3CCCC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use cyclopentylmethyl 4-methylbenzenesulfonate in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 57% yield: mp 196-198° C. (methanol); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 7.40-7.25 (m, 5H), 6.16 (d, J=8.1, 2.6 Hz, 1H), 6.09-6.05 (m, 1H), 5.94 (d, J=2.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 3.83 (d, J=7.0 Hz, 2H), 2.68 (s, 3H) 2.41-2.27 (m, 1H), 1.87-1.77 (m, 4H), 1.66-1.58 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 167.9, 162.2, 162.1, 153.6, 152.2, 137.7, 131.3, 128.8, 127.9, 127.7, 122.1, 104.2, 96.6, 73.3, 44.1, 38.4, 29.3, 25.3, 17.3; MS (ES+) m/z 424.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[NH:5][C:6](=[O:8])[CH3:7].Cl[C:15]1[CH:16]=C(C=[CH:23][C:24]=1O)NC(=O)C.ClC1C(C)=C(C=C(Cl)C=1O)[NH:30]C(=O)C>>[OH:12][C:11]1[C:2]2[C:3](=[CH:16][CH:15]=[CH:24][CH:23]=2)[C:4]([NH:5][C:6](=[O:8])[CH2:7][NH2:30])=[CH:9][C:10]=1[Cl:13]
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1C
Reactant: CC(=O)Nc1ccc(O)c(Cl)c1
Product: NCC(=O)Nc1cc(Cl)c(O)c2ccccc12

Procedure:
The preferred peroxidase stabilizers are 3',5'-dichloro-4'-hydroxyacetanilide, 3'-chloro-4'-hydroxyacetanilide and 3',5'-dichloro-4'-hydroxy-2'-methylacetanilide.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])(=[O:15])=[O:16])[CH3:30])[CH:6]=[C:5]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3OC)c2n1COC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3OC)c2n1COC
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of ethyl 1-(methoxymethyl)-7-{[(2-methoxyphenyl)sulfonyl]amino}-1H-indole-2-carboxylate (11.0 g) and potassium carbonate (5.9 g) in N,N-dimethylformamide (80 mL) was added methyl iodide (2.7 mL) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:2-4:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (10.9 g, yield: 89%) as colorless needle crystals. melting point: 124-125° C.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=C.[O:15]=[O+][O-].S(C)C>C(Cl)Cl>[CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=[O:15]
Reactant: O=[O+][O-]
Reactant: C=CC1COCc2c(C#N)cccc21
Solvent: CSC
Solvent: ClCCl
Product: N#Cc1cccc2c1COCC2C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-ethenyl-3,4-dihydro-1H-isochromene-8-carbonitrile (62 mg, 0.334 mmol) in DCM (10 mL) was bubbled with O3 for 10 mins at −78° C. until the blue color appeared. Then Me2S (1 mL) was added and the mixture was stirred at r.t. for 5 hours. Then the mixture was concentrated in vacuo to give the desired product 4-formyl-3,4-dihydro-1H-isochromene-8-carbonitrile, which can be used for next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[C:10]=1[Cl:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[O:24])[N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCCc1n[nH]c(C(=O)OCC)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C(=O)OCC)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 5.0 (s, 2H), 4.36–4.40 (q, 2H), 3.62–3.82 (m, 4H), 3.04–3.18 (m, 4H), 2.58–2.66(t, 2H), 1.64–1.76 (m, 2H), 1.34–1.38 (t, 3H), 0.94–1.0 (t, 3H). 13C NMR (400 MHz, CDCl3): 165, 160.2, 156.2, 152.4, 147, 133, 118.4, 118.2, 115.8, 115.4, 112.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.4, 14.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:18]3[CH2:25][CH2:24][C@:23]4([CH3:28])[C@H:26]([CH3:27])[C@H:19]3[CH2:20][C:21]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:22]=34)=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1>CN(C)C=O.O.CC#N>[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:18]3[CH2:25][CH2:24][C@:23]4([CH3:28])[C@H:26]([CH3:27])[C@H:19]3[CH2:20][C:21]3[CH:32]=[CH:31][C:30]([C:33]5[NH:34][N:3]=[N:2][N:1]=5)=[CH:29][C:22]=34)=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1
Reactant: C[C@@H]1[C@H]2Cc3ccc(C#N)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: C[C@@H]1[C@H]2Cc3ccc(-c4nnn[nH]4)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of sodium azide (105 mg), NH4Cl (87 mg), and (2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrile (0.30 g) in dimethylformamide (3 mL) is stirred at 100° C. overnight. Then, another portion of NaN3 (50 mg) and NH4Cl (40 mg) is added and the mixture is stirred at 110° C. for additional 14 h. After cooling to ambient temperature, the mixture is diluted with water and MeCN and purified by HPLC on reversed phase (MeCN/H2O/NH3).
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[S:18]([CH3:21])(=[O:20])=[O:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]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]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:19])=[O:20])[C:8]([CH2:22][NH:23][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][NH:29]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-(methylsulfonyl)phenyl) quinolin-3-yl)methanamine (0.060 g, 0.173 mmol), 6-chloropurine (0.032 g, 0.21 mmol, 1.2 eq) and DIEA (0.34 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=222 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.29 (s, 1 H), 8.13 (s, 1 H), 8.01-8.09 (m, 2 H), 7.78-7.81 (m, 1 H), 7.66-7.76 (m, 1 H), 7.57-7.65 (m, 1 H), 7.46 (d, J=7.83 Hz, 2 H), 4.87-4.98 (m, 2 H), 3.28 (s, 3 H), Mass Spectrum (ESI) m/e=465 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CCCCCC.C1COCC1>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[CH:1][O:2][CH3:3])[C:31]=1[Cl:30]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=Cc1cccc(Cl)c1Cl
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
Into a flask under argon containing 700 ml of dry THF was placed 159 g (0.47 mole) of methyl(triphenylphosphoranylidene)acetate. To the stirred suspension cooled in an ice/water bath was added dropwise 320 ml (0.47 mole) of 1.45M n-butyllithium in hexane. After stirring for 20 min, 74 g (0.42 mole) of 2,3-dichlorobenzaldehyde in 700 ml of dry THF was added. After 2 hr the reaction mixture was washed with an ammonium chloride solution, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was taken up in ether, the undissolved solid was filtered off, and the solvent was evaporated in vacuo. The residue was distilled in a Kugelrohr apparatus at 0.005 mm Hg and the fraction distilling between 80°-100° C. collected. The distillate was distilled at 0.005 mm Hg using a Vigro column and the product collected between 101°-116° C. A preparative hplc on silica gel using hexane as the elutant gave 28.02 g of the title compound as an oil (33%).
Reaction SMILES: O.Cl[CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11].O.[SH-:13].[Na+]>CN(C=O)C>[SH:13][CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11]
Reactant: O=S(=O)([O-])CC(O)CCl
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)([O-])CC(O)CS
Yield: 172.6 %

Procedure:
To sodium 3-chloro-2-hydroxypropanesulfonate hydrate (2.0 g), sodium hydrosulfide hydrate (0.42 g) was added in 10 mL DMF. The mixture was refluxed overnight. When the reaction mixture was cooled down, white solid was isolated, rinsed with ether and acetone to obtain 1.9 g crude sodium 3-mercapto-2-hydroxypropane sulfonate. The crude product was dissolved in water and preferentially precipitated the desired product by adding acetone. The precipitated product was then filtered and dried under vacuum to get 1.04 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])C=O.[CH3:15][C:16]1[C:17](B(O)O)=[CH:18][C:19]2[C:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]=2[CH:25]=1.[CH2:33]([OH:35])C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=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.O>[F:14][C:11]([F:12])([F:13])[O:10][C:9]1[CH:8]=[C:7]([CH:4]=[CH:3][C:2]=1[C:17]1[C:16]([CH3:15])=[CH:25][C:24]2[C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21][C:20]([CH3:29])([CH3:28])[C:19]=2[CH:18]=1)[CH:33]=[O:35]
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1-c1ccc(C=O)cc1OC(F)(F)F)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (11.0 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL), ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28 g, 74.4 mmol, 2 eq). The mixture was degased with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol, 0.02 eq) was added and the mixture heated at reflux under argon for 22 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane 5:95) to give 3-trifluoromethoxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (11.1 g, 76%), 1H NMR (300 MHz; CDCl3) 1.25 (s, 6 H); 1.32 (s, 6 H); 1.70 (s, 4 H); 2.08 (s, 3 H); 7.06 (s, 1 H); 7.18 (s, 1 H); 7.48 (dd, J1=8.4 Hz, J2=1.5 Hz, 1 H); 7.84 (d, J=2.0 Hz, 1 H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz, 1 H), 9.91 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5]([CH3:16])=[C:6]([CH3:15])[CH:7]2[CH3:14].N#N.C(O)(C)C.[Li]CCCC.[P:28](Cl)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30].[H+].[B-:37](F)([F:40])([F:39])[F:38].CCOCC>CCOCC>[CH3:13][O:12][C:9]1[C:10]([PH+:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[C:7]([CH3:14])=[C:6]([CH3:15])[CH:5]2[CH3:16].[B:37]([F:40])([F:39])[F:38]
Reactant: CC(C)P(Cl)C(C)C
Reactant: COc1ccc(OC)c2c1C(C)=C(C)C2C
Reactant: F[B-](F)(F)F
Agent: N#N
Agent: [H+]
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc([PH+](C(C)C)C(C)C)c(OC)c2c1C(C)C(C)=C2C
Product: FB(F)F
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
In a 100 ml Schlenk flask 4,7-dimethoxy-1,2,3-trimethylindene (39) (1.7 g, 7.79 mmol) was dissolved in Et2O (50 ml) under an argon atmosphere. The mixture was cooled to −60° C. (N2/isopropanol) and n-BuLi (3 ml, 2.5 M solution in hexane, 7.43 mmol) was added. The solution was stirred for 10 min at −60° C., then for 3 hours at ambient temperature. A white precipitate was formed. Then the mixture was cooled to −60° C. and iPr2PCl (1 ml, 6.24 mmol) was added. The mixture was allowed to come to room temperature, stirred for additional 2 h at ambient temperature and the formed LiCl was removed by filtration over a pad of Celite® under Schlenk conditions. The resulting slightly yellowish filtrate was treated dropwise with HBF4-Et2O (1 ml, 7.72 mmol) to give a white precipitate which was separated via filtration and dissolved in 10 ml chloroform. After filtration the clear filtrate was dropped into Et2O (700 ml, vigorously stirred). The formed white precipitate was separated via suction filtration. Removal of the volatiles in vacuo afforded (21a) as a white solid (1.73 g, 66%).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([O:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5](Br)[C:3]=1[NH2:4].O.O.[Sn](Cl)Cl.C(O)(=O)C.Cl>C(OCC)(=O)C>[Br:1][C:2]1[C:8]([F:9])=[C:7]([O:10][C:11]([F:13])([F:12])[F:14])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1c(Br)cc(OC(F)(F)F)c(F)c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(OC(F)(F)F)c(F)c1Br
Temperature: 115 °C

Procedure:
In a 40 mL vial was added 2,6-dibromo-3-fluoro-4-trifluoromethoxyaniline (172 mg, 0.489 mmol), followed by tin(II) chloride dihydrate (122 mg, 0.540 mmol, 1.1 eq.). Acetic acid (725 μL) and concentrated hydrochloric acid (580 μL) was added to make a solution. The reaction mixture was heated at 115° C. for 1.5 hours. After cooling the reaction to room temperature, most of acetic acid was removed under vacuum. Water was added and the product was extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude material was purified using silica gel column chromatography. The recovered 2,6-dibromo-3-fluoro-4-trifluoromethoxyaniline was eluted using a gradient of 5˜10% ethyl acetate in hexanes followed by the desired product, 2-bromo-3-fluoro-4-trifluoromethoxyaniline, which was eluted with 15% ethyl acetate in hexanes (64.8 mg, 0.236 mmol, 48%). 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=9.0, 9.0 Hz, 1H), 6.52 (dd, J=9.0, 2.0 Hz, 1H), 4.27 (br, 2H).
Reaction SMILES: [OH-:1].[Na+].C1N=C(N)[C:6]2[N:11]=[CH:10][N:9]([C@@H:12]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)[C:7]=2[N:8]=1.[N-]=[N+]=[N-].[Na+].[CH2:51]([NH:55][CH2:56]O)[C:52]([O-])=[O:53].[Na+]>O>[N:11]1([C:52](=[O:53])[C:51]2[NH:55][CH:56]=[N:8][C:7]=2[N:9]([CH3:12])[C:10]1=[O:1])[CH3:6]
Reactant: O=C([O-])CNCO
Reactant: [OH-]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
One liter of a first reagent was prepared as follows. Approximately 800 ml deionized water was dispensed into a container and 6.0 grams of ACES were added and dissolved. The pH was adjusted to 6.0 with 2 N NaOH. Then 0.66 grams NAD were added and dissolved completely. Then 0.95 grams sodium azide was added and dissolved, and finally 1.0 gram of SUTTOCIDE A was added and dissolved. The volume was adjusted to one liter with deionized water.