Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([SH:18])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[C:14]([S:18][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1
Reactant: Cc1cccc(S)c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cccc(Sc2cccc([N+](=O)[O-])c2)c1
Yield: 84.8 %

Procedure:
The general procedure in example 39 was followed. 3-Nitroiodobenzene (249 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-nitrophenyl 3-tolyl sulfide (208 mg, 85% yield) as yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NMR (CDCl3, 300 MHz) δ 7.95-7.99 (m, 2 H), 7.46 (dt, 1 H, J=7.5 Hz, 0.9 Hz), 7.38 (t, 1 H, J=8.1 Hz), 7.12-7.28 (m, 5 H), 2.36 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 141.0, 140.0, 134.3, 134.2, 131.7, 130.8, 130.0, 129.9, 129.8, 123.1, 122.9, 120.9. MS (EI) m/z (relative intensity) 245 (100), 184 (80).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.Cl.[CH3:15]O>>[NH2:1][C@H:2]([C:11]([O:13][CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[CH:8][CH:9]=1
Reactant: CO
Reactant: N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1ccc(Br)cc1

Procedure:
1.0 g (4.01 mmol) H-Phe(4-Br)—OH were refluxed in 20 ml methanol with 2.1 ml HCl (4 M in 1,4-dioxane) over night. Evaporation of the solvent gave H-Phe(4-Br)—OMe*HCl as white solid. 1.0 g (3.4 mmol) of this hydrochloride and 1.7 ml (10.2 mmol) DIPEA were suspended in 8 ml THF and 0.41 ml (3.4 mmol) 2,4,6-trimethylbenzoyl chloride were added dropwise at 0° C. After 18 h at room temperature the reaction was quenched with water and the solvent was removed. The residue was suspended in ethyl acetate, washed with saturated Na2SO4 and brine to give compound (13) as an oil.
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]CCCC.I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]>C1COCC1.[K]>[F:1][C:2]([F:17])([C:13]([F:14])([F:15])[F:16])[CH2:3][CH2:4][C:5]([CH:6]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:12]
Reactant: CCOC(=O)CC(=O)CCC(F)(F)C(F)(F)F
Reactant: C=CCCCCCCI
Agent: CCCC[O-]
Agent: [K]
Solvent: C1CCOC1
Product: C=CCCCCCCC(C(=O)CCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 6,6,7,7,7-pentafluoro-3-oxoheptanoate (262 mg, 1 mmol) in anhydrous THF (4 ml), potassium tret-butoxide (112 mg, 1 mmol) was added as a solid and the mixture was stirred at room temperature for 30 min. Then to a solution of 8-iodo-1-octene (357 mg, 1.5 mmol) in anhydrous THF (1 ml) was added and the mixture was stirred at room temperature continued for 3 days. The mixture was concentrated, diluted with diethyl ether, washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuum. Crude product was purified by flash chromatography on silica gel (hexane:ethyl acetate 10:1) to give ethyl 2-(4,4,5,5,5-pentafluoro-1-oxopentyl)-9-decenoate as a colorless oil. yield: 200 mg (54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH2:30]1[NH:35][CH2:34][CH2:33][N:32]2[CH:36]=[CH:37][CH:38]=[C:31]12.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[N:35]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=2)=[O:27])[CH2:34][CH2:33][N:32]2[CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: c1cc2n(c1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCn5cccc5C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
83 mg (0.21 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 37 mg (0.24 mmol) 1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine in 0.10 mL (0.72 mmol) TEA and 2.0 mL DMF were mixed with 77 mg (0.24 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the residue was dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:26]
Reactant: CNC
Reactant: FCCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Solvent: CO
Product: CN(C)c1nccc(-c2cc3ccc(OCCCF)cc3s2)n1
Yield: 68.6 %

Procedure:
2-[2-(N,N-Dimethylamino)pyrimidine-4-yl]-6-(3-fluoropropoxy)benzothiophene (1-39, 50 mg, 70%) was prepared in the same manner as in Example 36 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(3-fluoro propoxy)benzothiophene (105c, 70 mg, 0.22 mmol) obtained in Preparation Example 21 and a 2.0 M dimethylamine methanol solution (NHMe2 in MeOH, 0.17 mL, 0.34 mmol).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].CCN(CC)CC.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>C1(C)C=CC=CC=1>[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH:34][C:2]([NH:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:8][CH:9]=1)=[O:3])[CH3:30]
Reactant: CCN(CC)CCN
Reactant: O=C=Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)CCNC(=O)Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 95 °C
Yield: 57 %

Procedure:
A suspension of of 3-(4-isocyanatophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 2 (75 mg, 0.274 mmol), Et3N (0.191 mL, 1.37 mmol), N,N-diethylethylenediamine (0.112 mL, 1.37 mmol) in toluene (3 mL) was heated to about 95° C., for about 3 hours. The white solid was filtered off and washed with EtOAc and dried under vacuum to afford 61 mg (57%) of pure product. LC/MS 390 (M+1); LC retention time 2.76 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.ClC1N=CC(C(F)(F)F)=CC=1.[Cl-:22].[Al+3].[Cl-:24].[Cl-:25]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([Cl:25])([Cl:24])[Cl:22])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: [Cl-]
Agent: FC(F)(F)c1ccc(Cl)nc1
Agent: [Al+3]
Product: Clc1ccc(C(Cl)(Cl)Cl)cn1

Procedure:
The process according to claim 4 wherein 6-chloronicotinic acid is produced by reacting 6-chloro-3-trifluoromethyl pyridine with aluminum chloride to obtain 6-chloro-3-trichloromethyl pyridine and then hydrolyzing the 6-chloro-3-trichloromethyl pyridine in the presence of sulfuric acid or phosphoric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:7]([C:20]([F:23])([F:22])[F:21])=[CH:6][C:5]=1[NH2:24]>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:7]([C:20]([F:21])([F:23])[F:22])=[CH:6][C:5]=1[NH2:24]
Reactant: COC(=O)c1cc(C#CCOC2CCCCO2)c(C(F)(F)F)cc1N
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CCCOC2CCCCO2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A suspension of 2-amino-5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-4-trifluoromethyl-benzoic acid methyl ester (2.20 g, 6.16 mmol) and palladium on carbon (250 mg, 10%) in THF (15 mL) was stirred at r.t. for 30 min under hydrogen (5 bars). The mixture was then filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 5:1) to afford 2-amino-5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-4-trifluoromethyl-benzoic acid methyl ester (1.99 g, 5.51 mmol, 89%) as a colorless oil, ESI-MS: m/z 384 [M+Na]+, rt 6.20 min)
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:20]C)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:24]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1)[CH:23]=[CH2:22]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)c2oc(-c3ccc(OC)c(F)c3)nc2c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Product: C=CCc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route c, step b, from 7-bromo-2-(3-fluoro-4-methoxyphenyl)-5-methoxy-1,3-benzoxazole, allyltributyltin and dichlorobis(tri-o-tolylphosphine)palladium, followed by demethylation according to Example 20, step e. The desired product was obtained as a light pink solid, m.p. 169-171° C.; MS m/e 284 (M−H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20]Cl)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:22].[Li+]>C1COCC1>[Br:22][CH2:20][C:15]1[C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CBr)c2CC1
Yield: 85.2 %

Procedure:
Combine 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.17 g, 8.14 mmol) and lithium bromide (0.98 g, 11.3 mmol) in anhydrous THF (60 mL) and stir at room temperature for 1 h. Concentrate in vacuo and partition the residue between dichloromethane/water. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 10:1) to obtain the title compound as a white solid (2.6 g, 85%). MS (APCI+) m/z: 274 (M-Boc+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of 29 (9.85 g, 20.6 mmol) in CH2Cl2 (100 mL) was added Dess-Martin periodinane (9.61 g, 22.6 mmol). After 30 min, water (75 mL) and saturated Na2S2O4 solution (75 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 8.32 g of 30. 1H-NMR: 400 MHz, (CDCl3) δ: 7.91 (s, 1H), 4.40 (q, 2H, J=7 Hz), 2.49 (s, 3H), 1.39 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCN(Cc2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
0.226 g (0.001 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol was dissolved in 5 ml of dimethylformamide and treated with 0.061 g (0.0005 mol) of dimethylaminopyridine and 0.14 g (0.001 mol) of 4-fluoro-benzoic acid. The mixture was cooled to 0° and 0.211 g (0.0011 mol) of N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide hydrochloride was added. The mixture was warmed to room temperature and stirred for 72 hrs. The solvent was distilled off and the residue was taken up in ethyl acetate and treated with silica gel. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.29 g (83%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:28]([F:31])([F:30])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2].[SiH](CC)(CC)CC>C(Cl)Cl>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:28]([F:30])([F:31])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To 3-{[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (211 mg, 0.48 mmol) in anhydrous CH2Cl2 (5 mL) at room temperature under Ar is added Et3SiH (0.61 mL, 3.8 mmol) and BF3 ether complex (0.12 mL, 0.96 mmol). The reaction mixture is stirred at room temperature for 2 h and quenched into saturated aqueous NH4Cl (20 mL). The aqueous mixture is extracted with CH2Cl2 (3×25 mL). The organic layers are combined, washed with brine, dried over sodium sulfatesodium sulfate, and concentrated. The residue is purified by flash column chromatography using 50% ethyl acetate/hexane as eluent to give the title compound (108 mg, 53%). LC-MS (m/e): 424 (M−1).
Reaction SMILES: [CH:1](=[C:8]([CH2:12][OH:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.O.[H][H]>CO.[C].[Pd]>[OH:13][CH2:12][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 93 %

Procedure:
2-Benzylidene-3-hydroxypropionic acid (490.4 mg, 2.752 mmols) was dissolved in 7 ml of methanol, and 0.5 ml of 28% aqueous ammonia and 2 ml of water were added thereto. Then, 38 mg (water content 52.7%) of 5% palladium-carbon were added thereto, and catalytic reduction was conducted in a hydrogen atmosphere for 160 minutes. After the completion of the reaction, the reaction solution was filtered with Celite to remove the palladium-carbon. The resulting filtrate was subjected to the HPLC analysis. As a result, the filtrate contained 461 mg (2.558 mmols) of the above title compound (yield 93.0%).
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]Cl)=[CH:7]2.[H-].[Na+].[I:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[NH:26][N:25]=1>CN(C=O)C>[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:26]1[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:33])=[C:32]3[C:24]([I:23])=[N:25]1)=[CH:7]2
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure I using 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.235 g, 0.73 mmol), NaH (0.047 g 60% in oil, 1.17 mmol, 1.6 eq) and 3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.209 g, 0.8 mmol, 1.1 eq) in DMF. 1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained after purification as a white solid [PI3KδIC50=14 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (1 H, s), 8.09 (1 H, dd, J=8.6, 1.2 Hz), 7.98-8.05 (2 H, m), 7.66 (1 H, t), 7.48 (1 H, dd, J=8.2, 0.8 Hz), 7.36 (1 H, dt, J=7.8, 1.6 Hz), 7.25 (1 H, dt, J=7.4, 1.2 Hz), 7.13 (1 H, dd, J=7.4, 1.6 Hz), 5.53 (2 H, s) Mass Spectrum (ESI) m/e=547.0 and 549.0 (M+1)
Reaction SMILES: Cl.F[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11](=[O:30])[O:12][C:13]=2[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24](Cl)[CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[CH2:31](O)C>>[ClH:28].[C:3]1([CH3:31])[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11](=[O:30])[O:12][C:13]=2[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CCO
Reactant: O=c1oc(CCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(-c2ccc(F)cc2)o1
Agent: Cl
Product: Cc1ccc(-c2oc(=O)oc2CCN2CCN(c3ccccc3)CC2)cc1

Procedure:
4-(4-fluorophenyl)-5-[2-(4-(3,5-dichlorophenyl)-1-piperazinyl)ethyl]-1,3-dioxol-2-one hydrochloride m.p.=277°-9° C. (from ethanol
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:19])([CH3:18])[C:15](Br)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:19])([CH3:18])[C:15]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1Br
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1N1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of (3E)-6-bromo-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (2.3 g, 6.0 mmol) and morpholine (1.0 mL, 11.4 mmol) in 10 mL of DMF was heated in 96 C bath for 3 hours. The mixture was cooled to room temperature and poured into 200 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 2.1 g, 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O-:34][CH2:35]C.[Na+].C(=O)(OCC)OCC>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]3[O:33][C:35](=[O:34])[NH:32][C:30]3=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(C[C@H](O)C(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)OCC
Product: CCC(CC)N1C(=O)[C@@](C)(CC2OC(=O)NC2=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
To a solution of 10.3 mg (0.02 mmol) of (S)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide (Example 81, Step D) in MeOH (2.5 mL) was added 0.50 mL (1.22 mmol) of sodium ethoxide (21 wt. % solution in ethanol) and 1.20 mL (9.90 mmol) of diethyl carbonate. The resulting mixture was heated at reflux for 15 min, and then was concentrated under reduced pressure. The residue was partitioned between 0.5 M HCl and EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 60 MeCN in water to 80 MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound (mixture of ether epimers) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41].Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3,4-dichlorophenylacetic acid (0.49 g, 2.4 mmol) were added. The mixture was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo. The resulting oil solidified on standing and the mixture was stirred in acetone (10 mL) then in MeOH (10 mL). The resulting solid was filtered and dried in vacuum oven to afford 2-(3,4-dichloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as an off-white solid (0.69 g, 67%): mp, 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.5 min. (98%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.58 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.26-7.82 (m, 6H), 8.69 (t, J=6 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.92, 40.80, 48.83, 121.95, 127.16, 129.13, 129.58, 130.29, 130.65, 131.15, 131.52, 133.31, 134.68, 137.19, 138.92, 166.88, 167.39, 169.77, 172.72. Anal Calcd for C22H17Cl2N3O5+0.2H2O: C, 55.29; H, 3.67; N, 8.79; Cl, 14.84. Found: C, 55.19; H, 3.33; N, 8.83; Cl, 14.71.