Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:9]=2)=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][N:17]1[CH:18]=[C:14]([C:10]2[CH:9]=[C:8]([C:5]3[N:4]=[CH:3][C:2]([C:36]4[CH:35]=[N:34][N:33]([CH:30]5[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]5)[CH:37]=4)=[CH:7][N:6]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=[N:16]1
Reactant: Cn1cc(-c2cccc(-c3ncc(Br)cn3)c2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cn3)c2)cn1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A solution of 5-bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2, 160 mg, 0.50 mmol), 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Combi-blocks, 287 mg, 0.76 mmol) and Na2CO3 (140 mg, 0.12 mmol) in dry Toluene: Ethanol (1:1) (5 mL) was purged with nitrogen for 30 min before the addition of Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was then heated at 100° C. O/N and filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the crude product. Purification by Flash chromatography on silica (hexane:EtOAc) afforded the title compound as a yellow solid (230 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 2H), 8.53 (d, J=8.0 Hz, 2H), 8.25 (s, 1H), 8.21 (d, J=7.76 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.91-7.48 (m, 10H), 4.45-4.44 (m, 1H), 4.07-4.04 (m, 2H), 3.88 (s, 3H), 2.12 (s, 2H), 2.70 (d, J=3.44 Hz, 1H), 2.08-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): Rt 4.68 min (purity 87%). MS (ESI+): 486.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:13](OCC)(=[O:17])[C:14]([O-:16])=[O:15]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccncc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
15.0 g. (0.095 mol) of 4-bromopyridine in 7 ml. of dry tetrahydrofuran (THF) was added dropwise at -70° C. to a solution of butyl lithium (1.6 M, 60.9 ml., 0.098 mol) dissolved in 120 ml. of dried THF over a ten minute period. The resulting very deep purple mixture was stirred at -70° C. for 30 minutes and then transferred by nylon tubing under positive nitrogen pressure into a stirred 0° C. solution of ethyl oxalate (55.2 g., 0.38 moles) in 90 ml. of dry THF. The solution was stirred at 0° C. for 45 minutes and then quenched by addition of 65 ml. glacial acetic acid. This was warmed to room temperature and poured into 500 ml. of water adjusted to pH 7.0 with saturated sodium bicarbonate and extracted with 3×200 ml. ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate filtered and concentrated to a brown oil. This oil was flash chromatographed on silica gel eluted with 1:2 ethyl acetate hexane. A viscous yellow oil was obtained; 5.8 g (34%), m/e 179, spectral data consistent with structure of title product.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:22]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (76 mg, 0.378 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.24 mL, 1.70 mmol), and 4-pentylbenzene-1-sulfonyl chloride (140 mg, 0.567 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (148 mg, 95%). 1H NMR (400 MHz, CD3OD) δ 7.77 (d, 2H, J=7.6 Hz), 7.35 (d, 2H, J=7.3 Hz), 4.00 (q, 2H, J=6.7), 2.69 (t, 2H, J=7.0 Hz), 2.57 (s, 2H), 2.46-2.36 (m, 2H), 2.20-2.02 (m, 7H), 1.68-1.60 (m, 4H), 1.41-1.25 (m, 4H), 1.20 (t, 3H, J=6.4 Hz), 0.89 (t, 3H, J=6.7 Hz); MS ESI 411.3 [M+H]+, calcd for [C21H34N2O4S+H]+ 411.58.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]#[N:6].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)(=O)C>[C:7]([O:3][CH2:4][C:5]#[N:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Aqueous sodium hydroxide solution (4N, 60 mL) was added to aqueous hydroxyacetonitrile solution (52%, 25 g), and benzoyl chloride (25 mL) was slowly added dropwise under ice-cooling. After warming to room temperature, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the solvent, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, and the residue was purified by silica gel column chromatography to give the object product (27.5 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH2:56][NH:57][CH2:58][CH:59]=2)=[CH:51][CH:50]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH2:56][N:57]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:58][CH:59]=2)=[CH:53][CH:54]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Fc1ccc(C2=CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CC=C(c3ccc(F)cc3)C2)cc1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 3-(4-fluorophenyl)-2,5-dihydro-1H-pyrrole hydrochloride (20 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z calcd for C21H17F N2O2: 348.1274, found 348.1266.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 90 °C
Yield: 62.7 %

Procedure:
A mixture of 10 g (42.4 mmol) 1,4-dibromobenzene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)Palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 9.5 g (63%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3].[Cl:25][CH:26]([CH3:30])[C:27](Cl)=[O:28]>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:27](=[O:28])[CH:26]([Cl:25])[CH3:30])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Br)c2)c(Cl)c1CC
Reactant: CC(Cl)C(=O)Cl
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)Cl)c(Br)c2)c(Cl)c1CC
Yield: 93.1 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate (80 mg) was coupled with 2-chloropropionyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 90 mg of ethyl(3,5-dichloro-4-[3-bromo-4-(2-chloropropionamido)phenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 30 mg of 3,5-dichloro-4-(3-bromo-4-[2-chloropropionamido]phenoxy)phenylpropionic acid.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11](CC=C)[C:10]([C:18]#[N:19])=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>C1COCC1.CS(C)=O.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>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:18]#[N:19])=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c2[nH]c(C#N)nc2n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
A solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (140 mg, 0.43 mmol) in anhydrous THF (4 ml) and anhydrous DMSO (0.4 ml) was treated with Pd(PPh3)4 (74 mg, 0.064 mmol). The mixture was degassed under gentle vacuum, morpholine (371 uL) added, and left to stir at rt under nitrogen for 4 hours. The yellow solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE (5 g), eluting with MeOH followed by 5%→50% AcOH/MeOH. The product eluted with a small impurity which was washed out, after concentrating, with cyclohexane to afford the title compound as an off-white solid (30 mg, 24%). NMR δH (400 MHz, d6-DMSO) 0.89 (app. td, 6H, J=7 and 3 Hz), 1.25-1.35 (m, 4H), 12.48-1.55 (m, 2H), 1.58-1.69 (m, 2H), 3.87 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), NH not observed to δH 15; m/z 290.3 [MH+].
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:15][O:8][C:7]([C:3]1[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1
Temperature: 5 °C
Yield: 93 %

Procedure:
To a solution of m-toluic acid (175 g, 1.28 mol) in methanol (2 L) was added dropwise thionylchloride (612 g, 5.14 mol) under stirring at 5° C. The mixture was refluxed overnight, then the solvent evaporated. The residue obtained was treated with a 10% aqueous NaHCO3 solution (pH ˜8). The product was extracted with ethyl acetate, washed with water and dried. The solvent was removed and the crude was purified by column chromatography (pet ether/ethyl acetate) to give methyl-m-toluate as colorless liquid (180 g, 93%).
Reaction SMILES: CC(C)([O-:4])C.[K+].[Si:7]([O:14][C@@H:15]1[C@@:32]2([CH3:33])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=[O:34])[CH2:18][C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>O1CCCC1>[Si:7]([O:14][C@@H:15]1[C@@:32]2([CH3:33])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][C@@H:25]([OH:4])[C:26]2=[O:34])[CH2:18][C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(=O)[C@H](O)C[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Under an argon atmosphere, a solution of potassium t-butoxide (4.13 g, 36.8 mmol) in dry tetrahydrofuran (500 ml) was cooled to -78° C., and a solution of 1α,3β-bis(t-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene (13.0 g, 24.5 mmol) in tetrahydrofuran (40 ml) was added dropwise. After the mixture was stirred at the same temperature for 1 hour, a solution of 2-(phenylsulfonyl)-3-phenyloxazyldine (9.62 g, 36.8 mmol) in tetrahydrofuran (40 ml) was added dropwise and the mixture was further stirred at -78° C. for 1.5 hour. The reaction mixture was quenched with an aqueous saturated ammonium chloride solution, poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the deposited solids were filtered, then the filtrate was concentrated again and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate:chloroform=7:1:2) to give the title compound as a white solid (3.10 g, 23%).
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][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)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][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-c1ccccc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 6-chloropurine (0.051 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (3 mL). N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=68 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (1 H, s), 8.11 (1 H, s), 8.08 (1 H, s), 8.00 (1 H, dd, J=8.2, 1.2 Hz), 7.93 (1 H, dd, J=7.4, 1.2 Hz), 7.42-7.67 (5 H, m) Mass Spectrum (ESI) m/e=421.0 and 423.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)([CH3:17])[CH3:16].[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[N:32]1.N1CCCCC1>CO>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](/[CH:40]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][C:15]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]4)([CH3:17])[CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:32]1
Reactant: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate (0.113 g, 0.273 mmol) in methanol (1 mL) was added with 1H-indazole-3-carboxaldehyde (0.0399 g, 0.273 mmol) and piperidine (0.0186 g, 0.218 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (0.136 g, 91%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24]C(=O)[NH:22]2)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:22][C@@:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]3[CH2:6][CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)[CH:12]=2)[CH:17]=1)([CH3:27])[CH2:25][OH:24]
Reactant: CC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 32.8 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-Isopropyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 56 mg of the desired compound as a yellow brown solid (30%). ESI-MS: 325 (M-16)+. 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3 H), 7.50 (d, J=8.5 Hz, 1 H), 7.23-7.05 (m, 2 H), 4.67 (br. s., 1 H), 4.33-4.17 (m, 1 H), 3.84-3.51 (m, 2 H), 2.35-1.75 (m, 4 H), 1.68-1.08 (m, 10 H), 1.01-0.68 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:19])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)CCCN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC1

Procedure:
Compound 753 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 4-methyl-piperazine using the method described for compound 751. The title compound was isolated as a white powder (0.0508 g, 42% yield). HRMS (M+H) calcd for C22H29N4Cl2O4: 483.1566. found: 483.1581.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:26])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(Cl)c3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
10.0 g (32 mmol) of N-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine are stirred for 24 h in 100 ml of phosphorus oxychloride at 110°. The reaction mixture is stirred at 50° into 2N sodium hydroxide solution and extracted with tetrahydrofuran. Concentration and crystallisation (tetrahydrofuran/ethanol) of the residue give N-(3-chloro-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine; m.p. 196°-198°, Rf =0.7 (methylene chloride:methanol=95:5).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].[NH2:19][C:20]1[N:25]=[C:24]([F:26])[CH:23]=[C:22]([O:27][C:28]([F:31])([F:30])[F:29])[N:21]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:19][C:20]1[N:25]=[C:24]([F:26])[CH:23]=[C:22]([O:27][C:28]([F:30])([F:31])[F:29])[N:21]=1)=[O:17])(=[O:13])=[O:14])(=[O:4])=[O:5]
Reactant: Nc1nc(F)cc(OC(F)(F)F)n1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(F)cc(OC(F)(F)F)n1
Reaction time: 16 h
Yield: 21.5 %

Procedure:
5.9 g (20 mmol) of 2-(dimethylamino)sulfonylbenzenesulfonyl isocyanate were added to a solution of 4.0 g (20 mmol) of 2-amino-4-fluoro-6-trifluoromethoxypyrimidine in 30 ml of methylene chloride at 25° C. Stirring was carried out for 16 hours at 25° C., and the product which separated out was filtered off under suction, washed with a little ether and dried at 50° C. under reduced pressure from a water pump. 2.1 g of the title compound (22% of theory) of melting point 167°-169° C. were obtained in this manner. Further product can be isolated from the mother liquor.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([OH:16])([CH3:17])[CH3:14])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromopyridine in diethyl ether (5 mL/mmol) was cooled to −78° C., and n-butyllithium 2.5M in hexanes (1.05 eq) was added slowly. After 2 hrs in the cold, acetone (1.3 eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product from the organic phase was triturated with 1:1 ether-hexane and filtered to afford the 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine compound as a solid.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].O>CO>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=1)[CH3:10])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(C=O)o1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole-5-carbaldehyde (457 mg, 1.79 mmol) was dissolved in MeOH (8 mL). NaBH4 (92 mg, 2.33 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 20 min. Water (16 mL) was added and the MeOH removed under reduced pressure. The mixture was then extracted with EA (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound was obtained as a colorless oil. LC-MS-conditions 02: tR=0.97 min; [M+H]+=258.37.