Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Cu][C:29]#[N:30]>N1C=CC=CC=1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:14][N:13]=[C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([CH:3]=3)[C:29]#[N:30])[N:16]=2)=[CH:18][CH:19]=1
Reactant: N#C[Cu]
Reactant: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Br)c3)no2)cc1
Solvent: c1ccncc1
Product: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(C#N)c3)no2)cc1
Temperature: 230 °C
Yield: 39.3 %

Procedure:
A 25 mL microwave vial equipped with a stirring bar was charged with 3-(3-bromo-4-isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.25 g, 0.577 mmol), copper(I) cyanide (0.133 g, 1.485 mmol) and pyridine (15 ml). The vessel was capped and the reaction heated to 230° C. for 30 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was concentrated, to the residue was added hydrated ferric chloride (0.8 g), concentrated hydrochloric acid (2 mL) and water (12 mL). The solution was heated at 65° C. for 20 min, the aqueous mixture was extracted by DCM (3×30 mL), the combined DCM layers were washed with FeCl3 solution (2×20 mL), then water (2×20 mL), dried (brine, MgSO4) and concentrated to yield yellow solid, which was purified via silica gel chromatography (40 g, 20% EtOAc:Heptane) to afford 5-(5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.086 g, 0.227 mmol, 39.3% yield) as pale yellow solid.
Reaction SMILES: C(OC(O[C@@H]([O:10][C:11]([C:13]1[N:14]2[CH:17]([CH:18]([CH3:37])[C:19]=1[S:20][C@@H:21]1[CH2:25][N:24](C(OCC=C)=O)[C@H:23]([CH2:32][O:33][CH2:34][CH2:35][F:36])[CH2:22]1)[CH2:16][C:15]2=[O:38])=[O:12])C)=O)C=C.[CH2:39]([OH:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1>CC(C)CC(=O)C.C(OCC)(=O)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>[F:36][CH2:35][CH2:34][O:33][CH2:32][C@@H:23]1[CH2:22][C@H:21]([S:20][C:19]2[C@H:18]([CH3:37])[C@H:17]3[N:14]([C:15](=[O:38])[C@@H:16]3[C@H:39]([OH:41])[CH3:40])[C:13]=2[C:11]([OH:10])=[O:12])[CH2:25][NH:24]1
Reactant: CCO
Reactant: C=CCOC(=O)O[C@H](C)OC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)C(C)C2CC(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl-3-[(2S,4S)-1-allyloxycarbonyl-2-(2- fluoroethyl)oxymethylpyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (350 mg) in a mixture of 4-methyl-2-pentanone (4.2 ml), ethanol (2.1 ml) and water (170 μl) was added triphenylphosphine (16 mg), 5,5-dimethyl-1,3-cyclohexanedione (255 mg) and tetrakis(triphenylphosphine)palladium(0) (68 mg) at room temperature for 3 hours under nitrogen atmosphere. Evaporation of the solvent gave a residue, which was dissolved in a mixture of ethyl acetate (40 ml) and water (20 ml). The aqueous layer was separated and concentrated. The residual solution was chromatographed on "Diaion HP-20" eluting with 10% aqueous acetone. The fractions containing the desired compound were collected, and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyl)oxymethylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (100 mg).
Reaction SMILES: O=[C:2]1[C:10]2(CCN(C(OC(C)(C)C)=O)C[CH2:11]2)[C:9]2[C:4](=[CH:5][C:6]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:7][CH:8]=2)N1.BrC1C=CC2C(C)(C)[O:40][C:39](=[O:44])[N:38](C)[C:37]=2C=1>>[CH3:37][N:38]1[C:4]2[CH:5]=[C:6]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)[CH:7]=[CH:8][C:9]=2[C:10]([CH3:11])([CH3:2])[O:44][C:39]1=[O:40]
Reactant: CN1C(=O)OC(C)(C)c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: CN1C(=O)OC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21

Procedure:
Following the procedure described for intermediate 7.33 (Step 2), starting from 7-bromo-1,4,4-trimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.38 (540 mg), 560 mg of 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one 7.40 was obtained. LCMS [M+H]+: 318.12.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH2:11][C@H:12]2[CH2:16][C@H:15]([O:17]S(C)(=O)=O)[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:34]=[C:33](O)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:34]=[C:33]([O:17][C@H:15]2[CH2:14][O:13][C@@H:12]([CH2:11][O:10][C:8](=[O:9])[C:7]3[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:16]2)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37]
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C1NCCc2c(Cl)cc(O)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OC[C@H]1C[C@@H](Oc2cc(Cl)c3c(c2Cl)C(=O)NCC3)CO1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A solution of ((2R,4S)-4-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl 4-nitrobenzoate (296m, 300 mg, 0.869 mmol), 5,8-dichloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (296 g, 222 mg, 0.956 mmol), and cesium carbonate (566 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was heated to 100° C. for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to give 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 128 mg, 31% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.18-8.33 (m, 4H), 7.03 (s, 1H), 6.09 (br. s., 1H), 4.99 (td, J=4.28, 1.96 Hz, 1H), 4.56-4.62 (m, 2H), 4.42-4.52 (m, 1H), 4.27 (d, J=10.64 Hz, 1H), 4.02 (dd, J=10.58, 4.34 Hz, 1H), 3.48 (td, J=6.36, 3.91 Hz, 2H), 2.99-3.09 (m, 2H), 2.56 (ddd, J=14.24, 8.19, 6.42 Hz, 1H), 2.18 (dd, J=14.12, 5.07 Hz, 1H). MS: 481 [M+1]
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[C:17]([O:19]CC)=[O:18])#[N:4].O.Cl>C(O)C>[C:3]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:8]=[CH:7][C:6]=1[C:17]([OH:19])=[O:18])#[N:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Yield: 83.4 %

Procedure:
A hot solution of 5.61 g of potassium hydroxide dissolved in 110 ml of 3A ethanol was added to a hot solution of 11.3 g of 5-cyano-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester dissolved in 225 ml of 3A ethanol. The precipitated salt that was formed was dissolved into 1 liter of water and the solution was acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtraton and recrystallized from toluene to provide 8.47 g of 5-cyano-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid. MP=192°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: O=C=Nc1cccc(Br)c1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)Nc1cccc(Br)c1
Yield: 66.2 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 3-bromophenyl isocyanate (0.0095 mL, 0.076 mmol) were reacted to give the title compound as an off-white solid (22.4 mg, 66%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 7.97-7.99 (m, 1H), 7.85 (t, J=1.9 Hz, 1H), 7.42-7.45 (m, 3H), 7.29-7.31 (m, 1H), 7.21-7.27 (m, 3H), 7.13-7.15 (m, 1H), 7.05-7.08 (m, 1H), 7.01 (d, J=7.9 Hz, 1H), 4.20-4.24 (m, 1H), 3.70-3.75 (m, 1H), 3.52-3.59 (m, 2H), 2.94-3.00 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[S:33][C:32]([C:34]([NH:36][NH2:37])=[O:35])=[CH:31][CH:30]=2)=[O:28])[CH2:23][CH2:22]1)([CH3:20])[CH3:19].Cl.O1CCOCC1.CN(C)C=O>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:37][NH:36][C:34]([C:32]3[S:33][C:29]([C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:26][CH2:25]4)=[O:28])=[CH:30][CH:31]=3)=[O:35])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)N1CCN(C(=O)c2ccc(C(=O)NN)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCN(C(C)C)CC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 54 %

Procedure:
28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO2004/108683) and 29.7 mg of 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carbohydrazide prepared in Reference Synthetic Example 1 in 2 mL of isopropyl alcohol were heated with 3 mg of p-tosylic acid monohydrate and 25 μL (1 eq) of 4 M hydrogen chloride/dioxane at 105° C. for 8 hours. The reaction solution was further heated with 2 mL of dimethylformamide at 105° C. for 5 hours and cooled to room temperature. The precipitated solid was recovered by filtration and washed with 1 mL of isopropyl alcohol and 1 mL of chloroform, and the resulting crystals were dried to give the desired product (yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C[O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][CH2:35][O:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([OH:38])=[O:26])[CH2:21][CH2:20]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Reactant: COC(=O)c1ccccc1OCCCl
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2CCc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 87 (part E) starting with 1.7 g (5 mmol) of 5-methoxy-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.2 g (5.5 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up and purification by flash chromatography, 0.6 g (24% of yield) of the expected acid were obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1.[Li+].[OH-].Cl.CCOC(C)=O>O1CCOCC1.O>[CH3:15][S:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:16])=[O:2])=[CH:10][CH:9]=1)(=[O:14])=[O:13]
Reactant: COC(=O)Cc1ccc(OS(C)(=O)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(4-Methanesulfonyloxy-phenyl)-acetic acid methyl ester (615 mg, 2.51 mmol) was dissolved in a 1:1 mixture of dioxane and water (6 mL) and an aq. solution of LiOH (2 eq., 5.05 mL, 1N) was added and the mixture was stirred at ambient temperature for 15 min. After the addition of aq. HCl (3N) and EtOAc, the phases were separated and the organic layer was dried (MgSO4), filtered and evaporated under reduced pressure. The title compound was obtained without further purification as a solid (497 mg, 85.7%). 1H NMR (400 MHz, CDCl3): δ 7.35-7.38 (d, 2H), 7.25-7.29 (d, 2H), 3.64 (s, 2H), 3.19 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:13]3[N:14]=[CH:15][CH:16]=[CH:17][N:12]3[NH:11][C:10]=2[NH2:18])[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>CN(C=O)C>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:13]3[N:14]=[CH:15][CH:16]=[CH:17][N:12]3[NH:11][C:10]=2[NH2:18])[CH:4]=1)=[O:27]
Reactant: CSc1cc(C2=C(N)NN3C=CC=NC23)ncn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CS(=O)c1cc(C2=C(N)NN3C=CC=NC23)ncn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
3-(6-(Methylthio)pyrimidin-4-yl)-1,3a-dihydropyrazolo[1,5-a]pyrimidin-2-amine (22′, 7.2 g, 27.9 mmol) was suspended/dissolved in 70 mL of DMF and stirred at 0° C. while mCPBA (8.0 g, 34.8 mmol) in 20 mL of DMF was added drop wise over 30 minutes. After addition, the reaction was stirred for an additional hour at ambient temperature. The ppt was isolated via suction filtration, and washed with acetonitrile, and finally ethyl ether and air dried. Isolated 5.1 g of solid (66.7% yield)
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])N.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([S:18][CH3:17])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: CSSC
Reactant: Cc1ccc(N)cc1F
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl nitrite (4 ml) was added to a mixture of 3-fluoro-4-methylaniline (5 g) and dimethyldisulphide (36 ml) in chloroform. After the reaction had initiated t-butyl nitrite (22 ml) and a solution of 3-fluoro-4-methylaniline (20.0 g) in chloroform were added simultaneously. The mixture was then stirred at room temperature for 2 hours. The mixture was washed with water, hydrochloric acid (2M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-fluoro-4-(methylsulphenyl)toluene (25.37 g) as a red oil which was not further purified.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].Cl>O1CCCC1>[CH2:17]([CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:18][CH3:19]
Reactant: CCCC(CCC)CCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCC(CCC)CCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a 250 mL flask containing potassium tert-butoxide (13,27 g, 108,7 mmol, 4,6 eq.) under nitrogen atmosphere was added anhydrous tetrahydrofuran (100 mL) and via cannula 1-bromo-6-propylnonane (5,87 g, 23,54 mmol) in solution with anhydrous tetrahydrofuran (20 mL) was transferred at 0° C. The mixture was then stirred at room temperature for 2 h. Hydrochloric acid (230 mL, 1 M) was added slowly and the mixture was extracted with cyclohexane (300 mL+3×100 mL). The combined organic phase was washed with aqueous sodium bicarbonate (100 mL, 1 M) and dried over magnesium sulfate. The solvent was carefully evaporated under moderate vacuum (at room temperature because of the high volatility of the alkene) to give 3,3 g (84%) of 6-propylnon-1-ene as a brown liquid. 1H NMR (CDCl3, 400 MHz) d?(ppm): 5,82 (ddt, J=6,8 Hz, J=10,2 Hz, J=16,9 Hz, H); 5,00 (broad d, J=16,9 Hz, H); 4,93 (broad d, J=10,2 Hz, H); 2,02 (dt, J=6,8 Hz, J=6,8 Hz, 2H); 1,41-1,30 (m, 2H); 1,32-1,15 (m, 11H); 0,88 (t, J=7,1 Hz, 6H′). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 139,3; 114,1; 36,8; 36,1 (2C); 34,3; 33,2; 26,0; 19,8 (2C); 14,5 (2C ). MS (IE) m/z (%): 169,1 [M+] (25); 141,1 (30); 125,0 (57); 113,0 (40); 99,0 (44); 85,0 (67); 71,0 (73).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:25][C:26]1[CH:27]=[C:28]([CH3:51])[C:29]2[O:33][C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[N:31][C:30]=2[CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32]4[O:33][C:29]5[C:28]([CH3:51])=[CH:27][C:26]([CH3:25])=[CH:50][C:30]=5[N:31]=4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
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: COCCOC
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
The mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.6 g, 0.00135 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.59 g, 0.00162 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ethylene glycol dimethyl ether (50 mL) and water (10 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. After cooled the mixture to the room temperature, more N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.24 g, 0.00066 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) were added, and the mixture was stirred at 80° C. for 5 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish oil which was purified by flash column chromatography on silica using 5%-25% isopropanol/dichloromethane as a mobile phase, and the product was triturated with N,N-dimethylformamide to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.28 g, 0.00051 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.9 min.
Reaction SMILES: [BrH:1].[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])O1.[CH2:13]([OH:15])[CH3:14]>>[C:13]([O:12][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:2][Br:1])(=[O:15])[CH3:14]
Reactant: Br
Reactant: CCO
Reactant: O=C1Cc2ccccc2CO1
Product: CC(=O)OCCc1ccccc1CBr
Temperature: 70 °C
Reaction time: 8 h

Procedure:
An ethanol solution of hydrogen bromide (25%, 10 ml) was added to 1,4-dihydro-3H-isochromene-3-one (500 mg) and stirred at 70° C. overnight. After removing the solvent, the residue was roughly purified with a silica gel chromatography (hexane-ethyl acetate) to obtain a crude material of [2-(bromomethyl)phenyl]ethyl acetate. Methyl 3-(4-aminophenyl)-2-[(2,6-dichlorobenzoyl)amino]propionate (520 mg), triethylamine (490 μl) and DMF (5 ml) were added to the crude material and stirred at 125° C. for six hours. After removing the solvent, the residue was purified with a silica gel chromatography (hexane-ethyl acetate) to obtain methyl 2-[(2,6-dichlorobenzoyl)amino]-3-(4-{[2-(2-ethoxy-2-oxoethyl)benzyl]amino}phenyl)propionate (510 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:42])=[O:41]
Reactant: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=S)c1cc(-c2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)c(C)s1
Temperature: 25 °C
Reaction time: 192 h
Yield: 66.4 %

Procedure:
Methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (200 mg, 0.55 mmol) was dissolved in dry dichloromethane (20 mL). To this, N-methyl morpholine (150 μL, 1.38 mmol) and dimethylaminopyridine (6.1 mg, 0.055 mmol) were added, the mixture was cooled on an ice bath, and methanesulfonyl chloride (43 μL, 0.55 mmol) was added dropwise. The mixture was then stirred for 8 days at room temperature. The mixture was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (20 mL). The aqueous layer was extracted with dichloromethane (3×20 mL), and the combined organic layers were washed with saturated sodium bicarbonate (20 mL), brine (2×20 mL), and dried over anhydrous sodium sulfate. The solvent was remove in vacuo. Column chromatrography on silica gel (100 g) eluting with dichloromethane:methanol 99/1 (v:v), gave methyl 4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (155 mg, 64%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.92 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.40 and 6.90 (AB quartet, 2H, J=8.7 Hz), 3.87 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix m/z): Calcd. for C17H16N2O4S4441.0 (M+H), found 441.2.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[C:15]([CH3:22])=[C:14]([C:23](=[O:25])[CH3:24])[C:13]=2[CH3:26])[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C[O-].[Na+].[H][H]>CO.[Pd]>[C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[C:17]([CH3:18])=[C:16]([NH2:19])[C:15]([CH3:22])=[C:14]([C:23](=[O:25])[CH3:24])[C:13]=2[CH3:26])[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(C(C)=O)c(C)c([N+](=O)[O-])c2C)CC1=O
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)C1=C(O)CC(c2c(C)c(N)c(C)c(C(C)=O)c2C)CC1=O
Yield: 84.5 %

Procedure:
A stirred solution of 2-propionyl-3-hydroxy-5-[3-acetyl-5-nitro-2,4,6-trimethylphenyl]cyclohex-2-en-1-one (4.2 g, 11.3 mmol) and sodium methoxide (0.61 g, 11.3 mmol) in methanol (80 ml) was hydrogenated at atmospheric pressure over 10% palladium on charcoal (0.3 g). After uptake of hydrogen ceased the solution was neutralized and the methanol was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to yield 2-propionyl-3-hydroxy-5-(3-acetyl-5-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a red brown solid (3.28 g, 85%) the compound was characterized by proton magnetic resonance spectroscopy (CDCl3, δ in ppm): 1.18 (3H,t ; 2.0 3H,s); 2.12 (3H,s); 2.18 (3H,s ; 2.40 3H,s); 2.4-4.1 (5H,m); 3.07 (2H,q); 3.6 (2H, brs); 18.05 (1H,brs).