Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([CH2:22][O:23][CH2:24][CH3:25])=[N:14][C:13]=1[C:26]#[N:27])[C:5]([O:7][CH3:8])=[O:6].Cl.O1CCOCC1>C(OCC)(=O)C>[NH2:27][C:26]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[C:12]=2[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOCc1nc(C#N)c(-c2ccc(C(=O)OC)cc2N)n1CC(C)(C)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 90 °C
Yield: 109.3 %

Procedure:
Methyl 3-amino-4-(4-cyano-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazol-5-yl)benzoate (2.79 g, 7.49 mmol) was combined with a solution of HCl in dioxane (4M, 56.2 mL, 225 mmol) to give an orange solution. The reaction mixture was heated to 90° C. under argon with stirring. After 1 h at 90° C. the mixture was cooled to room temperature and concentrated in vacuo to obtain a beige solid. The solid was dissolved in ethyl acetate (500 mL) washed with a mixture of water (100 mL) and saturated sodium bicarbonate solution (250 mL). The water phase was extracted with ethyl acetate (2×250 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo to obtain a yellow solid (3.05 g). The solid material was re-crystallized from ethyl acetate/heptane to give the title compound (2.4 g, 86%) as light yellow solid; LC-MS (UV peak area, ESI) 99%, 373.1884 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH2:32][CH2:31][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[N:13]=[C:12]2[NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:10][CH2:9]1)([O-])=O>CCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH2:32][CH2:31][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[N:13]=[C:12]2[NH:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][CH2:9]1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc([N+](=O)[O-])c3)CC2)N1c1cccc(F)c1
Solvent: CCO
Product: Nc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reaction time: 8 h

Procedure:
A 100 mL EtOH solution of 1.0 g (2.1 mmol) 8-(3-nitrobenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (example 104) and 0.57 g (2.5 mmol) SnCl2 dihydrate was heated to reflux and allowed to stir overnight. HPLC/MS showed complete conversion so the reaction mixture was filtered through celite washed with EtOH then the filtrate was concentrated. The remaining oil was partitioned between 3N NaOH and EtOAc. A thick white precipitate formed in the aqueous layer. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to pure product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[C:23](I)[C:24]([CH3:28])=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[CH3:30][NH:31][C:32]1[N:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[N:33]=1>O1CCOCC1>[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:37]5[CH:38]=[C:39]6[C:34](=[CH:35][CH:36]=5)[N:33]=[C:32]([NH:31][CH3:30])[N:41]=[CH:40]6)[C:24]([CH3:28])=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc2c(Nc3ccc4c(c3)CCC4)ncnc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5ccc6c(c5)CCC6)ncnc34)ccc2n1
Temperature: 180 °C

Procedure:
2 M Aqueous sodium carbonate (857 μl, 1.7 mmol), tetrakis (triphenylphosphine)palladium (0) (99 mg, 86 μmol), N-(2,3-dihydro-1H-inden-5-yl)-8-iodo-7-methylquinazolin-4-amine hydrochloride (250 mg, 571 μmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (326 mg, 1142 μmol) and dioxane (5 mL) were added to a microwave vial. The reaction mixture was heated in a microwave at 180° C. for 20 min. The solid residue was filtered off through Celite® and washed with methanol and DCM. The filtrate was concentrated and purified by flash chromatography (0-10% MeOH in DCM) to give 6-(4-(2,3-dihydro-1H-inden-5-ylamino)-7-methylquinazolin-8-yl)-N-methylquinazolin-2-amine as an off-white amorphous solid. MS (M+H)+ 433.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (302 mg, 1.78 mmol) in acetone (20 mL) was added cesium carbonate (765 mg, 2.35 mmol), followed by ethyl bromoacetate (0.30 mL, 2.7 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 361 mg of an oil (79% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.25 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.20 (q, J=7.2 Hz, 2H), 4.89 (t, J=1.6 Hz 2H), 7.34 (dd, J=10.3 Hz, 1.6 Hz, 1H), 7.41 (s, 1H), 9.88 (d, J=1.5 Hz, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.0, 57.6, 62.1, 70.3 (d, J=1.9 Hz), 110.0, 111.8 (d, J=20.6 Hz), 133.1 (d, J=7.2 Hz), 141.8, (d, J=12.7 Hz), 154.8 (d, J=4.5 Hz), 155.0 d, J=46.1 Hz) 169.7, 191.3.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[C@H:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)[NH2:8]
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(F)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1.8 g (10 mmole) of 4-fluorophenylalanine is suspended in 3.0 ml of methanol and cooled to -10° C. under nitrogen and 0.81 ml of thionylchloride added dropwise, keeping the temperature at or below -2° C., and stirred for 1 hour at -5° C. to -10° C. About 10 ml of methanol was added and the solution stirred at room temperature overnight. The solution was concentrated in vacuo and the residue triturated with dry ether and filtered to give the hydrochloride salt of 4-fluorophenylalanine methyl ester, m.p. 177.5° to 178° C. The ester hydrochloride is substituted for L-phenylalanine methyl ester hydrochloride in the procedure of Example 6a to yield 6b.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:10][C:9]1[C:8]([O:11][CH3:12])=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[F:1])(=[O:15])[CH3:14]
Reactant: COc1ccc(C#N)c(F)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C#N)c(F)c1OC(C)=O

Procedure:
0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile are dissolved in 10 ml of acetic anhydride and 0.5 ml of pyridine, whereupon the mixture is stirred at 120° for 2 hours. The reaction mixture is subsequently evaporated and the residue is partitioned between ice-water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride/hexane. There is obtained 3-cyano-2-fluoro-6-methoxyphenyl acetate of m.p. 90°-91°.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[O:11]1[C:16]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:24]=[C:25]([CH2:30][CH2:31][OH:32])[CH:26]=[C:27]([F:29])[CH:28]=3)[CH2:18][CH2:17]2)[CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:29][C:27]1[CH:26]=[C:25]([CH2:30][CH2:31][OH:32])[CH:24]=[C:23]([CH2:22][N:19]2[CH2:18][CH2:17][C:16]3([O:11][CH2:12][CH2:13][N:14]([S:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:9])=[O:8])[CH2:15]3)[CH2:21][CH2:20]2)[CH:28]=1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)s1
Reaction time: 1 h

Procedure:
A solution of 5-methylthiophene-2-sulfonyl chloride (0.15 g) in DCM (3 mL) was added dropwise to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g) and N-ethyl-N-isopropylpropan-2-amine (0.14 mL) in DCM (20 mL). The resulting mixture was stirred for 1 h and the solvent evaporated. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogen carbonate solution (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 47.5:47.5:5 ethyl acetate:isohexane:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow gum. Yield 0.21 g.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O>C1(C)C=CC=CC=1>[CH3:5][C:4]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:5]1[C:6]2[C:1](=[CH:11][CH:2]=[CH:1][CH:6]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(-c3cccc4ccccc34)c2C1
Yield: 4030.6 %

Procedure:
The crude product was taken up in 200 cm3 of toluene, 0.5 g of p-toluene sulfonic acid was added, the reaction mixture was refluxed for 2 hours on a water separator and washed 3 times with 50 cm3 of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 10 g (86%) of 22 as a colorless oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[NH:35][N:34]=[C:33]([CH2:36][C:37](O)=[O:38])[N:32]=1)([O-:30])=[O:29]>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:37](=[O:38])[CH2:36][C:33]1[N:32]=[C:31]([N+:28]([O-:30])=[O:29])[NH:35][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c([N+](=O)[O-])n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (5-nitro-1H-[1,2,4]triazol-3-yl)-acetic acid to afford (S)-1-[2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-(5-nitro-1H-[1,2,4]triazol-3-yl)-ethanone as white solid (58 mg). The resulting nitrotriazole was reduced with 10% Pd/C under 1 atm of hydrogen in MeOH to afford the title compound as an off-white solid (15 mg, 39% overall). LC/MS (Method B) 2.20 min, [M+1]+ 491.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:7][N:6]=1)=[O:4]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(C(=O)OC)c(Cl)c1

Procedure:
To a solution of 5-bromo-3-chloro-pyridine-2-carboxylic acid methyl ester [1458-18-0] (376 mg, 1.5 mmol) in dioxane (3.7 ml) was added tributyl-(1-ethoxy-vinyl)-stannane [97674-02-7] (596 mg, 1.65 mmol), the solution was degassed and flushed with nitrogen (3×), Pd(PPh3)4 (87 mg, 0.075 mmol) was added, after degassing and flushing with nitrogen the mixture was heated to reflux for 4 h. The reaction mixture was diluted with EtOAc and treated with 10% aq. KF, the precipitate was filtered off and the layers were separated. The aq. Phase was extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 12:1 to 6/1) to provide the title compound as yellow solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][CH3:22])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.BrC[C:32]([O:34][CH3:35])=[O:33]>CN1C(=O)CCC1>[CH3:35][O:34][C:32](=[O:33])[CH2:22][NH:21][CH2:20][C@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[O:17]1
Reactant: CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 0 °C

Procedure:
(R)-(7-Benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine (81 mg, 2.6 mmol) and triethylamine (0.2 mL) were added to 0.5 mL NMP and the mixture was cooled to 0° C. with stirring. Methyl 2-bromoacetate (26 uL) was added, and the reaction mixture was stirred for two hours at room temperature, then quenched by addition of water. The mixture was extracted with methylene chloride and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography gave 40 mg of (R)-[(7-benzenesulfonyl-chroman-2-ylmethyl)-amino]-acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:30][C@H:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:29])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: C[C@H](N)c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccccc1
Temperature: 140 °C
Yield: 26.3 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.3238 mmol, prepared as described in WO 2007/095188) was dissolved in n-butyl alcohol (1 mL). To the butyl alcohol solution thus obtained were then added (1S)-1-phenylethanamine (750 μL, 5.830 mmol) and DIPEA (167.4 mg, 225.6 μL, 1.295 mmol). The resulting solution was heated at 140° C. in microwave for 90 minutes. Additional (1S)-1-phenylethanamine (500 μL, 3.887 mmol) was added and the reaction mixture heated for 90 minutes in microwave at 140° C. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed sequentially with 0.5M HCl (three times, 5 mL each), saturated aqueous sodium hydrogen carbonate solution (three times, 5 mL each), and brine (once, 5 mL). The washed solution was dried over MgSO4, filtered, and concentrated in vacuo to give yellow oil. The oil was purified by mass directed HPLC and the product fractions passed through a bicarbonate cartridge and lypholized to afford the title compound as a white solid (33.5 mg, 26% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24]1[CH:33]=[C:32]([NH:34][C:35](=[O:51])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=3)[C:35]([NH:34][C:32]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:23][CH3:22])[CH:33]=3)=[O:51])[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(NC(=O)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1OC
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1OC
Yield: 63.6 %

Procedure:
To a solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (155 mg, 0.48 mmol) and methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 0.44 mmol) in 10 mL of 1,4-dioxane and 1 mL of water was added Na2CO3 (140 mg, 1.32 mmol) followed by Pd(PPh3)4 (26 mg) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation. The residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=1:1) to give methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)-2-methoxybenzoate (160 mg, 64%) as solid. LC-MS: 572 [M+H]+, tR=1.62 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20](C2C=CC=CC=2)[C:19]([O:31][CH3:32])(C([O-])=O)[CH2:18][C:17]=1[N+]([O-])=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:31][CH3:32])=[CH:11][CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COC1(C(=O)[O-])CC([N+](=O)[O-])=C(Cl)C=C1c1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Yield: 55 %

Procedure:
This compound was prepared in a manner similar to that of methyl-(5'-fluoro-2'-fluoro-2'-methoxy-4-nitro-2-biphenyl)carboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.25 g, 4.8 mmol, 1.0 equivuiv), tetrakis(triphenylphosphine) palladium (Aldrich: 0.16 g, 0.14 mmol, 2.9 mol%), and 5-chloro-2-methoxy-4-nitro-2-biphenylcarboxylate as a to afford 0.85 g (55%) of methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate as a yellow-orange solid. Data for methyl-5'-2'-methoxy-4-nitro-2-biphenylcarboxylate: 1H NMR (400 MHz, CDCl3): 8.73 (d, J=2.4, 1 H); 8.38 (dd, J=8.5, 2.5, 1 H); 7.49 (d, J=8.5, 1 H); 7.36 (dd, J=8.7, 2.5, 1 H); 7.23 (d, J=2.5, 1 H); 6.85 (d, J=8.7, 1 H); 3.76 (s, 3 H); 3.70 (s, 3 H).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(Cl)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (61.3 g, 0.26 mol) in CH2Cl2 (120 ml) was added dropwise over 90 minutes to a stirred solution of (4-chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (39.0 g, 0.17 mol) and trifluoroacetic acid (1.30 ml, 0.02 mol) in CH2Cl2 (170 ml). The reaction mixture was stirred at 25° C. for 72 h and afterward evaporated to dryness. The residue was dissolved in dioxane (390 ml). An aqueous solution of NaOH (45.0 ml, 0.48 mol, 2.8 eq.) was added, and the resulting emulsion was stirred at r.t. for 18 h. The low boiling organic solvent was removed under vacuum. Water (100 ml) was added, the aqueous layer was separated and washed with TBME (2 times 100 ml). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 42.0 g (75%) of IId as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].F[B-](F)(F)F.[CH2:19]([O+](CC)CC)[CH3:20]>ClCCl>[CH2:19]([O:13][C:3](=[N:2][CH3:1])[CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])[CH3:20]
Reactant: CC[O+](CC)CC
Reactant: CNC(=O)Cc1c(F)cccc1F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(Cc1c(F)cccc1F)=NC
Temperature: 25 °C
Reaction time: 25 h

Procedure:
5.55 g (30 mmol) of 2,6-difluorophenylacetic acid methylamide are dissolved in 70 ml of dichloromethane, 7.4 g (39 mmol) of triethyloxonium tetrafluoroborate are added thereto and the whole is stirred for 25 hours at room temperature. The reaction mixture is then extracted by shaking in succession with cold 2N sodium carbonate solution, ice-water and cold saturated sodium chloride solution, dried over magnesium sulphate and concentrated. A mixture of ether and hexane is added to the residue, the unreacted educt remaining undissolved and being filtered off. The filtrate is concentrated and subjected to distillation in a bulb tube. 4 g (62.6% of the theoretical yield) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane which boils at 70° (0.02 mm) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:23]([O:26][CH2:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of 4-amino-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (2 g; 4.49 mmol; 1 eq) in DCM (100 mL) is added acetoxyacetyl chloride (1.23 mL; 9 mmol; 2 eq) and N-ethyldiisopropylamine (2.3 mL; 13.5 mmol; 3 eq) and the reaction mixture is stirred at room temperature for 30 min. DCM is removed under reduced pressure and the crude residue is dissolved in EtOAc. The organic phase is washed twice with 10% citric acid then brine. The solvent is evaporated and the residue is taken up in iPrOH then refluxed and left at room temperature until precipitation. The precipitate is filtered off then dried under reduced pressure to afford 1.9 g (95%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 10.70 (s, 1H), 8.25 (m, 2H), 8.09 (m, 4H), 7.88 (m, 2H), 4.71 (s, 2H), 2.13 (s, 3H). HPLC (max plot) 98%; Rt 4.03 min. UPLC/MS (ES+) 435.2.