Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=[O:13]
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: Oc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(C(=O)COc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-difluorophenol (3.71 g; 29 mmol) and 2-bromo-1-(4-methylsulfanylphenyl)ethanone (7.00 g; 29 mmol) in methylene chloride (50 ml) was added a solution of potassium carbonate (5.91 g; 43 mmol) and tetrabutylammonium hydrogensulfate (0.48 g; 1.4 mmol) in water (20 ml). The mixture was stirred at room temperature for 16 hours. Water (100 ml) was added, the organic phase was decanted, and the basic phase was extracted with methylene chloride (2×100 ml). The organic solution was dried (Na2SO4) and the solvent removed under reduced pressure. The resulting solid was washed with ethyl ether. 2-(2,4-Difluorophenoxy)-1-(4-methylsulfanyl phenyl)ethanone was obtained (6.60 g, 76%) as an off-white solid. b) A solution of 80% magnesium monoperoxyphthalate hexahydrate (15.26 g; 25 mmol) in water (20 ml) was added to a solution of the above compound (6.60 g; 22 mmol) in methylene chloride (100 ml). The mixture was stirred at room temperature for 16 hours. The reaction was poured into saturated solution of sodium bicarbonate (200 ml) and extracted with methylene chloride (3×100 ml). The organic phase was dried (Na2SO4) and the solvent removed under reduced pressure. 2-(2,4-Difluorophenoxy)-1-(4-methanesulfonylphenyl)ethanone was obtained (4.97 g, 89%) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][C:15]1=[O:28])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13].O1CCCC1.O.[OH-].[Li+]>O>[Cl:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[CH2:5][CH:4]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=2[F:26])=[CH:16][C:15]1=[O:28])[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
A mixture of 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (56 mg, 0.13 mmol) in a 1:1 solution of tetrahydrofuran:water (4 mL) was treated with lithium hydroxide monohydrate (11 mg, 0.26 mmol). The mixture was then stirred for 1 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with 1N aqueous hydrochloric acid until the pH was acidic and then extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to afford 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (40 mg, 74%) as a tan solid: HR-ES-MS m/z calculated for C19H13NO4Cl2F2 [M+H]+ 428.0263, observed 428.0263.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[NH:51][CH:52]=[CH:53][N:54]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[NH:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ncc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ncc[nH]1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 90.8 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-aminoimidazole (241 mg; 1.79 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) provided after flash chromatography (Biotage 40M; eluent: 4% methanol/methylene chloride) 320 mg of (S)-3-Cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl) propionamide which was then recrystallized from ethyl acetate/hexanes to give 209 mg of pure material: EI-HRMS m/e calcd for C20H24N4O2 (M+) 352.1899, found 352.1895.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:17]=3[OH:27])[C:11]=2[CH2:12][CH2:13][CH2:14]O)=[O:6])[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]3[C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:17]=4[O:27][CH2:14][CH2:13][CH2:12][C:11]=23)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)c(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc2c(c1)OCCCc1c(C(=O)NC3CC3)nnn1-2
Reaction time: 8 h
Yield: 12.1 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (260 mg) obtained in Example 335c) and tributylphosphine (4.1 ml) were dissolved in THF (50 ml), ADDP (4.16 g) was added under an argon atmosphere, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. This ethyl acetate solution was washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) and further triturated with ether to give the title compound as a white powder (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([N:11]2[CH2:15][CH2:14][S:13][C:12]2=[S:16])=[O:10])=[CH:7][C:6]([C:17]([N:19]2CCSC2=S)=[O:18])=[CH:5][C:4]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29][C:28]1=[S:32])=[O:26].C(N(CC)CC)C.Cl.[CH2:41]([O:43][C:44](=[O:48])[C@H:45]([CH3:47])N)[CH3:42].CO>ClCCl.CN(C=O)C>[CH2:41]([O:43][C:44](=[O:48])[CH2:45][CH2:47][NH:19][C:17](=[O:18])[C:6]1[CH:7]=[C:8]([C:9]([N:11]2[CH2:15][CH2:14][S:13][C:12]2=[S:16])=[O:10])[C:3]([O:2][CH3:1])=[C:4]([C:25]([N:27]2[CH2:31][CH2:30][S:29][C:28]2=[S:32])=[O:26])[CH:5]=1)[CH3:42]
Reactant: CCOC(=O)[C@H](C)N
Reactant: COc1c(C(=O)N2CCSC2=S)cc(C(=O)N2CCSC2=S)cc1C(=O)N1CCSC1=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To slurry of the 2-methoxy-TIAM-trithiazolide 5 (27.1 g, 0.05 mol) and triethylamine (2 mL) in dichloromethane (600 mL), a solution of □-alanine ethyl ester HCl salt (1.1 g, 7 mmol) in DMF (15 mL) and dichloromethane (100 mL) was added dropwise over 36 h. The reaction mixture was applied directly onto a gradient flash silica column (1-3% methanol in dichloromethane). The desired product was obtained as thick, yellow oil. Yield 2.3 g (61% based on the □-alanine ethyl ester HCl salt).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23](O)=[O:24])[CH:20]=[CH:19][S:18]2.[F:28][C:29]([F:37])([F:36])[C:30]1[S:34][C:33]([NH2:35])=[N:32][N:31]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:35][C:33]1[S:34][C:30]([C:29]([F:37])([F:36])[F:28])=[N:31][N:32]=1)=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Reactant: Nc1nnc(C(F)(F)F)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nnc(C(F)(F)F)s2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (150 mg, 0.388 mmol) with 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (78 mg, 0.465 mmol) in the presence of EDCI hydrochloride (148 mg, 0.776 mmol) and DMAP (71 mg, 0.582 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 80 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.02 (s, 9H), 3.56 (s, 2H), 3.83 (s, 3H), 6.79-6.82 (m, 2H), 6.84-6.94 (m, 2H), 7.28 (d, J=16.5 Hz, 1H), 7.66 (d, J=15.9 Hz, 1H), 8.11 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 538.27 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=1>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[NH:28][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:18][C:19]=1[C:24]([F:25])([F:26])[F:27]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
4-hydroxybenzoic acid hydrazide (3.0 g, 19.66 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.8 g, 19.66 mmol) were suspended in 100 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. Then it was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow oil was re-dissolved in a small amount of ethyl acetate, loaded on a short pad of silica gel and eluted with 5:1 hexane/ethyl acetate, then with 100% ethyl acetate to collect the product. The product was re-purified by a second silica gel column chromatography, using ISCO system (80 g pre-packed column, 25 min run, 20% to 50% EtOAc gradient in hexane). Solvent was removed in vacuo to give the title product as a white solid (2.83 g). Yield 40.4%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[CH:28]/[C:29]([OH:31])=[O:30])/[C:19]3[S:20][CH:21]=[CH:22][C:23]=3[C:24]([O:26][CH3:27])=[N:25][C:16]=2[CH:15]=1.[Cl:34]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:34][C:21]1[S:20][C:19]2/[C:18](=[CH:28]\[C:29]([OH:31])=[O:30])/[C:17]3[CH:32]=[CH:33][C:14]([Cl:13])=[CH:15][C:16]=3[N:25]=[C:24]([O:26][CH3:27])[C:23]=2[CH:22]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COC1=Nc2cc(Cl)ccc2/C(=C/C(=O)O)c2sccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC1=Nc2cc(Cl)ccc2/C(=C/C(=O)O)c2sc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A round-bottomed flask, equipped with a magnetic stirrer, digital thermometer, addition funnel and a condenser with nitrogen inlet-outlet, is charged with diisopropylamine (462.9 mL) and tetrahydrofuran (4.2 L). The solution is cooled to −78° C. and n-butyl lithium (1.71 L, 1.6 M in hexane) is added over a period of 1 hour. After addition the reaction mixture is stirred for 1 hour and [7-Chloro-10-methoxy-3-thia-9-aza-benzo[f]azulen-(4Z)-ylidene]-acetic acid (350 g), dissolved in tetrahydrofuran (1.4 L), is added dropwise over 1 hour while maintaining the temperature at −70° C. Stirring is maintained for 1 hour at −78° C. Afterwards the yellow solution is transferred through a cold tube to a solution of hexachloroethane (779 g), dissolved in tetrahydrofuran (4.2 L), over a period of 45 min while maintaining the temperature at −25° C. The yellow solution is then allowed to slowly warm up to 0° C. over 30 min and kept at this temperature for 30 min. Then, deionized water (2.26 kg) is added over 5 min and the resulting emulsion concentrated under vacuum to remove the solvent. Then tert-butylmethylether (5.25 L) and water (3 L) are added. After vigorous stirring the organic phase is removed and replaced with isopropyl acetate (7 L). Then the mixture is acidified with phosphoric acid (339 L) to get a pH value of 2-3. Afterwards, the organic phase is separated and concentrated to 1/10, methanol (6.2 L) is added and the temperature raised to 65° C. over 40 min. The solution is distilled to a volume of 3.4 L, the resulting suspension cooled to −15° C. and stirred for 1 hour. The crystalline precipitation is collected by filtration, washed with cold methanol (500 mL) and dried under vacuum (50° C., 20-50 mmbar) to yield [2,7-Dichloro-10-methoxy-3-thia-9-aza-benzo[f]azulen-(4Z)-ylidene]-acetic acid with a melting point of 195-197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17]C2C=NC=CC=2[C@H]2C[C@@H](NC(=O)OC(C)(C)C)[C@@H](SCCOC)[C@@H](C)C2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:44].OOS([O-])=O.[K+].C(O)(C(F)(F)F)=O.C(Cl)Cl>C1COCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][C:10]=1[F:44]
Reactant: COCCS[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-(2-methoxyethylthio)-3-methylcyclohexylcarbamate (1.0 equiv.) in THF (0.04 M) in a 0° C. bath was added oxone (2.0 equiv.) as a solution in H2O. The solution was left stirring at rt for 5 hrs. The solution was diluted with EtOAc, washed with H2O, NaCl(sat), dried over MgSO4, filtered, concentrated to yield Boc protected product. The material was treated with 25% TFA/CH2Cl2 for 30 minutes, at which time the volatiles were removed in vacuo, the residue was dissolved in DMSO and purified by reverse phase HPLC. The product fractions were lyophilized directly to yield N-(4-((1R,3R,4S,5S)-3-amino-4-(2-methoxyethyl)sulfonyl)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 76% yield. LC/MS (m/z)=563.3 (MH+), Rt=0.62 min. 1H NMR (400 MHz, <dmso>) δ ppm 10.52 (s, 1H), 8.53 (s, 1H), 8.50 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1H), 7.80 (bs, 2H), 7.70 (quintet, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 7.31 (d, J=4.0, 1H), 3.82-3.88 (m, 2H), 3.73-3.78 (m, 2H), 3.55-3.61 (m, 1H), 3.42-3.49 (m, 1H), 3.31 (s, 3H), 3.06-3.16 (m, 1H), 1.92-2.18 (m, 4H), 1.54-1.64 (m, 1H), 1.22 (d, J=4.0, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=2)[CH:21]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1F
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxyphenyl boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[C:50]([O:49][C:47]([NH:46][CH:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)[CH:37]=1)[C:43]([OH:45])=[O:44])=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(NC(=O)OC(C)(C)C)C(=O)O)c3)cc12
Yield: 452.5 %

Procedure:
To a mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (0.9 g, 0.19 mmol) and the crude (3-bromo-phenyl)-tert-butoxycarbonylamino-acetic acid (0.69 g, 2.1 mmol) in a 20 mL microwave reaction flask was added THF (6 mL), acetonitrile (6 mL), and sodium carbonate (1 N in water, 6 mL, 6 mmol). The resulting suspension was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (62 mg, 76 μmol) was added and the purging was continued for another minute. The flask was sealed and was irradiated in a microwave reactor to 90° C. for 10 minutes. The reaction mixture was adjusted to pH 4 using 1 N hydrochloric acid, extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford tert-butoxycarbonylamino-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a pale yellow solid (520 mg, 50%). MS: m/z 605 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](OC)=[O:10].[H-].[Na+].[CH:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:9][OH:10])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1ccccc1Br
Yield: 87 %

Procedure:
To a stirred solution of methyl 2-(2-bromophenyl)acetate (5.2 g, 22.7 mmol) in ethyl formate (40 mL) was added in portions the powder of sodium hydride (100%, 2.18 g, 90.8 mmol) over a period of 1 hour at 10-15° C. After the mixture was stirred for an additional hour, the reaction was quenched with ice water (100 mL) and the two layers were separated. The aqueous layer was acidified with 10% hydrochloric acid aqueous solution and then extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with water (2×20 mL), saturated sodium bicarbonate solution (2×40 mL) and brine in turns. Then organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 2-(2-bromophenyl)-3-hydroxyacrylate as a pink oil (5.33 g, 87%). 1H NMR (300 MHz, CDCl3): δ 11.99 (d, J=12.7 Hz, 1H), 7.59 (dd, J=7.8 Hz, 0.9 Hz, 1H), 7.46-6.98 (m, 4H), 4.25 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)[O:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1cc(CBr)occ1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(=O)c(O)co2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one (8.9 g, 43.4 mmol), tert-butyloxycarbonylpiperazine (8.5 g, 45.6 mmol), triethylamine (7 mL, 49.9 mmol) and acetonitrile (200 mL) were charged in a 500 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 2 h at 90° C. Acetonitrile was evaporated and EtOAc (50 mL) was added. The precipitate of (C2H5)3N, HCl was filtered off and ethyl acetate was evaporated at 40° C. to dryness. The crude compound was purified by column chromatography (deactivated SiO2:CH2Cl2:triethylamine 98:2 to CH2Cl2:MeOH 95:5, purification: CH2Cl2:MeOH 99.5:0:5 to 96:4) to give after evaporation tert-butyl 4-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)piperazine-1-carboxylate 24 (10.5 g, 78% yield) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH3:12][C:13]1[S:14][C:15]([CH:19]=[O:20])=[C:16]([CH3:18])[N:17]=1>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH3:12][C:13]1[S:14][C:15]([CH:19]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[OH:20])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1nc(C)c(C=O)s1
Agent: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)c2cnnn2C)s1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
1-Methyl-1H-1,2,3-triazole was prepared according to the literature reference W02008/98104. To a 2 L flask containing 1-methyl-1H-1,2,3-triazole (9 g, 108.3 mmol) was added THF (1500 mL) and the solution was cooled to −40° C. To this colorless homogeneous solution was added n-butyllithium (2.5 M in hexanes, 45 mL, 112.5 mmol) dropwise which immediately afforded a dark brown viscous mixture. The mixture was kept between −10 to −20° C. for 60 minutes, then a THF solution of 2,4-dimethylthiazole-5-carbaldehyde (17.2 g, 121.8 mmol in 200 mL THF) was introduced via cannula. Once the aldehyde was added the reaction was allowed to warm to room temperature. After 3 hours, the reaction was quenched by pouring it into a saturated solution of aqueous NH4Cl. The aqueous portion was extracted with EtOAc in portions, 7×400 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford a brown oil. Chromatography on silica gel (10% acetone-DCM increasing to 50% acetone and increasing to 10% MeOH-DCM) provided the title compound as an amber solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22].C(Cl)(=O)C(Cl)=O.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:5][CH:4]=[C:3]1[C:21]([O:23][C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=1)=[O:22]
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C=C(OC(=O)c2cnc(-c3ccccc3)n(Cc3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-2-phenyl-1-(phenylmethyl)-5-pyrimidinecarboxylic acid (i.e. the product from Step C) (1.00 g, 3.26 mmol) in dichloromethane (30 mL) at 0° C., was added oxalyl chloride (823 mg, 6.53 mmol) followed by a catalytic amount of N,N-dimethylformamide (2 drops). The reaction mixture was allowed to warm to room temperature and stir for 1 h. Then the reaction mixture was concentrated under reduced pressure. To the resulting residue was added dichloromethane (30 mL) and 1,3-cyclohexanedione (440 mg, 3.90 mmol), followed by triethylamine (990 mg, 9.80 mmol), and the reaction mixture was stirred at room temperature for 30 min Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product as a white solid (500 mg).