Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:26][C:27](=[O:29])[CH3:28])=[N:10][C:11]([CH:24]=[CH2:25])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2C=C)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([C:8]1[C:9]([NH:26][C:27](=[O:29])[CH3:28])=[N:10][C:11]2[CH:24]=[CH:25][C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[C:12]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(NC(C)=O)nc1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: COc1ccc2c(ccc3nc(NC(C)=O)c(Cc4ccccc4)nc32)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 85.8 %

Procedure:
Under an argon atmosphere, to a solution of Hoveyda-Grubbs second generation catalyst (61.3 mg, 97.8 μmol) in 1,2-dichloromethane (150 mL) was added N-(3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazin-2-yl)acetamide (10) (348 mg, 903 μmol) at room temperature. The mixture was then heated to 90° C. and stirred overnight (17 hours). After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=4/3→1/1) to give N-(2-benzyl-8-methoxybenzo[f]quinoxalin-3-yl)acetamide (11) (277 mg, 775 mot, 85.8%) as a white solid. TLC Rf=0.27 (n-hexane/ethyl acetate=1/1); 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 4.00 (s, 3H), 4.50 (s, 2H), 7.24-7.34 (m, 5H), 7.38 (dd, 1H, J=2.6, 8.8 Hz), 7.42 (br, 1H), 7.90 (d, 1H, J=8.8 Hz), 7.93 (d, 1H, J=8.8 Hz), 9.01 (d, 1H, J=8.8 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[N:15]2)=[CH:11][CH:10]=1.[NH3:24].O>CN(C=O)C.C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]([NH2:24])=[O:20])[CH:16]=[N:15]2)=[CH:11][CH:10]=1
Reactant: N
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
According to Scheme 1 Step 3: Oxalyl chloride (227 mmol, 19.5 mL) and three drops of DMF were added to a solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (114 mmol, 26.4 g) in DCM (227 mL). The reaction mixture was stirred for 30 minutes at room temperature. After evaporation of the solvent, dry DCM (100 mL) was added to the crude residue. The acyl chloride solution was then added at 0° C. to a solution of ammonia in water (454 mmol, 23.4 g) and the reaction mixture was stirred overnight. After filtration and evaporation to dryness, 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol, 25.1 g, 96%) was obtained as a colorless solid. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:15]1([NH2:19])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:19][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCC1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)NC3CCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and cyclobutylamine to give N-Cyclobutyl-7-methoxybenzofuran-2-carboxamide (Compound 289a). Successively, it was formylated to give N-cyclobutyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 289b), then compound 289b was reacted with methylamine hydrochloride to give Compound 289 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[Br:18][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][OH:7]
Reactant: COc1cccc(CO)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c(CO)c1

Procedure:
The title compound was prepared by reacting 3-methoxybenzyl alcohol (13.82 g, 0.1 mol) and NBS (19.58 g, 0.11 mol) in acetonitrile (250 mL) at room temperature for 3 hr. The solvent was removed and the resulting mass slurried in dichloromethane (250 mL) and filtered to remove the insoluble succinimide side product. The crude material was purified by chromatography (20% EtOAc-hexanes) to provide a white solid (17.69 g, 81%), mp 57-58° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:12]([C:10]1[S:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:14]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Product: COc1ccc(CNC(=O)c2ccc(-c3ccccn3)s2)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 5-pyridin-2-yl-thiophene-2-carboxylic acid and 2,4-dimethoxy-benzylamine. MS (M+H, 355.2).
Reaction SMILES: BrCC1C(Cl)=NC=CC=1.[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[N:25]=[C:26](Cl)[C:27](F)=[CH:28][C:15]=2[CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[N:25]=[CH:26][CH:27]=[CH:28][C:15]=2[CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Agent: Clc1ncccc1CBr
Product: CC(=O)N1Cc2cccnc2C=Cc2ccccc21

Procedure:
Compound 12C was prepared from bb and 12B by a route analogous to that used for the preparation of 1D. HPLC Rt=1.326 min; LCMS Found: (M+H)+=251.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[CH2:28][O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:42](Br)[CH:43]=[CH2:44]>CN(C=O)C>[CH2:44]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:28][O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:43]=[CH2:42]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Methyl 3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate (1 eq.) was dissolved in DMF (0.34M solution) and the solution was degassed. NaH (1.1 eq.) was added and the mixture was left stirring for 5 min. Allyl bromide (1.2 eq.) was added and stirring was continued for 5 h. All volatiles were evaporated in vacuo and the residual material was dissolved in Et2O. The solution was washed with 0.5N HCl, saturated aq. NaHCO3 solution and with brine. After drying the organic phase over Na2SO4 all volatiles were evaporated in vacuo and the residual material was purified by flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvents the product was obtained as a colorless sticky solid (84%). The material was used without further characterization in the next reaction.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:18]2[C:19]([C@@H:21]([NH:22][C:23](/[C:25](/[C:29]3[N:33]=[C:32]([NH2:34])[S:31][CH:30]=3)=[N:26]\[O:27][CH3:28])=[O:24])[C@H:17]2[S:16][CH2:15][C:14]=1[CH2:35][O:36][CH3:37])=[O:20])=[O:12])[CH3:9])=[O:6])[CH3:3].[CH:38]([O:41]C(OC(OC(C1N2C(=O)C(N)[C@H]2SC(C)C=1OC)=O)C)=O)(C)C.CO/N=C(/C1N=C(NC=O)SC=1)\C(O)=O>>[CH:2]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:20])[CH:21]([NH:22][C:23](=[O:24])/[C:25](/[C:29]3[N:33]=[C:32]([NH:34][CH:38]=[O:41])[S:31][CH:30]=3)=[N:26]\[O:27][CH3:28])[C@H:17]2[S:16][CH2:15][C:14]=1[CH2:35][O:36][CH3:37])=[O:12])[CH3:9])=[O:6])([CH3:1])[CH3:3]
Reactant: COCC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: COC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)C(N)[C@H]2SC1C
Agent: CO/N=C(\C(=O)O)c1csc(NC=O)n1
Product: COCC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC=O)n3)[C@H]2SC1

Procedure:
One process in the production of cefpodoxime proxetil may be carried out via acylation of 7-amino-3-methoxy-methyl-3-cephem-4-carboxylic acid-1-(isopropoxycarbonyloxy)ethyl-ester of formula with activated Z-2-(methoxyimino)-2-(2-formylaminothiazol-4-yl)-acetic acid to obtain 7-[2-(2-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester (N-formyl cefpodoxime proxetil) of formula
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1B1OCC(C)(C)CO1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:43][O:44][C:45]1[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[CH:49][C:46]=1[CH2:47]Br>O1CCCC1.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>[C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:18])=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:47][C:46]1[CH:49]=[CH:50][C:51]([C:53]([F:54])([F:55])[F:56])=[CH:52][C:45]=1[O:44][CH3:43])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(B3OCC(C)(C)CO3)c(C#N)c2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1CBr
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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3OC)c(C#N)c2)c(OC)c1
Temperature: 65 °C

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 29, 45.5 mg, 0.086 mmol) in tetrahydrofuran (1 mL) was added a 2 M aqueous solution of potassium carbonate (116 μL, 3.03 mmol) and 2-methoxy-4-(trifluoromethyl)benzyl bromide (21 mg, 0.08 mmol). The solution was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.0008 mmol). The reaction mixture was heated at 65° C. for 6 hours. The reaction mixture was cooled to ambient temperature and partitioned between 1N aqueous citric acid solution (2 mL) and ethyl acetate (10 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (2 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a yellow oil. The material was purified by silica gel column chromatography (ISCO™ companion, 12 g column, 0-50% ethyl acetate in heptane gradient elution). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[CH:13][C:14]#[N:15])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[CH:13][C:14]#[N:15])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)ccc1N
Temperature: 70 °C
Yield: 49 %

Procedure:
A suspension of 3-(3-methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (0.9 g, 2.4 mmol) and tin chloride dihydrate (4.0 g, 17.7 mmol) in ethanol (25 mL) was heated at 70° C. for 1 h. The mixture was cooled and poured into ice (200 mL). The pH was made strongly alkaline by the addition of 10N NaOH. The mixture was extracted with EtOAc (5×50 mL) and the combined organic extracts were washed with water (40 mL), brine (40 mL), and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, Hexane:EtOAc 1:13 to afford mixture isomers of 3-(4-amino-3-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (0.4 g, 42%) as a yellow solid: mp 123-125° C.; 1H NMR (CDCl3) δ 7.05-6.53 (m, 5H), 5.56(5.43) (s, 1H), 4.12 (s, 2H), 3.91-3.81 (m, 12H); 13C NMR (CDCl3) δ 163.19, 163.09, 152.99, 152.93, 146.63, 139.82, 138.74, 135.43, 132.66, 128.33, 126.35, 124.12, 118.96, 113.76, 113.74, 111.99, 110.22, 107.35, 106.42, 91.14, 90.52, 60.94, 56.28, 56.25, 55.74, 55.59; Anal Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: c, 66.92; H, 5.76; N, 8.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cc(Br)cc2c1NCC2
Product: CS(=O)(=O)N1CCc2cc(Br)cc(F)c21
Yield: 66.6 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 5-bromo-7-fluoroindoline (0.21 g, 0.97 mmol) and methanesulfonyl chloride (0.15 mL, 1.94 mmol) to provide 5-bromo-7-fluoro-1-(methylsulfonyl)indoline (0.19 g). MS (ES) m/z 293.6; HPLC purity 98.4% at 210-370 nm, 8.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18]Cl>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: ClSc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (3.75 g.) was dissolved in 100 ml. of methylene chloride and cooled in an ice-water bath. To the cold, stirred solution, 2,4-dichlorobenzenesulfenyl chloride (6.39 g., 30 mmoles) was added dropwise. The bath was removed and the reaction stirred at room temperature for 1 hour. An equal volume of ether was added, the mixture filtered and the filtrate evaporated in vacuo to crude product (9.0 g., oil). The oil was chromatographed on 300 g. of silica gel with 200 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 6 to 10 were combined and evaporated to yield purified methyl 5-(2,4-dichlorophenylthio)pyrrole-3-carboxylate (3.7 g., solid, m/e 302).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:6]=1.[I:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[S:3][C:4]([I:13])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCCCCc1csc(Br)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCCCCCc1nc(Br)sc1I
Yield: 78.3 %

Procedure:
4.07 g (16.4 mmol) of 2-bromo-4-hexylthiazole was dissolved in 8 mL of acetonitrile, and 32 mL of acetonitrile solution of 4.41 g (19.7 mmol) of N-iodosuccinimide was added under an argon gas atmosphere, and refluxed for 18 hours. Next, the resultant reaction mixed liquid was washed with a Na2S203 aqueous solution, and the aqueous layer was extracted with chloroform and added to the organic layer. The organic layer was concentrated, and subjected to silica gel column chromatography (development solvent:chloroform/hexane=1/1 (volumetric ratio)) to take out red transparent liquid. Since a peak of a molecular weight of 373 containing one bromine atom was observed in the mass spectrum, it could be confirmed that the above-described red transparent liquid was the intended 2-bromo-4-hexyl-5-iodothiazole. The amount obtained was 4.80 g, and the yield was 78.3%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.Br[C:29]1[CH:30]=[C:31]([C:36]2[O:37][C:38]3[C:39]([N:45]=2)=[N:40][CH:41]=[C:42]([F:44])[CH:43]=3)[C:32]([NH2:35])=[N:33][CH:34]=1.[F-].[Cs+]>[Pd](Cl)Cl.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.CO>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]3)[CH:13]=2)=[CH:30][C:31]=1[C:36]1[O:37][C:38]2[C:39]([N:45]=1)=[N:40][CH:41]=[C:42]([F:44])[CH:43]=2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(Br)cc1-c1nc2ncc(F)cc2o1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncc(F)cc5o4)c3)cn2)CC1
Temperature: 120 °C
Yield: 87.5 %

Procedure:
Tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (222 mg) and 5-bromo-3-(6-fluorooxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine (140 mg), bis(triphenylphosphine) palladium (II) chloride (15.9 mg) and caesium fluoride (172 mg) were weighed out in a microwave vial and sealed. Methanol (2 ml) was added and nitrogen was bubbled in the resulting suspension. The resulting mixture was heated in a 300 W microwave at 120° C. for 20 minutes. The crude product was purified by flash chromatography on silica gel (dried deposit with silica gel) eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(6-fluorooxazolo[4,5-b]pyridin-2-yl)-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (190 mg). NMR Spectrum: (CDCl3) 1.49 (s, 9H), 1.94-2.03 (m, 2H), 2.16-2.24 (m, 2H), 2.84-3.00 (m, 2H), 3.28 (bs, 2H), 3.29-3.37 (m, 1H), 6.94 (bs, 2H), 7.66 (dd, 1H), 7.68 (s, 1H), 7.79 (s, 1H), 8.35 (d, 1H), 8.45 (d, 1H), 8.48 (dd, 1H); Mass spectrum: M+H+ 480.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Cl.Br[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.[Cl:51][C:52]1[CH:53]=[C:54]([NH:58][C:59]([C:61]2[N:62]=[C:63]([CH3:67])[S:64][C:65]=2[NH2:66])=[O:60])[CH:55]=[CH:56][CH:57]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:51][C:52]1[CH:53]=[C:54]([NH:58][C:59]([C:61]2[N:62]=[C:63]([CH3:67])[S:64][C:65]=2[NH:66][C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[O:60])[CH:55]=[CH:56][CH:57]=1
Reactant: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(N)s1
Reactant: Brc1ccncc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(Nc2ccncc2)s1
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
Dry dioxane (1.00 ml) was added to a sealed microwave vial containing a mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.015 g, 0.026 mmol), palladium dibenzylideneacetone chloroform complex (0.008 g, 0.008 mmol), 4-bromopyridine hydrochloride (0.03 g, 0.15 mmol), 5-amino-2-methyl-thiazole-4-carboxylic acid (3-chlorophenyl)-amide (0.05 g, 0.19 mmol) and cesium carbonate (0.18 g, 0.54 mmol). The mixture was stirred for 10 min, then irradiated in a microwave oven at 150° C. for 10 min. The volatiles were then removed under vacuum, and the residue was purified by flash chromatography (dichloromethane/methanol), yielding the title compound (0.005 g, 9%), as a yellow solid, MS (ISP): m/e=345.5 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:30]=[C:22]3[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:27]([N:24]1[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:33]5[CH2:45][CH2:44][N:36]6[C:37]7[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=7[CH:43]=[C:35]6[C:34]5=[O:46])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:30]=[C:22]2[CH2:23]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A mixture of 209e (150 mg, 0.24 mmol) and lithium hydroxide (58 mg, 2.4 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and diluted with water (4 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 209 (75 mg, 53%) as a white solid. MS-ESI: [M+H]+ 583.3. 1H NMR (500 MHz, T=80° C., DMSO-d6) δ 8.44 (d, J=8.5 Hz, 1H), 7.93-7.90 (m, 2H), 7.34 (d, J=4.5 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 5.98 (s, 1H), 4.72-4.63 (m, 3H), 4.45-4.43 (m, 2H), 4.16-4.10 (m, 3H), 3.99-3.86 (m, overlap, 5H), 3.58 (s, 3H), 2.62-2.57 (m, 2H), 2.49-2.47 (m, 2H), 2.08 (s, 3H), 1.83-1.77 (m, 2H), 1.72-1.68 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([O:21][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=3)[CH:14]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3cccc(O)c3)c2)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(3-(tert-butoxycarbonyloxy)phenyl)benzoate 0.12 g and cesium carbonate 0.25 g were added 3-iodophenol 0.14 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.4 mg, tris(dibenzylideneacetone)dipalladium(0) 2.9 mg and palladium acetate 1.4 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.4 mg, tris(dibenzylideneacetone)dipalladium(0) 2.9 mg and palladium acetate 1.4 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=3:1] to give tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-((3-hydroxyphenyl)amino)benzoate.