Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1O[C@H](CO)CN1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at 25° C., and the resulting reaction mixture was stirred at 25° C. for 2 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled down to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried in vacuo to afford the crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1019: 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz); C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1[CH:21]=[C:11]2[N:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:10]2[N:9]=1.O>ClCCl>[OH:6][CH2:7][C:8]1[CH:21]=[C:11]2[N:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:10]2[N:9]=1
Reactant: CCOC(=O)c1cnc2cc(COC)nn2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(CO)nn2c1
Temperature: 0 °C
Yield: 101 %

Procedure:
Ethyl 2-formyl-3-oxopropionate (775 mg) was added to a solution of the thus obtained 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg) in ethanol (50 ml), and stirred overnight. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to the residue which were then extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (878 mg, Y.:69%). 1 M Boron tribromide solution in dichloromethane (0.51 ml) was added dropwise at −70° C. to a solution of the thus obtained ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (20 mg) in dichloromethane (2 ml). The temperature of the mixture under stirring was increased from −70° C. to −50° C. over 4.5 hours and then increased from −50° C. to room temperature over 2 hours. The reaction mixture was cooled to 0° C., water was added to the reaction mixture which was then extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give ethyl 2-hydroxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (19 mg, Y.:quant.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:18]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl imidazole-4-carboxylate (1.4 g), triethylamine (1.2 g) and chloroform (20 ml) was stirred at room temperature while trityl chloride (3.06 g) was added, and the mixture was stirred at room temperature for 1 h. The resulting solution was washed with water, dried and evaporated to dryness under reduced pressure, and the residue was crystallised from a mixture of ethyl acetate and cyclohexane, to give ethyl 1-tritylimidazole-4-carboxylate, mp 163°-164°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]C)=O)[N:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:1]1[CH:5]=[C:4]([C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[NH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1c[nH]cn1
Product: O=C(c1cnc[nH]1)N1CCCC1

Procedure:
A solution of methyl 4-imidazolecarboxylate (CAS#17325-26-7, 460 mg, 3.6 mmol), and pyrrolidine (7 mL) is heated by microwave irradiation at 110° C. for 3.5 hours in a sealed vessel. The reaction is then concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:10) to furnish (3H-imidazol-4-yl)-pyrrolidin-1-yl-methanone; MS: (ESI) m/z 166.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[N+](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][O:3]1
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Reactant: CC1(C)OCC(CO)O1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1OCC1COC(C)(C)O1
Temperature: 85 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Rhodium acetate dimer (30 mg) was added to a solution of solketal (0.87 ml) and ethyl 3-diazoindole-2-carboxylate (3 mg) in dichloroethane (10 ml), and stirred at 85° C. for 3 hours. The reaction was concentrated in vacuo and the residue purified by column chromatography using a gradient of 0% to 20% ethyl acetate:iso-hexane as eluent to afford the product as a pale yellow solid (435 mg, 97%); NMR d (CD3SOCD3) 1.27-1.38 (m, 9H), 3.88 (m, 1H), 4.11 (m, 3H), 4.30 (q, 2H), (m, 1H), 7.01 (t, 1H), 7.24 (t, 1H), 7.36 (d, 1H), 7.65 (d, 1H), 11.27 (s, 1H); M/z (+) 320.3 (MH+).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(O)C>[CH2:5]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:2]=[CH2:1])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C(=Cc1ccccc1)CNCc1ccccc1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCN(CC=Cc1ccccc1)Cc1ccccc1
Yield: 78 %

Procedure:
11.0 g (90 mmol) of allyl bromide were added to 10.0 g (44.8 mmol) of N-cinnamylbenzylamine in 60 ml of ethanol, and then 5.0 g (50.0 mmol) of triethylamine were added while stirring. The mixture was refluxed for 4 h. Concentration under water pump vacuum was followed by partition of the contents of the flask between methylene chloride and water, rendition alkaline with dilute sodium hydroxide solution and extraction twice more with methylene chloride. The combined organic phases were washed with dilute sodium hydroxide solution, dried and concentrated. The crude product (12.5 g) was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 98/2). 9.2 g (80%) of product (oil) were obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39]>CN(C=O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCC1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (25.7 mg, 0.078 mmol) in DMF (0.1 mL) at room temperature was added sodium hydride (6 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. 2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene (Enantiomer 1 from STEP D, 23.1 mg, 0.066 mmol) in DMF (0.2 mL) was added. The mixture was stirred at room temperature for 2 days. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-25% ethyl acetate in heptane) to afford the title compound (7.5 mg, 19%). 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.16 (m, 1H) 1.22-1.33 (m, 1H) 1.38-1.50 (m, 3H) 1.51-1.63 (m, 2H) 1.65-1.76 (m, 1H) 2.02-2.14 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz, 1H) 4.20-4.23 (m, 3H) 4.72 (d, J=2.49 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1) To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (27.2 mg, 0.084 mmol) in DMF (0.1 mL) at room temperature was added sodium hydride (6 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. 2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene (Enantiomer 2 from STEP D, 24.5 mg, 0.070 mmol) in DMF (0.2 mL) was added. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (18.6 mg, 45%). The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford a colorless oil (18.6 mg, 45%). 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.15 (m, 1H) 1.23-1.33 (m, 1H) 1.38-1.63 (m, 5H) 1.66-1.75 (m, 1H) 2.03-2.11 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz 1H) 4.21 (s, 3H) 4.72 (d, J=2.90 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:15]=1
Reactant: N#Cc1cccnc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccnc2)sc2ccccc12
Yield: 43.3 %

Procedure:
Methyl thiosalicylate (1.8 g, 10.7 mM) and 3-cyanopyridine (1.1 g, 10.56 mM) were dissolved in toluene (5 ml), and then triethylamine (2 ml, 14.4 mM) was added thereto. After heating the mixture under reflux for 48 hours, the same processes as described in Reference Example 1 were performed to give the title compound as crystals (1.1 g, 43.4%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([CH2:58][CH3:59])=[CH:54][CH:53]=4)=[CH:49][S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl.CO>ClCCl>[CH2:58]([C:55]1[CH:54]=[CH:53][C:52]([CH2:51][C:48]2[C:45]3[C:44](=[CH:43][C:42]4[CH2:41][O:40][C@:10]5([C:47]=4[CH:46]=3)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]5)[S:50][CH:49]=2)=[CH:57][CH:56]=1)[CH3:59]
Reactant: CCc1ccc(Cc2csc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2csc3cc4c(cc23)[C@]2(OC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-spiro[thieno[2,3,f]isobenzofuran-5(7H),2′-[2H]pyran] (34.1 mg, 0.042 mmol) was dissolved in dichloromethane (1.4 mL). To the resultant solution was added pentamethylbenzene (94.3 mg, 0.636 mmol), and then the solution was cooled to −78° C. Boron trichloride (1.0 M dichloromethane solution, 0.212 mL) was added dropwise, and the solution was stirred for 3 hours. To the solution was then added methanol (1.5 mL) to stop the reaction. The temperature of the solution was raised to room temperature. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (2:25)), and the resultant product was then further isolated and purified by reverse phase HPLC (developing solution=acetonitrile:water (35:65 to 100:0)), to thereby obtain the titled compound (13.3 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7]2.[Li]C(C)(C)C.C(=O)=O.[C:27](OC)(=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.CCOC(C)=O>[CH3:31][O:30][C:28](=[O:29])[C:27]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7]2)=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2cccc(Br)c21
Reactant: COC(=O)C(=O)OC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cccc2ccn(COCC[Si](C)(C)C)c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A solution of 7-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole (3.0 g, 9.19 mmol) in THF (100 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentanes (15 mL, 25.5 mmol) added dropwise over 15 min. After 15 min, the resultant bright yellow suspension was transferred over 15 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (3.61 g, 30.6 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 3 h. The cloudy yellow mixture was treated with pH 7.0 buffer, poured into-EtOAc and the EtOAc washed with pH 7.0 buffer (brine was added to clarify the layers), brine, dried (MgSO4) and concentrated to a cloudy oil. Flash chromatography (10% EtOAc/hexanes) afforded the title compound (2.59 g, 84%) as a bright yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.97 (dd, J=8, 1 Hz, 1H), 7.64 (d, J=3 Hz, 1H), 7.57 (dd, J=8, 1 Hz, 1H), 7.24 (dd, J=8, 8 Hz, 1H), 6.68 (d, J=3 Hz, 1H), 5.59 (s, 2H), 3.91 (s, 3H), 3.04 (t, J=8 Hz, 2H), 0.62 (t, J=8 Hz, 2H), −0.17 (s, 9H). 13C NMR (75.5 MHz, DMSO-d6) 185.17, 163.31, 132.59, 131.60, 130.87, 127.19, 126.15, 120.09, 118.95, 102.40, 77.05, 63.92, 52.83, 16.74, −1.69. IR (CHCl3, cm−1) 1740, 1683. HRMS 334.1481 (M++1, calcd for C17H24NO4Si 334.1475).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10](O)[N:11]=2)[N:8]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[N:8][N:7]2[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cn2nc(Cl)ccc2n1
Agent: [Na]
Product: Clc1cn2nc(Cl)ccc2n1

Procedure:
Sodium salt of 6-chloro-2-hydroxyimidazo [1,2-b]pyridazine (16.0 g) is gradually added to 100 ml of phosphorus oxychloride and heated under reflux for 5 hours. The mixture is distilled under reduced pressure to remove about two-thirds amount of phosphorus oxychloride used, and the residue is poured into ice water, neutralized with aqueous ammonia and extracted with chloroform. The extract is dried over anydrous sodium sulfate and distilled to remove chloroform. The residue then is purified by silica gel chromatography (eluent: dichloromethane) to give 1.5 g of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].[CH2:20]([CH2:22][NH2:23])[OH:21]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:23][CH2:22][CH2:20][OH:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6]
Reactant: NCCO
Reactant: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc(NCCO)c(Cl)c2)cc1O
Temperature: 140 °C

Procedure:
A solution of 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (1.0 g, 3.58 mmol, from above) in dimethylsulfoxide (5.0 mL) was treated with ethanolamine (10.0 mL) (Aldrich) and heated at 140° C. for 50 minutes in a microwave reactor. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous phase was acidified with 2N hydrochloric acid. The precipitate was filtered, washed with water and dried. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The two solid samples were combined and dried to give 3-chloro-4-(2-hydroxy-ethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide. (Yield 1.13 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]([N:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:38]([O:40][CH3:41])=[O:39])[CH:29]=2)[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:23]3[C:32]([N:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[N:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:38]([O:40][CH3:41])=[O:39])[CH:29]=4)[N:24]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccc(F)cc3)o2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(-c4ccc(F)cc4)o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 70.1 %

Procedure:
To a solution of 2-[5-(4-fluorophenyl)furan-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (442 mg, crude) in dioxane (5.5 mL) and water (3 drops) was added methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.51 mmol), K3PO4 (324.9 mg, 1.53 mmol) and Pd(PPh3)4 (29.5 mg, 0.03 mmol) with stirring for 40 min at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-[5-(4-fluorophenyl)furan-2-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as light yellow solid (150 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:25])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of ethyl 6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate (456 mg, 1.71 mmol) in anhydrous ethanol (20 ml) was added pulverized CaCl2 (395 mg, 3.42 mmol). The suspension was stirred and cooled to 0° C. and NaBH4 (325 mg, 8.55 mmol) was added slowly. The reaction was stirred at 0° C. for 2 h, quenched with water, and extracted with CHCl3 (×3). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (30→50% ethyl acetate in hexane) to yield a colorless syrup (308 mg) as a mixture containing tert-butyl[6-(hydroxymethyl)pyridin-2-yl]carbamate as the major component (˜4:1 ratio). To a solution of the above mixture in CH2Cl2 (10 ml) was added pyridine (144 μl, 1.79 mmol) and SOCl2 (120 μl, 1.65 mmol). The reaction was stirred at room temperature for 4 h, quenched with water and saturated Na2CO3, and extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexane) to yield the title compound as a colorless syrup (208 mg, 50% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[S:24][C:25]2[C:26]([N:31]=1)=[N:27][CH:28]=[CH:29][CH:30]=2.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:23]3[S:24][C:25]4[C:26]([N:31]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: Clc1nc2ncccc2s1
Reactant: COC(=O)c1coc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 6-hydroxy-benzofuran-3-carboxylic acid methyl ester (1.7 g, 8.8 mmol) in DMF (88 mL) was added Cs2CO3 (8.6 g, 1.8 mmol) followed by 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (1.8 g, 8.8 mmol) and the reaction mixture was stirred (rt, 3 h). The reaction mixture was treated with water (50 mL) to form a solid. The solid was filtered to provide the title compound as a white solid (2.5 g, 87%). MS (ESI): mass calcd. for C16H10N2O4S, 326.0; m/z found, 327.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.30 (s, 1H), 8.11 (d, J=8.6, 1H), 8.03 (dd, J=7.9, 1.6, 1H), 7.75 (d, J=2.1, 1H), 7.41 (dd, J=8.6, 2.1, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 3.97 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:8]1[C:7]2[CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
50% Oily sodium hydride (0.21 g) was suspended in N,N-dimethylformamide (5 ml), and the resultant suspension was cooled to 0° C. 6-Fluoro-5-nitro-2-(3H)-benzothiazolone (1.0 g) was portionwise added thereto at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Ethyl bromoacetate (0.86 g) was added to the reaction mixture at 0° C., and the temperature was gradually elevated to a temperature of 50° to 60° C., followed by stirring at that temperature for 3 hours. Water was added to the mixture, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and toluene (1:9) to give 0.35 g of 3-ethoxycarbonylmethyl-6-fluoro-5-nitro-2(3H)-benzothiazolone. m.p., 139.0°-140.0° C.