Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:48]=[N:47][CH:46]=[C:45]2[NH:49][CH:50]=[CH:51][C:44]=12>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.[Cu]I>[CH3:41][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:26][C:9]3[N:10]=[C:11]([C:43]4[CH:48]=[N:47][CH:46]=[C:45]5[NH:49][CH:50]=[CH:51][C:44]=45)[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]=3[N:28]=2)[CH2:31][CH2:32]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: Brc1cncc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cncc5[nH]ccc45)nc3s2)CC1
Temperature: 140 °C
Yield: 9.6 %

Procedure:
A mixture of 2-[4-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide (167 mg, 0.24 mmol), 4-bromo-1H-pyrrolo[2,3-c]pyridine (62 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 10 mol %) and CuI (55 mg, 0.28 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 15:85) to give 131 as an pale yellow solid (12 mg, 10%). LCMS (Method F): RT 4.70 min, [M+H]+ 522.2. 1H NMR (DMSO, 400 MHz): δ 11.94 (s, 1 H); 9.10 (s, 1 H); 8.88 (s, 1 H); 7.82 (s, 1 H); 7.35 (s, 1 H); 7.15 (s, 1 H); 7.04 (s, 1 H); 4.37 (s, 4 H); 3.95 (s, 2 H); 3.82 (t, J=4.6 Hz, 4 H); 2.68 (s, 4 H); 2.56 (s, 4 H); 1.13 (s, 6 H)
Reaction SMILES: [CH:1]12[CH:6]([CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.[CH2:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)[CH3:39]>C(Cl)Cl>[CH2:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:2]2)=[O:45])=[CH:42][CH:41]=1)[CH3:39]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(C(=O)N2CC3C(C2)C3CN(C(=O)c2cccs2)c2ccc(N3CCOCC3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a stirring solution of thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide (50 mg, 0.13 mmol) in 3 mL of anhydrous CH2Cl2, was added DIEA (0.065 mL, 0.37 mmol), followed by 4-ethylbenzoyl chloride (0.02 mL, 0.14 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated NaHCO3, and extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated. The resulting crude material was purified via flash chromatography with 75% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 50 mg of a clear colorless oil. 400 MHz 1H NMR (CDCl3) δ 7.25-7.28 (m, 3H), 7.14-7.16 (m, 2H), 6.82-6.92 (m, 4H), 6.76-6.78 (m, 1H), 4.02-4.09 (m, 1H), 3.84-3.91 (m, 5H), 3.48-3.54 (m, 2H), 3.37-3.44 (m, 2H), 3.08-3.11 (m, 4H), 2.60 (q, 2H), 1.45 (s, 2H), 1.16-1.19 (m, 3H), 0.82-0.85 (m, 1H); MS (M+1) 534.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[H-].[Na+].Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc2ccc(Cl)nn2c1=O
Temperature: 90 °C

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971)] (1, 1.00 g., 5.9 m.mole) in dry DMF (30 ml.) was added sodium hydride (50% in paraffin, 0.3 g., 6.3 m.mole) under stirring with formation of yellow crystals. To the mixture was added ethyl chloroacetate (1.4 ml., 13 m.mole) and the mixture was heated at 90° C. for 8 hours with stirring. After cooling, the reaction mixture was poured into water (50 ml.) and extracted with toluene (5 × 40 ml.). The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure. The residue was crystallized with benzene-n-hexane to give yellow needles of 2 (1.16 g., 77%), m.p. 114°-115° C. (lit. 110° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][C:28]([F:31])=[CH:29][CH:30]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Li+]>CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][C:28]([F:31])=[CH:29][CH:30]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 87 %

Procedure:
To N-[(4aR,7aR)-6-(5-fluoropyrimidin-2-yl)7a-(5-fluorothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (391 mg, 855 μmol) is added methanol (8.5 mL) and lithium hydroxide (179 mg, 4.27 mmol). The solution is heated to reflux for 2.5 hours under an atmosphere of nitrogen. The resulting solution is allowed to cool for a few minutes then concentrated under reduced pressure. The residue is extracted with dichloromethane (30 mL) and water (30 mL). The phases are partitioned and the aqueous phase further extracted with dichloromethane (1×30 mL). The combined dichloromethane extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol, gradient from 99:1 to 90:10, to give the title compound (263 mg, 87%) as an amorphous white foam. ES/MS (m/e): 354.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([OH:17])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42]([O:44][CH2:45][CH2:46]Br)[CH3:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH2:43][CH2:42][O:44][CH2:45][CH3:46])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1
Reactant: CN1CCN(Cc2csc(C(=O)Nc3c(O)cc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 60 °C

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide (2.0 g, 3.6 mmol) in DMF (20 mL) were added cesium carbonate (8.0 g, 25 mmol) and 2-bromoethyl ethyl ether (0.71 g, 4.6 mmol). The suspension was heated at 60° C. for 16 hours. The mixture was cooled to ambient temperature and filtered, and the filtrate was acidified with trifluoroacetic acid. Purification by HPLC on a C18 Dynamax column acetonitrile in water gradient with 0.1% trifluoroacetic acid afforded N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamide, trifuoroacetic acid salt as a white solid; NMR (DMSO-d6/TFA) 11.9 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s, 2), 4.2 (t, 2), 3.7 (t, 2), 3.5 (q, 2), 3.5 (br, 8), 2.9 (s, 3), 1.0 (t, 3) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1cccc(C2CCCN2)c1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1cccc(F)c1

Procedure:
The title compound, white solid, m.p. 126° C. and MS: m/e=339 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH2:29][CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:28]([O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH2:29][CH3:30]
Reactant: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.92 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{[-1-(2-chlorophenyl)propyl]oxy}thiophene-2-carboxamide in 35 ml THF is cooled to 0° C. At 0° C. 1.25 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH:6]3[CH:7]([CH:9]4[CH2:10][CH2:11]4)[CH2:8][NH:4][CH2:5]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Fc1ccc(C2CCN(CC3CNCC3C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.2 g (0.58 mmol) of 1-allyl-3-(RS)-(4-(4-fluoro phenyl)piperidinylmethyl)-4-(SR)-(cyclopropyl)pyrrolidine and 0.02 g (0.02 mmol) of Wilkinson's catalyst [Rh(PPh)3Cl] in 10 mL of an 90% solution of CH3CN and water in a Dean-Stark apparatus was heated at reflux and stirred for 3 h. The reaction mixture was cooled to rt and concentrated. The residue was purified by chomatography (silica, CHCl3: MeOH: NH3, 90: 10:1) to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][C:14]([N:18]4[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:19]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:32])=CC=1>C(O)(C(F)(F)F)=O>[C:28]([C:20]1[CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9](=[O:32])[CH:10]=[CH:11]3)[N:19]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2[nH]c(=O)ccc2c1
Yield: 89.3 %

Procedure:
A solution of ethyl 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3-t-butyl-1 H-pyrazole-5-carboxylate (1.5 g, 3.3 mmol) in TFA (25 mL) was heated in a sealed tube at 100° C. for 7 h. The mixture was cooled, concentrated and purified by silica gel column chromatography to yield ethyl 3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazole-5-carboxylate (1.0 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J=9.6 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.66 (dd, J=2.4, and 8.4 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 6.94 (s, 1H), 6.82 (d, J=9.2 Hz, 1H). LC-MS (EI) m/z: 340.3 (M+H+).
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].OO.[C:12]([OH:15])(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C>[C:12]([O:15][CH2:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: Cc1cc(C)nc(C)c1
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 24 %

Procedure:
To a stirred solution of 2,4,6-collidine (3.22 g, 26.6 mmol) in glacial acetic acid (21 mL) at room temperature was added 30% H2O2 (3.0 mL) and the resultant solution was heated to 70° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H2O2 (3.0 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CHCl3 (50 mL) and treated with solid Na2CO3 (9.9 g). After 1 hour, the supernatant was decanted and the residue was washed with warm CHCl3 (3×75 mL). The combined supernatants were filtered and concentrated to provide 2.43 g as a yellow oil. The oil was dissolved in acetic anhydride (22.5 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated. The crude product was purified by flash chromatography (40 g silica gel, 2:1 hexanes/ethyl acetate) to give 1.05 g (24%) of 2-acetoxymethyl-4,6-dimethylpyridine: 1H NMR (CDCl3) □ 2.31 (s, 3H), 2.35 (s, 3H), 2.51 (s, 3H), 5.14 (s, 2H), 6.92 (s, 1H), 6.97 (s, 1H); and 0.35 g (8%) of 4-acetoxymethyl-2,5-dimethylpyridine: 1H NMR (CDCl3) □ 2.15 (s, 3H), 2.53 (s, 6H), 5.04 (s, 2H), 6.92 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH3:35])[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH3:35])[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(C)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (7.63 g), ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (3.0 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.78 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carboxylate as pale-brown crystals (8.03 g, yield 98%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:5][CH:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)N=C(c2ccccc2)NC1c1ccncc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccncc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of ethyl 4-methyl-2-phenyl-6-(4-pyridyl)-1,6-dihydro-5-pyrimidinecarboxylate (13.4 g) in chloroform (300 ml) was added activated manganese dioxide (53.6 g) and the mixture was refluxed for two hours with stirring vigorously. After allowing to cool to room temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo and the residual precipitate was recrystallized from a mixture of ether (80 ml) and petroleum ether (40 ml). The crystal was filtered off, washed with ether and dried in vacuo to give ethyl 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylate (7.5 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]([NH:39][C@H:40]([C:43]([O:45][CH3:46])=[O:44])[CH2:41]O)=[O:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[CH3:46][O:45][C:43]([C:40]1[NH:39][C:37](=[O:38])[N:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:35][CH2:34]2)[CH:41]=1)=[O:44]
Reactant: COC(=O)[C@H](CO)NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dess-Martin periodinane (1.77 g, 4.16 mmol) was added to a solution of methyl N-({[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}carbonyl)serinate (1.15 g, 3.33 mmol) in dichloromethane (30 mL) at 0° C. and then warmed to ambient temperature. After 4 h, the reaction was quenched with a 1:1 mixture of saturated sodium thiosulfate and sodium bicarbonate solution. The mixture was extracted with dichloromethane (2×) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→12% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH:14][C:15]3[CH:19]=[CH:18][S:17][C:16]=3[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
To a solution of 2,3-dihydro-1H-indene-5-sulfonyl chloride (0.5 g; 2.3 mmol) in dichloromethane (5 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.3 g; 1.9 mmol) was added followed by pyridine (0.32 g; 4.0 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (50 mL) and extracted with water. The aqueous layer separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was recrystallized from acetonitrile to yield the title product as a white solid (0.3 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:44][C@H:45]1[CH2:53][O:52][CH2:51][C@H:50]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[C@@H:49]([O:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C@H:48]([CH3:67])[O:47][C:46]1=[O:68]>C(Cl)Cl>[OH:1][C:2]1[C:3]([C:10]([NH:44][C@H:45]2[CH2:53][O:52][CH2:51][C@H:50]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=3)[C@@H:49]([O:62][CH2:63][CH:64]([CH3:65])[CH3:66])[C@H:48]([CH3:67])[O:47][C:46]2=[O:68])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(C[C@H]2COC[C@H](N)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccc(C)cc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.8 %

Procedure:
To a mixture of 3-hydroxy-4-methoxypicolinic acid (0.198 g, 1.17 mmol), HATU (0.47 g, 1.25 mmol), and N-methylmorpholine (0.47 g, 4.7 mmol) in CH2Cl2 (9 mL) was added (3S,7S,8R,9S)-3-amino-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-1,5-dioxonan-2-one (272 mg, 0.78 mmol), and the tan mixture was stirred at room temperature for 7 h. The resulting homogeneous solution was adsorbed to Celite® and purified by flash chromatography (SiO2, 0→30% acetone/hexanes) to give 3-hydroxy-N-((3S,7S,8R,9S)-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-2-oxo-1,5-dioxonan-3-yl)-4-methoxypicolinamide (0.30 g, 77%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.09 (d, J=2.1 Hz, 4H), 6.85 (d, J=5.2 Hz, 1H), 5.01 (m, 2H), 4.02 (dd, J=11.7, 7.3 Hz, 1H), 3.92 (s, 3H), 3.46 (m, 4H), 3.34 (dd, J=8.3, 6.5 Hz, 1H), 3.13 (m, 2H), 2.31 (s, 4H), 1.93 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.15, 168.90, 155.31, 148.71, 140.62, 136.76, 135.58, 130.20, 129.15, 129.05, 109.56, 84.61, 79.28, 75.92, 72.53, 72.16, 56.08, 51.53, 47.47, 34.60, 29.20, 21.03, 19.50, 18.83; HRMS-ESI (m/z) [M+H]+ calcd for C27H36N2O7, 500.2523. found, 500.2529.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(Br)cn2)C1
Yield: 27.3 %

Procedure:
Dissolve 5-bromo-2-fluoro-pyridine (5.20 g, 29.53 mmol), and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.50 g, 29.53 mmol) in acetonitrile (100 mL) and reflux with K2CO3 (8.90 g, 64.96 mmol) for 3 h. Filter the reaction mixture and wash with EtOAc (100 mL). Concentrate the filtrate and purify the resulting crude material by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 2.76 g (27%) of the title compound. LC-MS/ES m/z (81Br) 344.3 [M+H]+.