Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[NH2:40])=[N:34][N:33]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:40][C:39]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:35]3[O:36][C:32]([CH3:31])=[N:33][N:34]=3)[CH:38]=2)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: Cc1nnc(-c2cc(N)cc(C(F)(F)F)c2)o1
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(-c3nnc(C)o3)cc(C(F)(F)F)c2)c(F)c1
Reaction time: 2 h
Yield: 12.9 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.729 mmol), 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline (195 mg, 0.802 mmol), and Et3N (0.203 ml, 1.458 mmol) in DCM (15 ml) was added HATU (333 mg, 0.875 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixture was concentrated to give the residue which was extracted with DCM (30 mL×2). The organic extract was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=30:1, Rf=0.7) to yield 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (60 mg, 0.094 mmol, 13% yield): 1H NMR (400 MHz, MeOD-d4) δ 8.52 (br. s., 1H), 7.99 (br. s., 1H), 7.95 (br. s., 1H), 7.42-7.39 (m, 2H), 7.30 (d, J=8.4 Hz, 3H), 6.89 (d, J=8.6 Hz, 3H), 6.52-6.50 (m, 1H), 5.11 (br. s., 2H), 4.64-4.62 (m, 2H), 4.31 (d, J=7.1 Hz, 2H), 2.63 (br. s., 3H), 1.38 (t, J=7.1 Hz, 3H); ES-LCMS m/z 637 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C-]#N.[Na+].C[C:35](O)=[O:36]>CO.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]([O:36][CH3:35])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of the aldehyde of Step 6 (17.26 g, 41.7 mmol) in 1.5 L of MeOH:THF 2:1, NaCN (20 g, 408 mmol), AcOH (5.7 mL, 98.9 mmol) and activated MnO2 (90 g, 1.01 mol) were added and the mixture was stirred for 16 h. The inorganic solid was then removed by filtration and washed with EtOAc. To the combined organic phases, 25% aq NH4OAc (1.7 L) was added. The two phases were separated and the aqueous layer was reextracted with EtOAc. The organic phases were washed with brine and dried over Na2SO4. Flash chromatography of the residue on silica with toluene and EtOAc:toluene 2.5:97.5 afforded 15.63 g (84%) of the title ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[S:5][C:6]=1[C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:30]([CH2:32][NH2:33])[OH:31]>O1CCOCC1>[OH:31][CH2:30][CH2:32][NH:33][S:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]2[S:5][C:4]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[N:3][C:2]=2[CH3:1])[CH:8]=1)(=[O:15])=[O:14]
Reactant: NCCO
Reactant: Cc1nc(Nc2cnccn2)sc1-c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc(S(=O)(=O)NCCO)c1
Reaction time: 8 h
Yield: 14.3 %

Procedure:
3-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonyl chloride (42c) (0.251 g, 0.68 mmol) is dissolved in dioxane (10 ml). The solution is treated with 2M aqueous sodium carbonate (0.7 ml, 1.36 mmol) followed by the addition of ethanolamine (0.125 ml, 2.05 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is taken into water (10 ml)/ethylacetate (30 ml) and sonicated. The layers are separated then the aqueous layer is extracted with ethyl acetate (2×30 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to give a residue which is purified by prep LC-MS to give the titled compound (0.038 g, 14%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:16])=[O:4].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][Br:17])=[O:4]
Reactant: COC(=O)c1oc(-c2ccccc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1oc(-c2ccccc2)nc1CBr

Procedure:
4-Methyl-2-phenyl-oxazole-5-carboxylic acid methyl ester (3.2 g, 14.7 mmol, prepared according to Cynkowski, T.; Cynkowska, G.; Ashton, P.; and Crooks, P. A. J. Chem. Soc., Chem. Commun. 1995, 2335), N-bromosuccinimide (2.69 g, 15.1 mmol), and benzoyl peroxide (356 mg, 1.47 mmol) were suspended in 37 mL of benzene and the mixture heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to give 1.88 g of the title compound as a yellow solid. MS: (+) m/z 296.0, 298.0 (M+1, 79Br/81Br).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:8])[CH2:7][CH2:6][CH2:5]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][CH2:3][C:4]2([OH:8])[CH2:7][CH2:6][CH2:5]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an atmosphere of nitrogen, potassium tert-butoxide was added under ice-cooling to a mixture of cyclobutanone, ethyl chloroacetate and THF, spending 40 minutes, followed by stirring at 0° C. for 2 hours, raising the temperature to room temperature, and stirring at room temperature for 1 day, thereby obtaining ethyl 1-oxaspiro[2,3]hexane-2-carboxylate. A diethyl ether solution of the resulting ethyl 1-oxaspiro[2,3]hexane-2-carboxylate was added to a THF suspension of lithium aluminum hydride under ice-cooling in an atmosphere of nitrogen, followed by stirring at room temperature for 7 hours to obtain 1-(2-hydroxyethyl)cyclobutanol. A mixture of the resulting 1-(2-hydroxyethyl)cyclobutanol, 4-methylbenzenesulfonyl chloride, triethylamine and THF was stirred at room temperature for 16 hours to obtain 2-(1-hydroxycyclobutyl)ethyl 4-methylbenzenesulfonate.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30][CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C>ClCCl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30][CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
To a 25 mL of dry round bottom flask containing a solution of ethyl (2E)-3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]prop-2-enoate (300 mg, 0.67 mmol) in dichloromethane (5 mL) was added 2-nitrophenylsulfonylhydrazide (2.91 g, 13.4 mmol) followed by a solution of triethylamine (5 mL) in dichloromethane (10 mL) under nitrogen. The suspension was gently stirred for 6 hour at room temperature under nitrogen, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-40% ethyl acetate in petroleum ether) to afford 151 mg of the desired product (yield was 50%). MS obsd. (ESI+) [(M+H)+] 453.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]=1[C:13]([O:15]C)=O)=[C:2]=[S:3].[CH3:17][C:18]1[N:19]=[CH:20][N:21]([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=1>>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([CH2:23][CH2:24][CH2:25][N:26]2[C:13](=[O:15])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCC2
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCCC4)cn1

Procedure:
The compound was synthesized starting from methyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (0.109 g. 0.43 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.060 g, 0.43 mmol) as described above.
Reaction SMILES: [OH:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].[Na]>ClCCl.CN(C)C1C=CN=CC=1>[C:38]([O:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4])(=[O:40])[CH3:39]
Reactant: Cc1cc(C)cc(Cc2c(C(C)C)c(=O)[nH]c(=O)n2COCCCN(O)C(N)=O)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON(CCCOCn1c(Cc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O)C(N)=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 1-(3-N1-hydroxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil obtained in the above Example 1-C (85 mg, 0.2 mmol) in dichloromethane (3.5 ml), was added DMAP (4-dimethylaminopyridine) (5 mg, 0.04 mmol), triethylamine (45 μl, 0.3 mmol) and acetic anhydride (25 μl, 0.24 mmol) and the mixture was stirred for 3 hours at 20° C. Then, it was added thereto dichloromethane (5 ml) and an aqueous saturated sodium hydrogenocarbonate solution (5 ml). The reaction medium was then extracted with dichloromethane (50 ml) and the organic phase was washed with water (10 ml) and then with a saturated sodium chloride solution (10 ml) and dried (sodium sulfate). The organic phase was then concentrated and subjected to a flash column chromatography on silica gel (dichloromethane/methanol 9:1) to give 70 mg (75%) of the desired 1-(3-N1-acetoxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil in the form of a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][OH:36])=[CH:4][N:3]=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C.CC1C=CN=C(N)C=1C>ClCCl>[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([O:36][CH2:35][CH2:34]/[CH:33]=[CH:32]/[C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2csc3c(/C=C/CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2csc3c(/C=C/CCOS(=O)(=O)c4ccc(C)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
A solution of N-(4-{4-amino-7-[(1E)-4-hydroxybut-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.20 g, 0.40 mmol) in dichloromethane (10 mL) was treated with p-toluene sulfonyl chloride (0.100 g, 0.521 mmol), triethyl amine (0.08 g, 0.80 mmol), and dimethyl amino pyridine (0.003 g, 0.02 mmol). The reaction mixture was stirred at room temperature for 24 hours. No workup was used. The compound was purified by flash chromatography on silica gel using 1:1 ethyl acetate: heptane then 100% ethyl acetate to give 0.075 g (29%) the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.70 (m, 1H), 8.60 (d, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.30 (m, 2H), 7.21 (m, 2H), 7.19 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.60-6.50 (d, 2H), 6.15-6.10 (m, 1H), 4.95 (s, 2H), 4.20 (t, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 2.70 (q, 2H), 2.39 (s, 3H); LCMS (conditions a) Rt 4.28 min (95%), M+ 653.4.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 145 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Potassium fluoride (69.6 g; 1.2 mole) and hexadecyltributylphosphonium bromide (25.2 g; 0.04 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1 mole). After stirring at 145° C. for 24 hours and a similar work-up to Example 1, 2-fluoronitrobenzene was obtained in 91.2% yield together with 2.4% recovered 2-chloronitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)ccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
To a solution of tert-butyl 4-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (280 mg, 0.597 mmol) in CH2Cl2 (3 mL) cooled to 0° C. was added TFA (0.46 mL, 5.97 mmol). The resulting mixture was stirred for 2 h at RT. The reaction was concentrated and then partitioned between saturated NaHCO3 solution and CH2Cl2. The organic extract was dried over Na2SO4, and concentrated under reduced pressure to give the title compound (250 mg).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C[Si]([C:16]#[CH:17])(C)C>C1(C)C=CC=CC=1.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>[C:16]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)#[CH:17]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 147.4 %

Procedure:
To a solution of methyl 4-iodobenzoate (1.5 g, 5.72 mmol) and trimethylsilylacetylene (Aldrich, 1.58 mL, 11.45 mmol) in toluene (12 mL) were added Pd(PPh3)4 (0.66 g, 0.57 mmol), CuI (0.16 g, 0.86 mmol), and TEA (6.4 mL, 45.80 mmol). The resulting reaction mixture was purged with nitrogen for 3 min and stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate and NH4Cl solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% EtOAc/hexane) to afford the title compound as a white solid (1.35 g, 96%). 1H NMR (CDCl3) δ 7.98 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 3.92 (s, 3H), 0.27 (s, 9H); MS(ESI+) m/z 233.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CN1CCOCC1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(NS(C)(=O)=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a slurry of 6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (Example 11B) (14 mg, 0.035 mmol) in CH2Cl2 (2 ml) was added N-methyl morpholine (12.3 μl, 0.113 mmol) followed by MsCl (4.5 μl, 0.057 mmol). The reaction mixture was stirred overnight, 10% citric acid (3 ml) was added. The resulting mixture was extracted with CHCl3 (10 ml), the organic layer was separated and dried with Na2SO4, concentrated to give the title compound (6.9 mg, 45%). It has a retention time of 6.01 min (standard LCl method, 8 min run). MS Found: (M+H)+=434.0
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:16][C:17]1[C:22](C(C2C=NN(C)C=2C2C=CC(C)=CC=2)O)=[C:21]([Cl:38])[N:20]=[CH:19][N:18]=1>>[Cl:16][C:17]1[C:22]([CH:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH:10]=[N:11][CH:12]=2)[OH:15])=[C:21]([Cl:38])[N:20]=[CH:19][N:18]=1
Reactant: CCc1ccc(-n2cncc2C=O)cc1
Reactant: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Product: CCc1ccc(-n2cncc2C(O)c2c(Cl)ncnc2Cl)cc1

Procedure:
1-(4-Ethylphenyl)-1H-imidazole-5-carbaldehyde (C19) was converted to the product using a procedure analogous to that described for the synthesis of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanol (C4) in Example 1, step 4. The crude product, a yellow solid, was washed with a 1:1 mixture of heptane and ethyl acetate to afford the product. Yield: 473 mg, 1.35 mmol, 74%. LCMS m/z 348.9 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.29 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 6.27 (br s, 1H), 7.14-7.15 (m, 1H), 7.28-7.33 (m, 4H), 7.69 (d, J=0.7 Hz, 1H), 8.68 (s, 1H).
Reaction SMILES: C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H:58]([NH2:64])[C@@H]2O)C=CC=CC=CC=CC=CC=CC=C1.[O:66]=[CH:67][C@@H:68]([C@H:70]([C@@H:72]([C@@H:74]([CH2:76]O)[OH:75])[OH:73])[OH:71])[OH:69]>CN(C)C=O>[CH3:58][NH:64][CH2:76][C@@H:74]([C@H:72]([C@@H:70]([C@@H:68]([CH2:67][OH:66])[OH:69])[OH:71])[OH:73])[OH:75]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Solvent: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 18 h
Yield: 426 %

Procedure:
20 g of amphotericin B and 6 g of glucose was dissolved in 200 ml of dimethyl formamide and allowed to stand at a temperature of 35° C. for 18 hours. The resulting solution was filtered and 500 ml of 5% ammonium sulphate, aqueous solution, was added to the filtrate the mixture was then allowed to stand at a temperature of +40° C. for 2 hours. The precipitate was filtered and washed with water. 1500 ml of methanol at a temperature of 50° C. and 6 g of N-methylglucamine salt dissolved in 60 ml of water was added to the precipitate whereupon the mixture was stirred for 30 minutes, then 1 l of n-butanol was added. The resulting solution was evaporated at a temperature of 45° C. under reduced pressure until the methanol and water were removed. The residue was allowed to stand at a temperature of +4° C. for crystallization. The sediment was filtered, washed with n-butanol then with petroleum ether and dried at the room temperature. 18 g of the N-methylglucamine salt of N-glycosyl derivative of amphotericin B of E1 cm1% =1140 at 380 nm and IC50 =0.1 mcg/ml were obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.N1C=CN=C1.[CH:35]([Si:38]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])Cl)([CH3:37])[CH3:36].O>C(Cl)Cl>[CH:35]([Si:38]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([CH3:37])[CH3:36]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314)(C(C)C)C(C)C

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 20 ml of methylene chloride, then imidazole (0.68 g, 10 mmol) and triisopropylchlorosilane (1.92 g, 10 mmol) were added with stirring. The whole system was refluxed to react for 4 hours. After the reaction was complete, water was added for extraction and then extracted with methylene chloride for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid.