Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][C:28](O)=O.N[C@H]([C:40]([OH:42])=[O:41])CCCC.C1(O)C=CC=CC=1.C([SiH](C(C)C)C(C)C)(C)C.C(O)(C(F)(F)F)=O>CS(C)=O.O>[NH2:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH2:28][C:40]([OH:42])=[O:41]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCC[C@H](N)C(=O)O
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
Synthesis of Diamine- and Gd-Substituted Aβ Derivatives. Aβ1-30, with the sequence Ahx (Fmoc-6-aminohexanoic acid)-DAEFRHDSGYEVHHQKLVFFAEDVGSNKGA (SEQ ID NO:5), was synthesized on an ABI 433 (Foster City, Calif.) peptide sythesizer using HBTU activation and the manufacturer's suggested synthesis protocols. The starting resin was Ala-NovaSyn TGA (Calbiochem-Novabiochem, San Diego, Calif.). Glutamic acid residues 3, 11, and 22 were synthesized with N-α-Fmoc-L-glutamyl-δ-N-(4-aminobutyl)carbamic acid tert-butyl ester (3b), and aspartic acid residues 7 and 23 were synthesized with N-α-Fmoc-L-aspartyl-γ-N-(4-aminobutyl)carbamic acid tert-butyl ester described above. After completion of the synthesis and final Fmoc deprotection, diethylenetriaminepentaacetic acid anhydride (DTPA) was added to the N-terminal Ahx residue by dissolving 120 mg of the DTPA in 2 ml of DMSO/8 ml DMF and reacting the DTPA solution with the peptide-resin, which had been washed previously with DIEA/DCM. The coupling of DTPA was allowed to proceed overnight at RT. Completion of the reaction was verified by a negative ninhydrin reaction. The Aβ1–30 peptide was then cleaved from the resin support using 5% crystalline phenol, 5% water, 2.5% triisopropylsilane, and 87.5% TFA for two hours at RT. The peptide was purified by reverse-phase HPLC on a C18 Jupiter column (250 mm×21.2 mm, Phenomonex Corp) using a gradient system of 0.1% aqueous TFA containing 80% acetonitrile. The calculated mass weight 3390 amu of for Aβ1–30 and 4231 amu for DTPA-[N-4ab/Q-4ab]Aβ30 was confirmed by electrospray ionization mass spectrometry (Sciex API 165). The element Gadolinium (Gd) was chelated at equal mole concentration to the DTPA functional group of the Aβ1–30 peptide using Gd(III) chloride hexahydrate (Sigma) in water at RT for one hour (now designated as Gd[N-4ab/Q-4ab]Aβ30) (FIG. 1). All Aβ peptides were labeled with 125I/131I using a modified chloramine T procedure as described previously (Poduslo, J. F., et al., Neurobiol. Dis. 4:27–34, 1997).
Reaction SMILES: [NH2:1][C:2](=[O:22])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=2)[N:9]=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=1)[CH3:4].[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2](=[O:22])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:13]=2)[N:9]=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=1)[CH3:4]
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(-c2ccnc(F)c2)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccnc(Oc3ccc(F)cc3)c2)n1)C(N)=O
Temperature: 160 °C
Yield: 50.5 %

Procedure:
A mixture of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(2-fluoropyridin-4-yl)pyrimidine-4-carboxamide (60 mg, 0.2 mmol), 4-fluorophenol (40 mg, 0.2 mmol) and Cs2CO3 (76 mg, 0.2 mmol) in DMF (1 mL) was placed in a microwave reaction vial and heated in a microwave oven at 160° C. for 20 minutes. The reaction was worked up with DCM then dried and evaporated. The residue was subjected to C18 flash chromatography using acetonitrile/H2O/0.1 TFA as the eluent and neutralized to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(2-(4-fluorophenoxy)pyridin-4-yl)pyrimidine-4-carboxamide as white solid (40 mg, yield 50%). 1H NMR (CD3OD): 7.90-8.21 (3H, m), 6.90-7.2 (5H, m), 4.4 (1H, m), 1.35 (3H, d, J=7.0 Hz). LC/MS: m/z=398 [M+H]+.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:21])([F:20])[CH2:15][CH2:16][C:17](Cl)=[O:18].Cl>C(OCC)C.C(O)C.C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([C:17](=[O:18])[CH2:16][CH2:15][C:14]([F:21])([F:20])[F:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(=O)CCC(F)(F)F)C(=O)OCC
Temperature: 55 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 20.35 g of magnesium (turning) and 148 ml of ethanol, 0.1 ml of carbon tetrachloride was added and heated to 55° C. To the mixture, a mixed solution of 197 ml of ethanol, 700 ml of diethyl ether and 168 g of diethyl malonate was added dropwise over one hour. After 2 hours, the reaction solution was cooled to -5° C. under a nitrogen flow and 112 g of 4,4, 4-trifluorobutyryl chloride was added. After the temperature was returned to ambient temperature over one hour, the reaction was further conducted for 12 hours. The reaction solution was poured into an aqueous 5% ice-cooled hydrochloric acid, and extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated 20 saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 179 g of 4,4,4-trifluorobutyryl-malonic acid diethyl ester (b.p.: 125°-134° C., 15 mmHg) (yield: 90%). 1H-NMR (CDCl3, internal standard TMS); δ value (ppm): 1.32 (t, 3H), 2.50 (m, 2H), 2.95 (t, 2H), 4.29 (q, 2H), 4.50 (s, 1H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:18]1([CH:24]([NH2:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:26][CH:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:25])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(N)c1ccccc1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NC1CCC(Nc2ccc3[nH]ncc3c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 1-phenylethylamine (61 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (20 mg) and a syn-form compound (15 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:7]=1I)(=[O:4])=[O:3].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>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>[CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:7]=1[CH:22]=[CH2:23])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NS(C)(=O)=O)c(I)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Reaction time: 4 h
Yield: 98.6 %

Procedure:
tert-Butyl N-[4-(methanesulfonylamino)-3-iodobenzyl]carbamate (1.0 g, 2.3 mmol) was dissolved in toluene (20 mL). Tributyl vinyltin (0.8 mL, 2.8 mmol) and Pd(PPh3)4 (140 mg, 0.12 mmol) were dropwisely added. The reaction mixture was stirred for 4 hrs in reflux. Toluene was removed in vacuo. The residue was extracted with EtOAc. A combined organic layer was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with column chromatography (EtOAc: n-hexane=1:2) to yield title compound (740 mg, 97%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1(C(OC(C)(C)C)=O)[CH2:17][CH:16]1[C:18]1[C:28]([F:29])=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([F:30])[C:19]=1[F:31])=[O:14])(C)(C)C.C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:13]([CH:15]1[CH2:17][CH:16]1[C:18]1[C:28]([F:29])=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([F:30])[C:19]=1[F:31])([OH:14])=[O:12]
Reactant: CCOC(=O)c1cc(F)c(C2CC2(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
18 ml of trifluoroacetic acid was added to 9.3 g of ethyl 4-(2,2-di-tert-butoxycarbonylcyclopropyl)- 2,3,5-trifluorobenzoate. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was directly heated with a burner for about 20 seconds to complete decarboxylation. To the reaction mixture were added 100 ml of diethyl ether and 200 ml of water in this order. The resulting mixture was adjusted to pH 9.5 with a 10% aqueous sodium carbonate solution. The aqueous layer was separated and 100 ml of diethyl ether was added thereto. The resulting mixture was adjusted to pH 1.5 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.30 g (yield: 54.7%) of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])[C:7]([CH3:20])([CH3:19])[CH2:6]1)[CH:2]=[CH2:3].[CH3:21][SiH:22]([CH3:24])[CH3:23]>C(O)(C)C>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][O:13][N:8]1[C:7]([CH3:20])([CH3:19])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: C=CCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Reactant: C[SiH](C)C
Solvent: CC(C)O
Product: CC(C)(O)CON1C(C)(C)CC(OCCC[Si](C)(C)C)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound prepared in Example 17 with trimethylsilane and hydrogen hexachloroplatinate(lV) in isopropyl alcohol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH2:12][NH2:13])[CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]=1[CH3:34].C(N(CC)CC)C.O>C(OCC)(=O)C>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][CH2:12][C@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]=1[CH3:34]
Reactant: NC[C@H]1CCCN1C1CCOCC1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2C2CCOCC2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A mixture of [(2R)-1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinyl]methylamine (preparation 157) (460 mg, 2.50 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17), and triethylamine (870 ml, 6.24 mmol) in ethyl acetate (8 ml) was heated under reflux for 18 hrs, then cooled. Water (1.5 ml) was added, the reaction mixture dried over MgSO4, and filtered through celite, washing the filter pad well with ethyl acetate. The combined filtrates were concentrated under reduced pressure and the residue purified by column chromatography on silica gel using hexane:ethyl acetate (50:50) as eluant to give the desired product as a white solid, (970 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 15.3) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.11 min, UPLC-MS (Condition 3) tR=1.23 min, m/z=480.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[N:16]=[C:15]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:13][C:12]=1[CH2:43][CH2:44][CH2:45]O)[NH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:39])=[O:40])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[CH2:43][CH2:44][CH2:45][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCCO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CCC4)cc12

Procedure:
To a solution of 5-(6-(4-fluoro-1H-indol-2-yl)-5-(3-hydroxypropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (153 mg, 0.237 mmol) and triphenylphosphine (62.2 mg, 0.237 mmol) in THF was added diisopropyl azodicarboxylate (0.046 mL, 0.237 mmol). The resultant mixture was stirred at ambient temperature for 10 h then was concentrated in vacuo and the residue purified by silica gel column chromatography using a step gradient of 0-50-100% EtOAc/Hexanes as eluent. 1H NMR δ (ppm) (CHCl3-d): 8.07 (1H, s), 8.02 (2H, dd, J=8.61, 5.32 Hz), 7.75 (1H, d, J=7.78 Hz), 7.70 (1H, s), 7.60 (1H, d, J=7.77 Hz), 7.26˜7.0 (4H, m), 7.09 (1H, s), 6.85˜6.81 (1H, m), 5.98 (1H, br s), 4.23 (2H, t, J=6.66 Hz), 3.35 (3H, s), 3.03 (3H, d, J=4.90 Hz), 2.85 (2H, t, J=7.00 Hz), 2.80 (3H, s), 2.47˜2.42 (2H, m), MS (M+H)+: 627.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH:10]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]2[O:18][C:17]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(OC)cc1)C(=O)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(OC)cc2)oc1-c1ccco1
Yield: 31.7 %

Procedure:
To a solution of 10 g of ethyl 3-(4-methoxybenzoylamino)-3-(2-furylcarbonyl)propionate in 60 ml of chloroform are dropwise added 15 ml of thionyl chloride at room temperature. The mixture is refluxed at 60° to 70° C. for 6 hours under stirring. After the reaction is completed, the mixture is treated in the same manner as described in Example 1. 3.0 g of ethyl 2-[2-(4-methoxyphenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 31.6%
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:25])[O:7]1)(=[O:3])[CH3:2].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(C#N)(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH:25][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[O:7]1)(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: CC(=O)C#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)Nc4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate (0.200 g, 0.572 mmol) in AcCN (3 mL) was added phenylisocyanate (0.068 g, 0.572 mmol) dropwise. The white mixture was stirred for two hours at ambient temperature, overnight at 50° C. and then concentrated to give the title compound (0.268 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20].N1C=CC=CC=1>C(O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:18])[CH2:19][OH:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: OCC1CO1
Solvent: c1ccncc1
Solvent: CCO
Product: OCC(O)COc1ccccc1OCc1ccccc1
Yield: 72.8 %

Procedure:
A solution of 49.6 g (0.248 mole) of 2-benzyloxyphenol, 22.2 g (0.3 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux overnight. The dark solution was concentrated to give an oil which gradually crystallized. The solid was purified by column chromatography on 1.2 kg of silica gel eluted with 0-25% acetone in benzene. Appropriate fractions were combined and concentrated to yield 49.5 g (73%) of the title compound as a white solid, mp 84°-85° C. (carbon tetrachloride) (lit.1 mp 81°-82.5° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]Br>N1C=CC=CC=1>[Br:9][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrBr
Solvent: c1ccncc1
Product: Cc1ccc(O)c(Br)n1
Reaction time: 1.5 h

Procedure:
To a solution of 5-hydroxy-2-methyl pyridine (20 g, 183.2 mmol) in dry pyridine (350 mL) was added a solution of bromine (10.3 mL, 201.5 mmol) in dry pyridine (100 mL) dropwise. After 1.5 h, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with water (160 mL) and filtered. The resultant pale solid was washed with water (300 mL) and air dried. The crude product was recrystallized in EtOH (200 mL) to give the title compound as a solid.
Reaction SMILES: [O-]CC.[Na+].[H-].[Na+].[NH2:7][C:8]([NH2:10])=[S:9].C([O:13][C:14](=O)[CH:15]([C:24]#[N:25])[CH2:16][C:17]1([CH2:22][CH3:23])[O:21][CH2:20][CH2:19][O:18]1)C>C(O)C>[NH2:25][C:24]1[NH:10][C:8](=[S:9])[NH:7][C:14](=[O:13])[C:15]=1[CH2:16][C:17]1([CH2:22][CH3:23])[O:18][CH2:19][CH2:20][O:21]1
Reactant: CCOC(=O)C(C#N)CC1(CC)OCCO1
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(Cc2c(N)[nH]c(=S)[nH]c2=O)OCCO1
Temperature: 75 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a 60° C. solution of sodium ethoxide, prepared from 1.92 g (80 mmol) of sodium hydride and 60 of ethanol, was added 6.09 g (80 mmol) of thiourea and 18.2 g (80mmol) of α-cyano-2-ethyl-1,3-dioxolane-2-propanoic acid ethyl ester. The mixture was heated to 75° C. for 4 hours then allowed to cool to ambient temperature and stirred for 18 hours. The reaction was then concentrated to a solid. The solid was dissolved in 100 mL of water and the solution adjusted to pH 6.9 with glacial acetic acid which caused a solid to precipitate. The solid was collected by filtration and washed with 100 mL of water. The wet cake was combined with 60 mL of ethanol and stirred for 15 minutes. The remaining solids were collected by filtration, washed with 40 mL of ethanol, and dried in vacuo (40° C., 10 torr) to provide 11.0 g (53.4%) of 6-amino-5-(2-ethyl-1,3-dioxolan-2-ylmethyl)-2-thiouracil as a cream colored solid. nmr (500 MHz, dmso-d6) δ0.80 (t, J=7.4 Hz, 3H), 1.51 (q, J=7.4 Hz, 2 H), 2.51 (s, 2H), 3.81 (m, 2H), 3.92 (m, 2H), 5.95 (s, 2H), 11.43 (s, 1H), 11.69 (s, 1H)
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23])[CH:12]=O.C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:10][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC#CCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCC#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.5 %

Procedure:
Piperidine (0.17 mL, 1.7 mmol) was added to a suspension of 3-methoxy-4-(hex-3-ynyloxy)benzaldehyde (0.40 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.35 g, 1.6 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(4-(hex-3-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.40 g, 65%) as a colourless crystalline solid; mp 165-166° C.; δH (400 MHz, DMSO-d6) 1.04 (t, J=7.6 Hz, 3H, CH3), 2.14 (q, J=7.6 Hz, 2H, CH3CH2), 2.61 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.83 (s, 3H, OCH3), 4.05 (t, J=7.6 Hz, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 14.0, 19.2, 55.7, 66.9, 76.1, 83.0, 110.9, 113.0, 116.6, 120.1, 120.3, 122.5, 122.6, 127.6, 131.1, 134.0, 141.0, 141.5, 149.1, 149.5, 164.1, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1647; vmax 755, 1235, 1510, 1601, 1669, 3234, 3563 cm−1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C([BH3-])#N.[Na+]>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:23])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:33]4[CH:32]=[CH:31][C:28]5[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=5[N:34]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: NC1CCN(CCN2C(=O)COc3ccc([N+](=O)[O-])cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc([N+](=O)[O-])cc54)CC3)nc2N1
Yield: 7 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-nitro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 81), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 7% yield.