Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:41]([O:48][C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[CH:55]=[C:54]([C:59]1[N:64]=[C:63]([NH:65][C:66]3[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=3)[N:62]3[N:73]=[CH:74][CH:75]=[C:61]3[CH:60]=1)[CH:53]=[CH:52]2)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:72][C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:63]3[N:62]4[N:73]=[CH:74][CH:75]=[C:61]4[CH:60]=[C:59]([C:54]4[CH:53]=[CH:52][C:51]5[C:56](=[CH:57][CH:58]=[C:49]([O:48][CH2:41][C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[CH:50]=5)[CH:55]=4)[N:64]=3)=[CH:67][CH:68]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc5cc(OCc6ccccc6)ccc5c4)cc4ccnn34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (251 mg) and N-hydroxy-benzotriazole (HOBt)(153 mg) in DMF (10 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(575 mg) and triethylamine (0.416 ml). The mixture is stirred for 0.5 h at ambient temperature. To this solution is added N-[5-(6-benzyloxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-yl]-benzene-1,4-diamine (compound B2)(0.38 g). After completion of the reaction the mixture is evaporated at high vacuum and the residue is treated with methanol. The resulting solid is filtered and dried. A colorless solid (0.523 g) is obtained in 91% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2([CH3:22])[CH3:21])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:17][C:16]2([CH3:22])[CH3:21])=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)OC(C)(C)C)nc3)C(C)(C)C2)cc1
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of [5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.3) (3.85 g, 12 mmol), 4-methoxybenzyl bromide (2.6 mL, 18 mmol, 1.5 equiv) and triethylamine (1.83 mL, 13.2 mmol, 1.1 equiv) in DCM (25 mL) was stirred for 16 h at it and concentrated. The residue was purified by silica gel column chromatography (DCM DCM/MeOH, 97:3) to afford 1.88 g of the title compound as a white solid. Title compound: ESI-MS: 441.3 [M+H]+; tR=3.12 min (System 1).
Reaction SMILES: [O-2:1].[Cr+6:2].[O-2:3].[O-2:4].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6].O.ClC1C=C([C@@H:19](C)[C@@H:20]([O:23]S(C)(=O)=O)[CH2:21]O)C=CC=1Cl>CC(C)=O.C(O)(C)C>[CH3:19][C:20]([CH3:21])=[O:23].[OH:8][S:5]([OH:9])(=[O:7])=[O:6].[O:1]=[Cr:2](=[O:4])=[O:3]
Reactant: [O-2]
Reactant: [Cr+6]
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](CO)OS(C)(=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=[Cr](=O)=O
Reaction time: 4 h

Procedure:
Jones reagent was prepared by mixing chromium (VI) oxide (2.87 g, 28.7 mmol), sulfuric acid (2.44 mL), and water (9.5 mL) for 10 min. The solution was used directly, and was added dropwise to a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol (1.50 g, 4.79 mmol) in acetone (100 mL). After 4 h, isopropanol (9 mL) was added and the mixture was concentrated. Water was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give the crude acid. To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid (1.57 g, 4.80 mmol) in DMF (20 mL) were added KHCO3 (1.44 g, 14.4 mmol) and MeI (0.90 mL, 14.4 mmol). After 12 h, the mixture was diluted with water and extracted with EtOAc (2×), and the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography to give 1.13 g (69% over 2 steps) of the desired product. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.3, 1H), 7.31 (d, J=2.1, 1H), 7.08 (dd, J=8.3, 2.1, 1H), 5.14 (d, J=4.7, 1H), 3.73 (s, 3H), 3.47-3.43 (m, 1H), 3.07 (s, 3H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([F:20])=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].P(Cl)(Cl)(Cl)=O.C([O:28][P:29](OCC)([O:31]CC)=[O:30])C.COP(OC)(OC)=O>O>[CH:18]1[N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][O:9][P:29]([OH:31])([OH:30])=[O:28])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11]2[C:16](=[C:15]([NH2:19])[N:14]=[C:13]([F:20])[N:12]=2)[N:17]=1
Reactant: CCOP(=O)(OCC)OCC
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: COP(=O)(OC)OC
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@@H]1O

Procedure:
Phosphorylation: The product from step (e) is mixed with phosphorous oxychloride in an alkyl phosphate such as triethylphosphate, or trimethylphosphate, followed by hydrolysis in water to yield the prodrug 9-β-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate or fludarabine phosphate.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:7]([Cl:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[CH:21]1(CN2C=CC(O)=CC2=O)CC1.C(N1C=CC(O)=CC1=O)CCC.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.C1(CBr)CC1>>[Cl:19][C:7]1[C:6](=[O:20])[N:5]([CH2:1][CH2:2][CH:3]([CH3:21])[CH3:4])[CH:10]=[CH:9][C:8]=1[O:11][S:12]([C:15]([F:16])([F:17])[F:18])(=[O:14])=[O:13]
Reactant: O=c1cc(O)ccn1CC1CC1
Reactant: CCCCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O
Agent: BrCC1CC1
Agent: CCCCn1ccc(O)cc1=O
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(C)CCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O

Procedure:
Intermediate D6 was prepared following the same procedure implemented for the synthesis of D4, using as starting material 1-cyclopropylmethyl-4-hydroxy-1H-pyridin-2-one which was prepared by the same method used for the synthesis of intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with cyclopropylmethyl-bromide.
Reaction SMILES: [C:1](O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].C(=O)(O)[O-].[Na+].ClCCl.[I:49]C>O.C(OCC)C>[I-:49].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH+:19]2[CH3:1])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc(C[C@@]2(CCC(=O)OC(C)(C)C)NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C[C@]2(CCC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc3CC[NH+]2C)cc1OC
Product: [I-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
(1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethylisoquinoline oxalate (1.0 g, 0.00178 moles) was dissolved in water (10 ml) and saturated aqueous sodium bicarbonate solution was added to produce a pH in the range of 9-10. Dichloromethane (20 ml) was added and the mixture was stirred for 15 minutes at ambient temperature. The upper organic layer was separated and the aqueous layer was extracted three times with dichloromethane (3×20 ml). The combined organic layer was dried over magnesium sulfate. The organic layer was evaporated under reduced pressure to afford a residual oil. Iodomethane (8 ml, 0.128 moles) was added to the oily residue and the mixture was stirred to obtain a solution and kept at room temperature overnight. The reaction mixture was added to diethyl ether (50 ml) to afford a suspension, which was stirred at ambient temperature for 30 minutes. The thus formed solid was collected by filtration, washed with diethyl ether (2×5 ml) and dried to afford a mixture of 70% of the cis and 30% of the trans isomers of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-tert-butoxycarbonylethyl-isoquinolinium iodide (0.95 g; 89% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:15][C:14]=1[F:20]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(Cl)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 4-chloro-3-fluorophenol.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl.O.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>>[C:34]([O:18][CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15]1)(=[O:35])[CH2:33][C:32]([CH3:31])=[O:36]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C=C1CC(=O)O1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
11.95 g (0.05 mole) of 1-benzhydryl-3-hydroxyazetidine and 0.5 ml of triethylamine were dissolved in 50 ml of chloroform 6.3 g (0.075 mole) of diketene were then added dropwise to the solution, after which the reaction mixture was stirred for 10 hours at room temperature, and then water was added to it. The reaction mixture was then stirred for 30 minutes. At the end of this time, the chloroform layer was separated and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The concentrate was subjected to silica gel column chromatography, and 15.07 g (93%) of 1-benzhydryl-3-azetidinyl acetoacetate were obtained, as a pale yellow oil, from the fractions eluted with a 9:1 by volume mixture of toluene and ethyl acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N:9]1[C:8](=[O:25])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:6]=2)[N:11]=[CH:10]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN3CCCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.27 g), piperidine (0.3 ml), N,N-diisopropylethylamine (0.53 ml) and KI (0.25 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (5.75 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[4-oxo-6-(2-piperidin-1-ylethoxy)quinazolin-3(4H)-yl]benzoic acid (0.14 g); NMR Spectrum: (DMSOd6) 1.42 (m, 6H), 2.13 (s, 3H), 2.48 (m, 4H), 2.72 (m, 2H), 4.20 (m, 2H), 7.49 (m, 2H), 7.56 (m, 1H), 7.69 (d, 1H), 7.88 (s, 1H), 7.96 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 408.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=1.B(OC)(OC)OC>C1COCC1.[Li+].[BH4-]>[NH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1cccc(CO)c1
Temperature: 72.5 °C
Yield: 66.1 %

Procedure:
To a solution of methyl-3-(cyanomethyl)benzoate (4 grams, 0.023 mol, 1 molequivalent) in 5 ml dry THF, 2M LiBH4 in THF (60 ml, 5 molequivalents) and (MeO)3B (3 ml, 1 molequivalent) were added under nitrogen atmosphere. The reaction mixture was stirred and heated at 70-75° C. for 16-18 hours. After cooling, THF was evaporated, and 2N H2SO4 was added to the residue (to acidify the solution to pH of 1-2). The resulting solution was washed with ether and powdered K2CO3 was added to the aqueous phase until the pH reached 7. NaCl was then added and the solution was extracted with THF. The organic phase was dried over MgSO4 and the solvent was evaporated, to give a 2.3 grams (67%) of a pure product, which was used without purification.
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])(O)[CH2:5]C)([O-:3])=[O:2].[CH2:11]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([OH:18])=[O:17])[CH2:12][CH2:13][CH3:14].Cl[CH:26](Cl)C>>[N+:1]([C:4]([N+:8]([O-:10])=[O:9])([CH3:5])[CH2:26][O:17][C:16](=[O:18])[CH:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:3])=[O:2]
Reactant: CC(Cl)Cl
Reactant: CCC(O)([N+](=O)[O-])[N+](=O)[O-]
Reactant: CCCCCCC(CCCC)C(=O)O
Product: CCCCCCC(CCCC)C(=O)OCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 74 %

Procedure:
Dinitropropanol (25.5 g, 0.17 mol), 2-butyloctanoic acid (38.1 g, 0.19 mol) and 50 g of polyphosphoric acid were added to 50 mL of dichloroethane and the resulting mixture was slowly stirred using a stirrer. The solution thus obtained was slowly heated to 70° C. and then reacted for 15 hr (overnight). After the reaction, the temperature of the reactor was lowered to room temperature, and the stirrer was powered off. When the temperature of the reactor was room temperature, the dichloroethane layer was decanted, followed by extraction with a 1 N sodium hydroxide aqueous solution and then distillation under reduced pressure, affording 2,2-dinitropropyl-2-butyloctanoate (41.8 g, yield: 74%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(O)ccc1C=NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of 27.4 g (0.18 mol) 4-hydroxy-2-methoxybenzaldehyde and 28.3 g (0.18 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 43.0 g (78.9%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15](O)=[O:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:21](CC)CC)C.ClC(OCC(C)C)=O.N>C1COCC1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15]([NH2:21])=[O:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCN(CC)CC
Reactant: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(N)=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxylic acid (6.8 g, 25 mmol) was dissolved in THF (100 ml), and triethylamine (2.53 g, 25 mmol) was added. After the mixture had been cooled to −20° C., a solution of isobutyl chloroformate (3.41 g, 25 mmol) in THF (10 ml) was added dropwise. After the mixture had been stirred for 30 minutes at −20° C., ammonia gas was passed into the pale brown suspension for 45 minutes. The mixture was then warmed to room temperature. The residue was filtered off with suction and extracted with THF, and the filtrates were concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[OH:17][C:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Benzyl-4-oxo-2-phenylpiperidine-1-carboxylate (1.64 g, 5.30 mmol) in THF (27 ml) was cooled to −78° C. and phenylmagnesium bromide (6.36 ml, 6.36 mmol) was added. The ice bath was removed and the solution stirred at room temperature for 2 h. Concentrate, dilute with EtOAc and wash twice with water. The organics were dried over MgSO4, concentrated, and purified on silica gel eluted using 30% EtOAc to afford 1.02 g of benzyl 4-hydroxy-2,4-diphenylpiperidine-1-carboxylate.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)/[CH:4]=[CH:5]/[Cl:6].[CH3:8][O:9][C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11].O>C1(C)C=CC=CC=1>[Cl:6]/[CH:5]=[CH:4]/[C:3]([CH2:2][Cl:1])=[CH:12][C:10]([O:9][CH3:8])=[O:11]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(/C=C/Cl)CCl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=C(/C=C/Cl)CCl
Yield: 14.1 %

Procedure:
trans 1,4-Dichlorobut-3-en-2-one(0.56 g, 4.0 mmol) in toluene (10 ml) was stirred with methoxycarbonylmethylenetriphenyl phosphorane (1.32 g, 4.0 mmol) at 90° C. for sixteen hours. Water (50 ml) was added and the mixture extracted with ether (50 ml, 2×25 ml). The extracts were dried (Na2SO4) and evaporated to give the title compound (0.11 g, 14%), spectral details as in Example 11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:12]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=3)=[O:14])[CH2:25][CH2:26]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc2cccc(O)c2n1)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of 8-hydroxyquinoline-2-carboxylic acid (15 mg, 0.079 mmol), 4-(4-chlorophenoxy)piperidine (20 mg, 0.096 mmol), and triethylamine (0.044 mL, 0.32 mmol) in DMF was added HBTU (46 mg, 0.12 mol) at room temperature. The reaction mixture was stirred at 60° C. for 2 hours. The mixture was diluted with ethyl acetate (3 mL) and washed with water (1.5 mL). The organic layer was dried over sodium sulfate, and concentrated by N2-flow. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated by N2-flow. The residue was purified by preparative LC-MS to give 6.6 mg (22% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11](O)(=O)[CH3:12].[NH3:15].C(OCC)(OCC)(OCC)C>>[CH3:11][C:12]1[N:8]=[C:7]([NH2:15])[C:6]2[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=2[N:1]=1
Reactant: N
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: CC(=O)O
Agent: CCOC(C)(OCC)OCC
Product: Cc1nc(N)c2c(C)c(C)sc2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
A mixture of 2-amino-4,5-dimethylthiophene-3-carbonitrile (200 mg, 1.32 mmol), ammonia acetate (204 mg, 2.64 mmol), and triethyl orthoacetate (2.0 mL) was stirred in a sealed tube at 120° C. overnight. After the reaction mixture was cooling down to room temperature, the precipitate was collected by filtration, rinsed with EtOAc and dried in the air to give title compound (52 mg, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ2.41 (s, 3H), 2.45 (s, 3H), 2.56 (s, 3H), 5.28 (bs, 2H). MS 194 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:3]1.[CH2:19]([Li])[CH2:20][CH2:21]C.BrC(C)C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:20]([CH3:21])[CH3:19])=[N:3]1
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCC1=NC(C)(C)CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)Br
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCC(C1=NC(C)(C)CO1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
A solution of 25.34 g (100 mmoles) of 4,4-dimethyl-2-undecyl-2-oxazoline in 250 ml of dry THF under nitrogen atmosphere was cooled to -78° C. To this was added 62.5 ml (100 mmoles) of 1.6M solution of n-butyl lithium in hexane over a period of 15 minutes and the solution was further stirred for 2 hours. 18.45 g (150 mmoles) of 2-bromopropane was added at -78° C. over a period of 30 minutes and the resulting solution was allowed to warm to room temperature overnight. The solution was poured into 250 ml of saturated ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted with 2×100 ml of ether, the organic phases were combined and extracted with 2×200 ml of brine. After drying over anhydrous magnesium sulphate, the solution was concentrated and the residue was distilled at reduced pressure 10.2 g of starting material was recovered. 8.82 g (50% based on recovered starting material) of product distilled at 131°-134° C./ 0.8 mm Hg. 2.98 g (14.8%) of disubstituted product was obtained as a higher boiling fraction.