Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=1.[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>N1C=CC=CC=1.CCOC(C)=O>[CH2:26]([O:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[N:14]([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[S:15]1(=[O:16])=[O:17])[CH2:4][C:3]1[CH:33]=[CH:34][CH:35]=[CH:36][C:2]=1[NH:1][S:44]([CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:46])=[O:45])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3NS(=O)(=O)Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[4-(2-aminobenzyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (150 mg, 0.29 mmol) in pyridine (3 mL) is added α-tolylsulfonyl chloride (66 mg, 0.35 mmol) and the solution is stirred at ambient temperature for 1.5 h. The mixture is neutralized using 1N HCl solution, then diluted with EtOAc. The organic phase is washed with brine and water and is dried with MgSO4, and concentrated. The residue is purified by flash column chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([N+:28]([O-])=O)[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C(OC(=O)C)C>O.C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH2:28])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Zinc (296 mg, 0.005 mol) was added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-6-methyl-8-nitro-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (400 mg, 0.0008 mol) and NH4Cl (322 mg, 0.006 mol) in water and THF (15 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 350 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCN2CCOCC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(4-morpholinyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-aminoethylmorpholine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:28])[CH:19]([CH2:29][C:30]([OH:32])=O)[S:18]2)[CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:45][CH2:44][C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[NH:41][C:40]2=[O:50])[CH2:35][CH2:34]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([N:33]3[CH2:34][CH2:35][CH:36]([N:39]4[CH2:45][CH2:44][C:43]5[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=5[NH:41][C:40]4=[O:50])[CH2:37][CH2:38]3)=[O:32])[S:18]2)[CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CC(C)(C)CCN1C(=O)C(CC(=O)O)SC1c1cccc(F)c1NCCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cccc(F)c1NCCN1CCOCC1

Procedure:
2-(2-(2-(2-Morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (420.8 mg, 0.9 mmol), 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (441 mg, 1.798 mmol), EDC (354 mg, 1.847 mmol), and HOBt (273 mg, 1.783 mmol) were stirred in DMF (5 mL) at RT. The mixture was transferred to a separatory funnel, then diluted with 100 mL EtOAc and washed with a saturated sodium bicarbonate solution. The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by reverse phase chromatography to give 3-(1-(2-((5S)-2-(2-(2-morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one. LC/MS: 695.33 (M+1) Rt=2.20 min (10-90% 3/5 min (grad/run) w/formic acid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([C:19](=[O:21])[NH2:20])[N:18]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([C:19]([NH2:20])=[O:21])[N:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2nc(C(N)=O)c(Nc3ccccn3)s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
To a suspension of {1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester (prepared as described in example 1) (359 mg, 0.86 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) to form a yellow solution. The mixture was stirred at ambient temperature for 30 minutes then evaporated to dryness in vacuo. The residue was taken up in dichloromethane (25 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (5×20 mL) until no further yellow color was extracted in to the organic layer. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide as a yellow solid (280 mg).
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[CH2:46]([NH2:50])[CH:47]([CH3:49])[CH3:48]>ClCCl.O>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([NH:1][C:34]([NH:50][CH2:46][CH:47]([CH3:49])[CH3:48])=[O:35])=[CH:3][C:4]=3[O:31][CH3:32])[CH2:13][CH2:12]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Reactant: CC(C)CN
Solvent: O
Solvent: ClCCl
Product: COc1cc(NC(=O)NCC(C)C)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
3-((4-(4-Amino-5-chloro-2-methoxybenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (1.712 g, 0.0037 mol) and 4-nitrophenol chloroformate (0.7518 g, 0.0037 mol) were combined and stirred at room temperature in dichloromethane for 1 hour. Isobutylamine (0.1536 g 0.208 mol) was added and the reaction was stirred for a further 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic frit. The organic phase was concentrated under vacuum and purified by acidic reverse phase HPLC affording the title compound (37 mg).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 3-(Bocamino)-1-propanol (10.51 g: 60 mmol) and TEA (6.07 g; 60 mmol) in dry DCM (100 mL) kept in an ice bath (0° C.) was slowly added methane sulfonyl chloride (6.87 g; 60 mmol) and the reaction mixture was stirred for 30 min at 0° C. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 5 h (completion of the reaction was monitored by TLC). Water (50 mL) was added with stirring and the resulting mixture was transferred to a reparatory funnel, the layers were separated, and the aqueous layer was extracted with DCM (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield compound 5 as a colorless oil (12.82 g: 100% yield). 1H NMR (CDCl3) δ 4.8 (s, 1H), 4.3 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 1.9 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([N:27]([CH2:30][CH3:31])[CH2:28]C)C.C([O-])([O-])=O.[K+].[K+].CC1NC1>O.CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]2[CH2:28][CH:30]2[CH3:31])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CCN(CC)CC
Agent: CC1CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CC1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
To 50 ml of DMF was added 5.0 g (0.0126 mol) of product of Example 28 , followed by 1.27 g (0.0126 mol) of triethylamine and 1.74 g (0.0126 mol) of K2CO3. To this mixture was added 0.922 g (0.0161 mol) of propyleneimine. This reaction mixture was stirred under N2 for 48 hours at room temperature. The reaction mixture was then poured into H2O and extracted with diethyl ether. The ether phase was then washed with H2O, and dried over MgSO4. The dry ether phase was then concentrated in vacuo to a crude yield of 4.8 g of a brown oil. This oil was kugelrohr distilled at 105° C./53 Pa, to yield 4.0 g of a yellow oil (76%), nD25 1.4763.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)[C:17](O)=[O:18].C1N2CN3CN(C2)CN1C3.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:6][C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:17]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccccc1CC1CCCC1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C=O)cc1CC1CCCC1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a stirred mixture of 1-cyclopentylmethyl-2-methoxybenzene (383 mmol, 72.7 g) in trifluoroacetic acid (3.83 mol, 435 g; 294 mL) was added hexamine (766 mmol, 107 g) in one portion at room temperature, resulting in an exothermic reaction. After the exotherm had subsided, the reaction mixture was heated to 100° C. for 18 hours and cooled to room temperature. The heterogenous mixture was diluted with CH2Cl2 (800 mL) and the resulting homogenous solution was cooled to 0° C. and neutralized to pH 7 by the dropwise addition of 2.5N NaOH (~1L). The layers were separated, the aqueous phase extracted with CH2Cl2 (1×600 mL), dried (Na2SO4), and concentrated in vacuo to afford a viscous oil. Purification by filtration through a plug of SiO2 (gradient elution: 1) hexane, 2) 36:1 hexane/EtOAc, 3) 18:1 hexane/EtOAc, 4) 12:1 hexane/EtOAc, 5) 8:1 hexane/EtOAc) afforded the title compound as a light yellow oil (46.6 g, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([O:14]C(OCC)OCC)[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:9])[O:14][CH2:12][CH2:13][O:10]2)=[C:4]([Cl:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1Cl
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2ccc(Br)cc2Cl)OCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(4-Bromo-2-chloro-phenyl)-ethanone (from step 2 below) (1.86 g, 5.66 mmol), below was dissolved in ethylene glycol (5 mL). Triethylorthoformate (0.71 g, 4.79 mmol), and tosic acid (0.02 g) were added and reaction was stirred under nitrogen for 24 hours at room temperature. The resulting reaction mixture was poured into NaHCO3 (10 mL) and extracted with EtOAC. The combined organics were washed with water (10 mL) and brine (10 mL) then dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (5% EtOAc in Hexanes) to yield the intermediate ether as a colorless oil (0.69 g, 58%). 1H NMR (CDCl3): δ 1.77 (s, 3H), 3.74-3.79 (m, 2H), 4.04-4.09 (m, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.9 Hz, 1H). ESIMS (MH+): 278.2.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]=[C:11]1[N:15](C(OC(C)(C)C)=O)[CH:14]([CH2:23][O:24]C(OC(C)(C)C)=O)[CH2:13][S:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[OH:24][CH2:23][CH:14]1[CH2:13][S:12][C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[N:15]1
Reactant: CC(C)(C)OC(=O)N=C1SCC(COC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Temperature: 20 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
10 cm3 of aqueous 1N sodium hydroxide are added to a solution of 2 g of tert-butyl 2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine-3-carboxylate in 20 cm3 of methanol and the mixture is then stirred at a temperature in the region of 20° C. for 4 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is taken up in 30 cm3 of water, filtered and washed with ethyl acetate and then with water. 0.37 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]-carbamate is obtained in the form of a white solid [mass spectrum: DCI m/z=233 MH+ m/z=177 (M-C4H7)+].
Reaction SMILES: [CH:1]1([C:7]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]#[C:24]CO)[CH3:20].C[O-].[Na+]>C1(C)C=CC=CC=1>[CH:12]1([C:7]([OH:18])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:24]#[C:23][CH2:22][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:19][CH3:20])=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCN(CC#CCO)Cc1ccc(OC)cc1
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1

Procedure:
reacting a single enantiomer of methyl α-cyclohexyl-α-hydroxybenzeneacetate (IV) with 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butyn-1-ol (V) in the presence of a catalytic amount of sodium methoxide in toluene to produce a single enantiomer of 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate (VI); and
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1([C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[N:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCCCC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(N1CCCCC1)N1CCNCC1COc1cccnc1
Reaction time: 12 h
Yield: 100 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(piperidine-1-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (43.0 mg, 0.083 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 31.3 mg (100%) of the desired product as a white solid. LC-MS: RT=3.34 min, [M+H]+=305.2.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([OH:16])(=[O:15])[CH3:14]>C(O)(C)C>[C:13]([O-:16])(=[O:15])[CH3:14].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC(=O)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CC(C)O
Product: CC(=O)[O-]
Product: CC1(C)CC(O)CC(C)(C)[NH+]1O
Yield: 59.1 %

Procedure:
5.0 g (0.029 mol) 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidine and 2.0 g (0.033 mol) acetic acid are recrystallized from 50 mL of isopropanol, yielding 4.0 g of the desired hydroxylamine salt as a white crystalline solid, mp 140-143° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCl>[CH3:1][CH:2]1[CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CBr
Reactant: CC1CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN1CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-methylaziridine (5.6 g, 99 mmol) and N,N-diisopropylethylamine (18.8 mL, 108 mmol) in dichloromethane (250 mL) under an atmosphere of nitrogen, ethyl bromoacetate (10 mL, 90 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum, and the residue was suspended in chloroform. A stream of anhydrous ammonia gas was bubbled into the mixture with stirring for a period of 15 min. The resultant suspension was filtered, and the filtrate concentrated under vacuum. The residue was further treated with anhydrous diethyl ether and the milky solution filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue subjected to distillation under reduced pressure (bp ˜60° C., 18 torr) to provide the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]([NH2:12])=O)[N:4]2[N:3]=1.COC(OC)[N:34]([CH3:36])C.O.[NH2:40]N>C(O)(=O)C>[CH3:1][C:2]1[C:19]([CH2:20][C:21]2[C:26]3[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=[CH:23][CH:22]=2)=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]3[N:34]=[CH:36][NH:40][N:12]=3)[N:4]2[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: Cc1nn2c(C(N)=O)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn2c(-c3nc[nH]n3)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 105 °C
Reaction time: 72 h
Yield: 34.3 %

Procedure:
A mixture of 2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine-7-carboxamide (55 mg, 0.137 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL, 14.94 mmol) was stirred at 105° C. for 3 days and concentrated to give the crude. To the crude was added Acetic Acid (2 mL) and hydrazine hydrate (0.047 mL, 0.959 mmol). The reaction mixture was heated at 100° C. for 1 h and concentrated. Brine (10 mL) and EtOAc (20 mL) was added in. The aqueous phase was extracted with EtOAc (20 mL×4). The organic phases were combined and concentrated. The crude was purified on silica column (EtOAc/Hexane: 10˜40%) to give the product (20 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3H) 3.56-3.82 (m, 8H) 4.39 (s, 2H) 7.14 (s, 1H) 7.29-7.59 (m, 4H) 7.77 (d, J=8.08 Hz, 1H) 7.85-7.98 (m, 1H) 8.38-8.61 (m, 2H); LC/MS: MS (ES+) m/e 426.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[C:12]([OH:14])=O.[C:15](C1NC=CN=1)([C:17]1[NH:18]C=CN=1)=O.C(N)C[NH2:29]>ClCCl>[NH2:18][CH2:17][CH2:15][C:8]1[C:7]2[C:3]([O:2][CH3:1])=[C:4]([C:12]([NH2:29])=[O:14])[S:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NCCN
Reactant: COc1c(C(=O)O)sc2ccccc12
Solvent: ClCCl
Product: COc1c(C(N)=O)sc2cccc(CCN)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Methoxy benzothiophene 2-carboxylic acid (6.24 g) and carbonyl diimidazole (5.8 g) were dissolved in dry dichloromethane (200 ml) and stirred at room temperature for 2 hours. The solution was then added to a solution of ethylene diamine (9.0 g) in dichloromethane (50 ml) and the solution stirred overnight. After evaporation to dryness under vacuum, the residue was partitioned between ethyl acetate and water. The organic layer was extracted several times with 2N hydrochloric acid, the aqueous layer washed with ethyl acetate and then made basic with 0.88 ammonia solution. This was extracted with ethyl acetate (3×100 ml), washed with water, dried and evaporated to dryness under vacuum, to give 2-amino ethyl-3-methoxy benzothiophene-2-carboxamide.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1)[CH:2]=[CH2:3].O=S(Cl)[Cl:21]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Cl:21])=[CH:13][CH:12]=1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOCCOCCOc1ccc(CO)cc1
Solvent: ClCCl
Product: C=CCOCCOCCOc1ccc(CCl)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
All four compounds were prepared by the same method. An example is presented below. 4-[2-(2-Allyloxyethoxy)ethoxy]benzyl alcohol (7.57 g, 0.03 mol) was dissolved in methylene chloride (100 mL), and SOCl2 (4.28 g, 0.036 mol) was added dropwise. After the addition was completed the reaction mixture was stirred at 40° C. for 1 hr. washed with water, 2% NaHCO3 aqueous solution, and water and dried over anhydrous MgSO4. The solvent was evaporated and the residual oil was purified by column chromatography (silica gel, a mixture of 1:3 ethyl acetate to n-hexane as eluent) to yield 6.52 g (80%) of a colorless oily product 14. 1H-NMR (CDCl3, TMS, δ in ppm): 3.55-4.19 (m, 10H, --CH2 --(O--CH2 --CH2)2), 4.55 (s, 2H, Ph--CH2 --), 5.23 and 5.78 (m, 3H, CH2 =CH--), 5.92 and 7.25 (2d, 4 aromatic protons).