Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH:5]=O)[CH3:3].C(=O)(O)[O-].[Na+].Cl.[NH2:23][OH:24].C1(C)C=CC=CC=1>CO.O>[CH3:1][CH:2]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH:5]=[N:23][OH:24])[CH3:3]
Reactant: NO
Reactant: COc1ccc(C(C=O)C(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc(C(C=NO)C(C)C)cc1OC
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
44.44 Grams (0.02 moles) of α-(1-methylethyl)-3,4-dimethoxybenzeneacetaldehyde prepared in example 2 are dissolved in 180 ml of methanol, then 17.64 g (0.21 moles) of sodium bicarbonate are added and, finally, 14.60 g (0.21 moles) of hydroxylamine hydrochloride are added portionwise in 30 minutes. After stirring for an additional 30 minutes, 150 ml of toluene and 150 ml of water are added and the layers are separated. The aqueous phase is discarded. The toluene phases are collected together, washed with 50 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum. The oily residue is purified by treatment with heptane obtaining 43.40 g of oxime with a yield of 91.4%. An oxime sample crystallized three times from tetrachloroethylene, shows m.p.=89° C.÷91° C. and a 1H-NMR spectrum showing characteristic resonance peaks at the following δ (expressed as p.p.m.): 0.8 (d, 3H); 1.01 (d, 3H); 2.07 (m, 1H); 3.04 (t, 1H); 3.87 (2s, 6H); 6.76 (m, 3H); 7.54 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:18]=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26]([NH:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=23)(=[O:13])=[O:12])=[O:27])[N:20]=1
Reactant: Cc1nc2c(S(N)(=O)=O)cccc2s1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3sc(C)nc23)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.23 g of the product from Example 2 and 0.28 g of 4,6-dimethoxypyrimidin-2-ylcarbamic acid, phenyl ester in 5 mL of dry acetonitrile was treated at room temperature with 0.15 mL of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), added over a period of about one minute. The reaction solution was stirred at room temperature for 1.5 hour and was then diluted with 2 mL of water and acidified by the addition of 5% aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed well with water and ether, and dried. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methyl-4-benzothiazolesulfonamide was 0.21 g as a white powder, m.p. 187°-194° C. NMR (CDCl3 /DMSO-d6): δ 2.7 (3H, s), 4.05 (6H, s), 5.8 (1H, s), 7.5 (1H, t, J=8 Hz), 8.15 (1H, dd, J=2,8 Hz), 8.25 (1H, dd, J=2.8 Hz), 8.7 (1H, br s), 13.3 (1H, br s); IR(KBr): 3330, 1830, 1610, 1350, 1160 cm-1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1.[CH3:12][O:13][CH2:14][CH2:15][Br:16]>>[BrH:16].[CH3:12][O:13][CH2:14][CH2:15][N:6]1[CH:5]=[C:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[S:8][C:7]1=[NH:9]
Reactant: COCCBr
Reactant: Nc1ncc(CC(F)(F)F)s1
Product: Br
Product: COCCn1cc(CC(F)(F)F)sc1=N

Procedure:
A mixture of Example 139A and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 241 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1
Reactant: O=CCCCCCCCCBr
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCCCCC1OCCO1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
9-Bromononanal (28.0 g, assumed 120 mmol), ethylene glycol (33.6 mL, 600 mmol) and para-toluenesulphonic acid (2.7 g, 13 mmol) in toluene (210 mL) were heated at reflux for 20 hours. The reaction was cooled to RT and quenched with saturated aqueous sodium bicarbonate solution (300 mL). The resultant mixture was extracted with diethyl ether (×2). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, water and brine (100 mL). The organic phase was dried (magnesium sulphate), filtered and evaporated under reduced pressure to afford the title compound (25.2 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:8][CH2:9][CH:10]3[CH2:15][O:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N+:8]([O-:31])[CH2:9][CH:10]3[CH2:15][O:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)N1CCOCC1CN=C2c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)N1CCOCC1C[N+]([O-])=C2c1ccco1
Yield: 36.4 %

Procedure:
A solution of 6 g of 1,2,4,4a-tetrahydro-10-methoxy-7-(2-furyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine (for the preparation, see Example 2) in 100 ml of methylene chloride is heated under reflux with 4.2 g of 3-chloroperbenzoic acid for 3 hours. The reaction solution is then rendered alkaline with aqueous dilute sodium hydroxide solution and is worked up in the customary manner. The crude product isolated is purified by chromatography on aluminum oxide of activity level II, using methylene chloride, and is crystallised from isopropanol. 2.3 g of 1,2,4,4a-tetrahydro-10-methoxy-7-(2-furyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine 6-oxide are obtained. Melting point: 183° to 186° C.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([CH3:30])([O:25][Si](C)(C)C)[CH2:9][CH2:10]S(C2N(C3C=CC=CC=3)N=NN=2)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:34][C@H:35]1[CH2:39][CH2:38][C@H:37]([CH:40]=O)[C@H:36]1[CH2:42][CH2:43][S:44][C:45]1[S:46][CH:47]=[C:48]([C:50]([O:52]CC)=[O:51])[N:49]=1)(=O)C>>[CH:1]1([CH2:7][C:8]([OH:25])([CH3:30])[CH2:9]/[CH:10]=[CH:40]/[C@H:37]2[CH2:38][CH2:39][C@H:35]([OH:34])[C@@H:36]2[CH2:42][CH2:43][S:44][C:45]2[S:46][CH:47]=[C:48]([C:50]([OH:52])=[O:51])[N:49]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(CCS(=O)(=O)c1nnnn1-c1ccccc1)(CC1CCCCC1)O[Si](C)(C)C
Reactant: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Product: CC(O)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)O)cs1)CC1CCCCC1

Procedure:
By the same procedure as a series of reactions of Example 43→Example 44→Example 45 using 5-({4-cyclohexyl-3-methyl-3-[(trimethylsilyl)oxy]butyl}sulfonyl)-1-phenyl-1 H-tetrazole instead of the compound 41 and using the compound 49 instead of the compound 42, the title compound having the following physical data was obtained.
Reaction SMILES: C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH:14]([N:17]([CH:26]([CH3:28])[CH3:27])[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)([CH3:16])[CH3:15].[CH3:29][O:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=1>O1CCCC1.C(NC(C)C)(C)C.O>[OH:36][C:35]([C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]=1[C:18]([N:17]([CH:14]([CH3:16])[CH3:15])[CH:26]([CH3:28])[CH3:27])=[O:25])([C:34]1[CH:45]=[CH:46][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)[C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1
Reactant: CC(C)N(C(=O)c1ccncc1)C(C)C
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(O)(c2ccc(OC)cc2)c2cnccc2C(=O)N(C(C)C)C(C)C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
In 480 ml of dry tetrahydrofuran was dissolved 81.5 ml of diisopropylamine under nitrogen atmosphere, and the solution was cooled to -70° C. Then, 375 ml of 1.6N n-butyllithium was dropwise added to the extent that the temperature of the mixture was not higher than -65° C., to thereby produce lithium diisopropylamide. The reaction mixture was kept at -70° C. for one hour, and to the reaction mixture was added a solution of 43.97 g of N,N-diisopropylisonicotinamide in 150 ml of dry tetrahydrofuran, to the extent that the temperature of the mixture was not higher than -65° C. The mixture was stirred for one hour and 15 minutes, and to the reaction mixture was dropwise added a solution of 46.94 g of 4,4'-dimethoxybenzophenone in 945 ml of dry tetrahydrofuran to the extent that the temperature of the mixture was not higher than -65° C., followed by stirring for 15 minutes. Thereafter, the temperature was allowed to be brought back to room temperature, and water was added thereto. After extraction with ethyl acetate, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 63.69 g of the desired compound as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22]>C1COCC1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:22])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
4-Hydroxypiperidine (50 g, 494 mmol) was added portionwise to a stirred suspension of potassium tert-butoxide (110.9 g, 990 mmol) in THF (900 ml) at room temperature and under nitrogen. The mixture was heated at reflux and 1,2-dichloro-4-fluorobenzene (98 g, 594 mmol) added dropwise over 30 minutes. The mixture was sired at reflux for another 1 hour then cooled down to room temperature, diluted with ethyl acetate (500 ml) and washed with water (500 ml). The organic phase was diluted further with ethyl acetate (500 ml) and extracted with 1M hydrochloric acid (200 ml), The aqueous extract was adjusted to pH>10 by addition of a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[C-:21]#[N:22].[Na+].C(OCC)(=O)C.O>CS(C)=O>[C:21]([C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1)#[N:22]
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C(C#N)(c2ccc(O)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirred solution of 2-chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (10.0 g, compound No. 2) in dimethylsulfoxide (100 ml), sodium cyanide (8.0 g) is added. The mixture is stirred for 2 hours at room temperature, and poured into a mixture of ethyl acetate and water. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 6.9 g (71.0%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=C[CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=O)C(C)C>C(Cl)Cl>[CH3:12][CH:13]([CH3:14])[C:4](=[O:5])[CH2:6][C:7]([O:9][C:2]([CH3:1])([CH3:10])[CH3:17])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)C(=O)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Meldrum's acid (80 g, 555 mmol) was dissolved in 600 mL of CH2Cl2 and cooled to 0° C. Freshly distilled pyridine (87.8 g, 1.11 mol) was added to the CH2Cl2 solution and then iso-butyryl chloride (65.0 g, 610.5 mmol) was added to the mixture via a pressure equalizing addition funnel. The reaction was stirred at 0° C. for 1 hr and then warmed to rt and stirred for 2 hr. Then, the reaction was quenched with water (200 mL) and washed with 0.5 M HCl (×2), water (×1), and brine (×1). The organize layer was dried over MgSO4 and concentrated in vacuo. The crude product was azeotropically dried with benzene (250 mL), and then dissolved in 200 mL of benzene and 200 mL of tert-butanol was added. The resultant reaction was heated at reflux for 4 hr. After this period, the volatiles were removed in vacuo and the product then distilled on the high vacuum pump (bp 62-63° C., 0.1 mm Hg). The desired β-keto ester 1E was obtained (58.6 g, 315.5 mmol) in 57% yield as a clear, colorless, light oil.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[SH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C.O>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[CH2:2][S:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Sc1ncccn1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1cnc(SCc2nc3ccccc3[nH]2)nc1

Procedure:
10.0 g (0.06 mole) of 2-chloromethylbenzimidazole are added to a solution of 6.7 g (0.06 mole) of 2-mercaptopyrimidine and 2.4 g (0.06 mole) of sodium hydroxide in 200 ml of ethanol and 20 ml of water. The mixture is maintained under reflux for 2 hours and the ethanol evaporated off. The residue is taken up with water (50 ml) and extracted with ethyl acetate (3×50 ml), the organic phase is dried with sodium sulfate, filtered and evaporated to a volume of 40 ml of solution, in which there crystallize 10.2 g (70%) of 2-(2-benzimidazolylmethylthio)pyrimidine, melting point 154°-155° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH3:15].[Cl:16]C1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[ClH:16].[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH3:15])=[O:21]
Reactant: CSc1ccccc1NCC1=NCCN1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccccc1NCC1=NCCN1
Product: Cl
Yield: 76.1 %

Procedure:
N-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2-(methylthio)aniline (32 mg, 0.144 mmol, prepared as described in Example 1) was stirred in dichloromethane (1 mL) and treated with m-chloroperoxybenzoic acid (35 mg of 70 wt %). After 15 minutes the mixture was evaporated and treated with ether (2 mL), 3 drops of methanol, and then 1N HCl in ether (0.2 mL). The resulting precipitate was collected and washed with ether (1 mL) to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(methylsulfinyl)aniline hydrochloride salt (30 mg).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].C(N(CC)C(C)C)(C)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:44])[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:43])[CH:38]=2)([OH:36])[C:32]([F:35])([F:34])[F:33])=[C:26]([Cl:45])[CH:25]=1.ClC(C1C=CC(C([O-])=O)=CC=1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:44])[C:31]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([Cl:43])[CH:38]=3)([OH:36])[C:32]([F:33])([F:34])[F:35])=[C:26]([Cl:45])[CH:25]=2)=[O:3])=[CH:5][CH:6]=1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=C([O-])c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-chlorocarbonylbenzoate (CAS Reg. No. 7377-26-6, 30 mg) and N,N-diisopropylethylamine (0.05 ml) in DCM (5 ml) was added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (50 mg) in DCM (1 ml). The mixture was stirred for 2 h at room temperature. Additional 4-chlorocarbonylbenzoate (CAS Reg. No. 7377-26-6, 54 mg) and N,N-diisopropylethylamine (0.1 ml) were added. The mixture was stirred for 4 h at room temperature. The mixture was poured on a saturated aqueous NaHCO3 solution (20 ml) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (57 mg) as a white foam. MS (m/e)=527.0 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A mixture of 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), dihydrofuran-3-one (145 μl, 161 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an oil (132 mg, 50%). 1H NMR (CDCl3, 300 MHz): δ 4.33-4.05 (m, 2H); 4.01-3.91 (m, 1H); 3.90-3.73 (m, 2H); 3.68-3.48 (m, 1H); 3.47-3.23 (m, 1H); 2.72-2.56 (m, 2H); 2.21 (s, 3H); 2.11-1.94 (m, 1H); 1.93-1.78 (m, 1H); 1.76-1.63 (m, 2H); 1.76-1.63 (m, 1H); 1.54-1.46 (m, 2H); 1.46 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]=[N+]=[N-])[CH2:10][CH:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][CH:9]1[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC1CC(N)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
The 4-azido-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (93.41 mg, 0.41 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 79.65 mg.C10H20N2O2 MS m/e=200.2 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Br)([CH3:10])([CH3:9])[CH3:8].[Cl:19][C:20]1[N:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1.O>CS(C)=O.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][O:26][C:23]1[CH:22]=[N:21][C:20]([Cl:19])=[N:25][CH:24]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Oc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCCCOc1cnc(Cl)nc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Potassium carbonate (2.54 g) was added to a solution of 5-bromovaleric acid tert-butyl ester (4.3 g) obtained in Reference Example 1 (1) above and 2-chloropyrimidin-5-ol (2 g) in dimethylsulfoxide (8.6 ml) and the mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, water and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=49:1→9:1) to give 5-(2-chloropyrimidin-5-yloxy)valeric acid tert-butyl ester (3.82 g). MS (m/z): 287/289 [M+H]+.