Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[C@H:10]([CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21]>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[C@H:10]([CH2:16][O:17][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=CN1CCN(Cc2ccccc2)C[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1CN(Cc2ccccc2)CCN1C=O
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a 0° C. solution of alcohol 22 (0.502 g, 2.14 mmol) in dry DMF (20 mL) was added NaH (95%, 0.154 g, 6.43 mmol) in one portion. After stirring 5 min, iodomethane (0.319 g, 2.25 mmol) was added (drop-wise) and the mixture stirred for 20 min at 0° C. then at ambient temperature for 1.5 h. The excess NaH was destroyed by the careful addition of water and the solution was diluted with 40 mL each of water and saturated NaHCO3. The aqueous mixture was extracted with ether (2×40 mL) and ethyl acetate (2×40 mL). The combined extracts were washed with brine (50 mL), dried (K2CO3) and concentrated to give a brown oil that was purified by column chromatography (silica gel, MeOH:CHCl3, gradient 1:199 to 1:49) to afford 23 as a pale colored oil (0.360 g, 69% yield). 1H NMR (400 MHz, CDCl3): δ 2.00-2.12 (m, 1.3H), 2.18 (dd, J=3.7, 11.7 Hz, 0.7H), 2.80-2.92 (m, 2H), 2.93-3.02 (m, 1H), 3.29-3.38 (m, 3H), 3.41-3.76 (m, 5H), 4.16 (bd, 0.7H), 4.60 (m, 0.3H), 7.25-7.35 (m, 5H), 8.04 (s, 0.7H), 8.07 (s, 0.3H); 13C NMR (100 MHz, CDCl3): δ 36.7, 42.7, 47.0, 52.3, 53.2, 53.7, 54.1, 58.8, 59.0, 62.5, 62.6, 69.5, 70.6, 127.2, 128.3, 128.7, 137.7, 161.3, 161.9. HRMS Calcd. for [C14H20N2O2+H+] 249.1603. Found 249.1598. [α]D25-37.6 (c 0.036, CHCl3).
Reaction SMILES: Br.[CH3:2][S:3]([CH2:5][CH2:6][CH2:7][NH2:8])=[O:4].C(N(CC)CC)C.[CH2:16]([N:34]=[C:35]=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH3:2][S:3]([CH2:5][CH2:6][CH2:7][NH:8][C:35]([NH:34][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])=[O:4]
Reactant: CS(=O)CCCN
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCS(C)=O
Temperature: 25 °C

Procedure:
10.6 Grams of 3-(methylsulfinyl)propylamine hydrobromide, 5.6 g of triethylamine and 100 ml of acetone were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred at room temperature. To the resulting solution was slowly added dropwise 14.8 g of octadecyl isocyanate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 14.9 g of the desired product. m.p. 105° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([NH2:17])=[CH:14]3)=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:17][C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][N:8]([CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:9]=3)[CH:14]=2)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2nn(CCN3CCCC3)cc2c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-pyrrolidin-1-yl-ethyl)-2H-indazol-5-ylamine (0.100 g, 0.434 mmol), 4-phenoxyphenyl isocyanate (0.0917 g, 0.434 mmol) and 6 mL of THF was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature and the solvents removed under vacuo. The resultant solid was triturated in ether and collected by filtration to provide the titled product. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.66 (m, 4 H), 2.50 (m, 4 H), 2.96 (m, 2 H), 4.48 (t, J=5.93 Hz, 2 H), 6.97 (m, 4 H), 7.11 (m, 2 H), 7.36 (m, 2 H), 7.50 (m, 3 H), 7.88 (m, 1 H), 8.26 (s, 1 H), 8.54 (s, 1 H), 8.64 (s, 1 H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])=[CH:6][CH:5]=1>>[Br:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][OH:13])=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Oc2ccc(Br)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc(Oc2ccc(Br)cc2)c1

Procedure:
This compound was prepared by a standard sodium borohydride reduction from 3-(4-bromophenoxy)benzaldehyde.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12].[NH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1>COC(OC)C>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[O:12]
Reactant: O=C=Nc1ccccc1OC(F)F
Reactant: Nc1cnccn1
Agent: COC(C)OC
Product: O=C(Nc1cnccn1)Nc1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
2-(Difluoromethoxy)phenylisocyanate (1.0 g, 5.4 mmol) and aminopyrazine (0.51 g, 5.4 mmol) were reacted for 6 hours in refluxing dimethoxy-ethane (20 mL). The reaction mixture was cooled to room temperature to precipitate the product, which was collected by filtration, washed with ethyl acetate, and dried in vacuo (765 mg, 50%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.49 (br s, 1H), 10.26 (s, 1H), 8.83 (s, 1 H), 8.35-8.24 (m, 3H), 7.53-7.00 (m,4H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1)[CH3:2].[C:8]1([OH:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>>[C:8]1([O:18][CH2:4][CH:5]([OH:7])[CH2:6][NH:3][CH2:1][CH3:2])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCN1CC(O)C1
Agent: [K+]
Agent: [OH-]
Product: CCNCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 70 %

Procedure:
To a mixture of 10.2 parts of 1-ethyl-3-azetidinol and 14.4 parts of α-naphthol 0.2 part of potassium hydroxide was added, and the mixture was heated under nitrogen gas at 160° C. for 18 hours. The reaction mixture was cooled and extracted with ether. The ether extract was washed with 2N-NaOH aqueous solution and then with water. The liquor was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from cyclohexane to yield 17.2 parts of 1-(α-naphthoxy)-3-ethylamino-2-propanol. The melting of the product was 106°-107° C. The yield was 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([N:1]3[C:20](=[O:21])[C:19]4[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=4[C:17]3=[O:22])=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(OCc2ccc(Cl)cc2)cn1

Procedure:
The compound, 2-amino-5-(4-chlorobenzyloxy)pyridine is reacted with 3,4,5,6-tetrahydrophthalic anhydride using the procedure of Example 1 to yield N-[5-(4-chlorobenzyloxy)-2-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cn1
Yield: 63.9 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanol (1.2 g, 6.38 mmol), 1,1′-(azodicarbonyl)-dipiperidine (2.093 g, 8.30 mmol), triphenylphosphine (2.176 g, 8.30 mmol) and phthalimide (1.221 g, 8.30 mmol) in THF (60 mL) at rt was stirred over the weekend. The reaction mixture was filtered and the filtrate was concentrated to a yellow solid that was triturated with methanol. Filtration and drying afforded 2-((5-bromopyridin-2-yl)methyl)isoindoline-1,3-dione (1.295 g, 4.08 mmol, 64.0% yield) as a colorless crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.4, 2.2 Hz, 1H), 7.90 (d, J=9.0 Hz, 4H), 7.44 (d, J=8.4 Hz, 1H), 4.89 (s, 2H). MS (ES+) m/z: 316.95, 318.96 (M+H); LC retention time: 2.297 min (analytical HPLC Method O).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CC(C)(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
3-Methyl-1-butyn-3-ol (25 ml, 21.7 g), dihydropyran (50 ml) and p-toluenesulphonic acid (5 mg) were mixed together at 0° C. for 1 hr, and then stirred at room temperature for a further 40 hr. The mixture was concentrated and the reside added to 5% aqueous NaHCO3 and extracted with benzene. The organic solution was dried to give after distillation 37.3 g (86%) of the title ether. b.p. 47° C./0.8 mm Hg (lit. 30°-33° C./ 0.5 mm50 ; 57° C./3.5mm170); 1Hnmr δ 5.6 (m, THP C-2'H), 2.45 (s. C-1H), 1.51 (s, CH3), 1.48 (s, CH3); IR (thin film) 3350 s), 2950 (s), 2900 (sh), 112S (s), 1070 (s), 1030 (s), cm-1.
Reaction SMILES: [CH3:1][Si:2](C#C)([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:26][CH2:25][C:23](=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:16][C:17](=[O:18])[NH:19][CH:20]1[CH2:21][CH2:22][C:23]([OH:24])([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:25][CH2:26]1)([CH3:12])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(O)([Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of trimethylsilyl acetylene at −78° C.(4.14 g, 0.042 mol) in THF (60 mL) was treated with n-butyl lithium (29 mL, 0.042 mol; 1.6 M solution in THF). The resulting mixture was stirred at −78° C. for 15 min. A solution of N-4-Boc-aminocyclohexanone (3 g, 0.014 mol; Astatech, Inc) in THF (120 mL) was added dropwise over a period of 30 min. The resulting mixture was stirred at −78° C. for 1 h and then allowed to slowly warm up to room temperature over 1 h. The reaction was quenched with a saturated solution of ammonium chloride and diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, H2O, and saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated to yield an off-white foam (4.38 g, 100%).
Reaction SMILES: CO[CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13]C)=O)=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1.CC(O)=O.CS(O)(=O)=O.[NH2:32][C@H:33](CO)[CH3:34]>CC#N>[CH3:34][C@@H:33]1[N:32]2[C:11](=[O:13])[C:10]3[N:5]([CH:6]=[C:7]([C:18]([OH:20])=[O:19])[C:8](=[O:17])[C:9]=3[O:15][CH3:16])[CH2:4][C@H:3]2[O:21][CH2:22]1
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1c2n(cc(C(=O)O)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Temperature: 61.5 °C
Reaction time: 15 h

Procedure:
1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3SO3H (1.4 mL) were added at room temperature and the mixture was heated to 58-65° C. for 19.5 h. Alaninol (7.511 g) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64° C. for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2Cl2 (170 mL). HCl (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (170 mL×2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20° C. and held at 20° C. for 15 h. The product was collected by filtration and dried under vacuum.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][CH2:8][CH:9]([OH:24])[CH2:10][NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[O:23])[CH2:14][CH2:13]1)[CH:2]=[CH2:3].C=O.[CH:31](O)=O.Cl>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][CH2:8][CH:9]([OH:24])[CH2:10][N:11]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[O:23])[CH2:14][CH2:13]1)[CH3:31])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1OCC(O)CN[C@H]1CC[C@@H](N2CCNC2=O)CC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CN(C)[C@H]1CC[C@@H](N2CCNC2=O)CC1
Temperature: 25 °C

Procedure:
A mixture of cis-1-(4-[3-(o-allyloxyphenoxy)-2-hydroxypropylamino]-cyclohexyl)-2-imidazolidinone (4.4 g) in 15 ml isopropanol, 37.5% aqueous formaldehyde (0.671 g), and formic acid (2.6 g) is stirred at reflux for 19 hours. The solution is cooled to room temperature, 1 ml concentrated hydrochloric acid is added and the mixture concentrated to dryness. The glassy residue is dissolved in 100 ml of water, made alkaline with excess of 25% aqueous sodium hydroxide and extracted with methylene chloride (1×50 ml, 1×25 ml). The extract is dried, filtered and concentrated to give a residue which is purified by preparative thin layer chromatography on silica gel, using ethyl acetate-methanol-ammonium hydroxide (90:5:5) as the eluent, to yield the cis-1-{4-[3-(o-allyloxyphenoxy)-2-hydroxy-N-methyl-propylamino]cyclohexyl}-2imidazolidinone as an oil. The hydrochloride salt, m.p. 80° dec., is prepared by dissolving 2.3 g of the base in 50 ml ethyl acetate, adding a saturated solution of hydrogen chloride gas in ethyl acetate, and collecting the resulting salt.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C@H:7]2[CH2:8][CH2:9][C@H:4]([CH3:3])[CH2:5][CH2:6]2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[C@H]1CC[C@H](O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Oc2cc(Cl)ncn2)CC1
Temperature: 25 °C

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.1 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.23 g of trans-4-methylcyclohexanol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes and then cooled to 0° C., to which 1 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.37 g of 4-chloro-6-(trans-4-methylcyclohexyloxy)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Reactant: NCCc1cccnc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccnc3)cc2Cl)cn1
Yield: 91.4 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and 2-(pyridin-3-yl)ethylamine (0.017 g, 0.140 mmol) gives the title compound (0.0490 g, 91.2%): TOF MS ES+ 383.1 (M+H)+, HRMS calcd for C20H20N4O2Cl 383.1275 (M+H)+, found 383.1248, time 0.39 min; Anal. Calcd for C20H19ClN4O2.0.1CH2Cl2: C, 61.90; H, 5.06; N, 14.38. Found: C. 61.90; H, 5.06; N, 14.38.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]1[CH3:26])[CH:2]([CH3:4])[CH3:3].[OH:34][C@@H:35]([CH3:39])[C:36](O)=[O:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:36](=[O:37])[C@@H:35]([OH:34])[CH3:39])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[N:9]=2)=[CH:28][N:29]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1c(N2CCN(C(=O)[C@H](C)O)CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 46.2 %

Procedure:
A methylene chloride (5 ml) solution of 5-{9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-8-piperazin-1-yl-9H-purin-2-yl}pyrimidin-2-amine (119 mg, 0.26 mmol), (S)-2-hydroxypropionic acid (28 mg, 0.32 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.32 mmol), and triethylamine (55 μl, 0.39 mmol) was stirred at room temperature for 2 days. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (chloroform:methanol=96:4) to give a solid. The resulting solid was purified by flash NH silica gel column chromatography (methylene chloride:methanol=99:1) to give the title compound (63 mg, 46%) as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[C@@H:16]([O:17]C(=O)[C@@H](C2C=CC=CC=2)OC)[CH2:15][O:14][C@@H:13]1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[C@@H:16]([OH:17])[CH2:15][O:14][C@@H:13]1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[C@@H](C(=O)O[C@H]1CO[C@H](c2cccnc2)[C@@H]1CCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H]1[C@@H](c2cccnc2)OC[C@@H]1O

Procedure:
A solution of 2.02 g (0.00416 mole) of (2S,3S,4R)-3-(3-t-butyldimethylsilyloxyprop-1-yl)-4-[(R)-(-)-α-methoxyphenylacetoxy)-2-(3-pyridyl)tetrahydrofuran, 8.32 ml (0.00832 mole) of 1N sodium hydroxide in 20 ml of methanol is stirred at room temperature for 1 h and evaporated. The residue is triturated with water and extracted with ethyl acetate (3×20 ml). The combined extracts are washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography to give (2S,3S,4R)-3-(3-t-butyldimethylsilyloxyprop-1-yl)-4-hydroxy-2-(3-pyridyl)tetrahydrofuran as an oil with [α]D25 =+43.8 (MeOH).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 570.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.10 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=O)=O)(C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:55][NH:56][C:57](=[NH:85])[C:58]1[CH:63]=[CH:62][C:61]([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[N:71]([CH3:83])[C:72](=[O:82])[CH:73]=[C:74]([C:76]4[CH:81]=[CH:80][N:79]=[CH:78][N:77]=4)[N:75]=3)[C@H:66]([CH3:84])[CH2:65]2)=[CH:60][CH:59]=1>CN(C)C=O.O>[NH2:8][CH2:9][C:10]1[O:55][N:56]=[C:57]([C:58]2[CH:59]=[CH:60][C:61]([N:64]3[CH2:69][CH2:68][N:67]([C:70]4[N:71]([CH3:83])[C:72](=[O:82])[CH:73]=[C:74]([C:76]5[CH:81]=[CH:80][N:79]=[CH:78][N:77]=5)[N:75]=4)[C@H:66]([CH3:84])[CH2:65]3)=[CH:62][CH:63]=2)[N:85]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@@H]1CN(c2ccc(C(=N)NO)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(-c3noc(CN)n3)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of N-tertbutoxycarbonylglycine (94 mg, 0.535 mmol) in N,N-dimethylformamide (2.0 ml) was added [2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (172 mg, 0.535 mmol), 1-hydroxybenzotriazole hydrate (14 mg, 0.107 mmol) and N,N-diisopropylethylamine (0.31 ml, 1.78 mmol), and the reaction mixture was stirred for 30 minutes at room temperature. After the addition of N-hydroxy-4-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzamidine (145 mg, 0.356 mmol), the reaction mixture was stirred for one hour at room temperature, and then heated to 110° C. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was treated with trifluoroacetic acid, and the reaction mixture was stirred for 1 hour. After removal of the solvent, the residue was purified with HPLC to afford 2-{(2R)-4-[4-(5-aminomethyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2-methyl-piperazin-1-yl}-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (44 mg, 0.096 mmol, 27%) as colorless crystals.