Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:22]([NH:24][O:25][CH3:26])=[O:23])[CH2:17][CH2:16]1.O.NN>CCO.CCOCC>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:22]([NH:24][O:25][CH3:26])=[O:23])[CH2:17][CH2:16]1
Reactant: CONC(=O)N(Cc1ccsc1)C1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CONC(=O)N(Cc1ccsc1)C1CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 1-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-3-methoxy-1-thiophen-3-ylmethyl-urea (0.69 g, 1.56 mmol) in EtOH (15 ml) was added hydrazine hydrate (0.49 ml, 15.6 mmol) and the reaction was stirred at rt for 16 h. The reaction mixture was diluted with Et2O (40 ml) to give a white precipitate. The solid was removed via suction filtration and the filtrate was concentrated in vacuo to give a white foam. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 83:15:2, v/v/v) gave 1-[1-(3-amino-propyl)-piperidin-4-yl]-3-methoxy-1-thiophen-3-ylmethyl-urea as a white foam (0.280 g, 57%). 1H NMR (CDCl3) δ 1.60-1.72 (m, 6H), 2.00 (t, 2H, J=9.0 Hz), 2.07 (br s, 3H), 2.39 (t, 2H, J=6.0 Hz), 2.75 (t, 2H, J=6.0 Hz), 2.98 (d, 2H, J=12.0 Hz), 3.65 (s, 3H), 4.25 (m, 1H), 4.29 (s, 2H), 6.95 (d, 1H, J=3.0 Hz), 7.10 (s, 2H), 7.34 (m, 1H).
Reaction SMILES: COC1C=C(N2CCC(N3CCN(C)CC3)CC2)C=CC=1N.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)[CH2:48][CH2:47]3)=[CH:42][C:41]=2[O:59][CH3:60])[C:36]([Cl:61])=[CH:35][N:34]=1.[CH3:62][P:63]([C:66]1[N:67]=[C:68]([O:73][CH3:74])[C:69]([NH2:72])=[N:70][CH:71]=1)([CH3:65])=[O:64]>>[Cl:61][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)[CH2:48][CH2:47]3)=[CH:42][C:41]=2[O:59][CH3:60])=[N:38][C:33]([NH:72][C:69]2[C:68]([O:73][CH3:74])=[N:67][C:66]([P:63]([CH3:62])([CH3:65])=[O:64])=[CH:71][N:70]=2)=[N:34][CH:35]=1
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nc(Nc2ncc(P(C)(C)=O)nc2OC)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine. 2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine is then reacted with 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33) according to the procedure described in Example 32.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[CH:6][NH+:5]=1.[F:15][C:16]1([F:29])[O:28][C:19]2=[CH:20][C:21]3[NH:25][C:24]([SH:26])=[N:23][C:22]=3[CH:27]=[C:18]2[O:17]1.O>C(O)C.[OH-].[Na+]>[F:29][C:16]1([F:15])[O:28][C:19]2=[CH:20][C:21]3[NH:25][C:24]([S:26][CH2:3][C:4]4[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[CH:6][N:5]=4)=[N:23][C:22]=3[CH:27]=[C:18]2[O:17]1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: COc1c[nH+]c(CCl)c(C)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.96 g of 2-chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride are added to a solution of 0.92 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol in 10 ml of ethanol and 10 ml of 1N sodium hydroxide solution. The yellow reaction mixture is stirred at 20° C. for 1 hour, a further 10 ml of water are added, whereupon a colorless solid precipitates out, the mixture is stirred for a further 5 hours and filtered and the residue is rinsed with 1N sodium hydroxide solution and water and dried to constant weight. The amorphous powder is recrystallized from methylene chloride/diisopropyl ether. 1.5 g (93% of theory) of the title compound are obtained in the form of colorless crystals of m.p. 160°-161° C.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7]([NH:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>Br>[N:13]1([CH2:12][CH2:11][NH:10][C:7]2[C:6]3[CH:19]=[CH:20][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COc1ccc2c(NCCN3CCOCC3)noc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc2c(NCCN3CCOCC3)noc2c1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
6-Methoxy-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine (2.9 g) was dissolved in 48% hydrobromic acid (50 ml) and heated to reflux under nitrogen for 3 hours. The reaction was cooled to room temperature, neutralized with saturated sodium carbonate (Na2CO3) solution, and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 3:2 acetone/heptane and subsequently titration with DCM/heptane provided the product (1.0 g), m.p. 151-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[C:16]([F:22])[C:17](OCC)=[O:18])[C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[O:9][CH2:10][C:4]=2[CH:3]=1.CO.[NH3:27]>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[C:16]([F:22])[C:17]([NH2:27])=[O:18])[C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(F)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C(F)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Temperature: 55 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
[step 2] Ethyl 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-fluoroacetate (1.6 g, 4.05 mmol) obtained in step 1 was dissolved in THF (14 mL), 2 mol/L ammonia methanol solution (20 mL, 40.5 mmol) was added, and the mixture was stirred at 55° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 v/v) to give 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-fluoroacetamide (910 mg, 61%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]#N)[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4].[OH:22]O.[OH-].[Na+].C[C:27](O)=[O:28]>CO>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([O:28][CH3:27])=[O:22])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: OO
Reactant: CCCCc1nc(C)nc(C#N)c1Cc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(C)nc(C(=O)OC)c1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 306 mg 6-butyl-4-cyano-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 6 mL methanol was added 0.885 mL (~7.81 mmol) 30% H2O2 and 0.937 mL (2.34 mmol) 2.5 N NaOH. The mixture was allowed to stir for 1 hour at room temperature. To the mixture was added ~1 mL HOAc. Solvent was removed in vacuo. The crude material (409 mg) was dissolved in ~20 mL methanol. To this was added 4.0 g Amberlyst-15®. The mixture was heated to 60° for 18 hours. After cooling to room temperature, ~5 mL pyridine was added. After stirring for 1 hour, the mixture was filtered through powdered cellulose flock, stripped of solvent in vacuo, stripped from toluene to remove remaining pyridine, then was medium pressure chromatographed on silica gel using 25% EtOAc/hexane to give 152 mg of the title compound, 46% yield. Rf 0.21 in 30% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric gulfate stain; 1H-NMR (300 MHz, CDCl3); δ 7.58 (m, 2H0, 6.81 (m, 2H), 4.12 (s, 2H), 3.87 (s, 3H), 2.75 (s, 3H), 2.67 (3 line m, 2H), 1.53 (m, 2H), 1.31 (m, 2H), 0.86 (3 line m, 3H).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:29])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=[O:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>CO>[OH2:26].[ClH:2].[ClH:1].[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)([OH:29])[CH2:10][CH2:11]1)=[O:28].[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][C:9]([OH:29])([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:28].[ClH:2].[ClH:2]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Product: O

Procedure:
A mixture of 3.5 parts of N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-2-nitrobenzamide hydrochloride, 90 parts of tetrahydrofuran and 40 parts of methanol is hydrogenerated at normal pressure and at room temperature with 0.2 parts of platinium dioxide. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt is filtered off and dried, yielding 2.6 parts of 2-amino-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}benzamide dihydrochloride hemihydrate; mp. 195.7° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16]=[CH2:17])=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C1CCN2C(=NCCC2)CC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][CH2:14][NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: Nc1nccs1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc(CC2CCN(CCCNc3nccs3)CC2)cc1
Reaction time: 0.17 h
Yield: 10.8 %

Procedure:
To a solution of 4-benzylpiperidine (3.51 g, 20.0 mmol) and DBU (0.030 ml, 0.20 mmol) in THF (40 ml) was dropwise added a solution of acrolein (90%, 1.485 ml, 20.0 mmol) in THF (10 ml) at −20° C. with stirring over a period of 10 minutes. The mixture was stirred for 1 hour while the temperature of the mixture is elevated from −20° C. to −10° C. To the mixture were added 2-amino-1,3-thiazole (2.00 g, 20.0 mmol) and sodium triacetoxyborohydride (8.48 g, 40.0 mmol), successively, at −10° C., and the mixture was stirred for 15 hours while the temperature of the mixture is elevated to room temperature. Under ice cooling, aqueous solution of 1N-sodium hydroxide (120 ml) was added, and the mixture was stirred for 30 minutes and extracted with diethyl ether (60 ml×4). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 100 g, ethyl acetate/methanol=1/0 to 85/15), and the desired fraction was concentrated under reduced pressure to give the titled compound (680 mg, 2.16 mmol) as white crystals. Yield 11%.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])[CH3:8]>ClC1C=CC=CC=1Cl>[CH2:7]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:20]=[C:2]([OH:3])[C:1]1=[O:5])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCCCNc1ccccc1N
Solvent: Clc1ccccc1Cl
Product: CCOCCCn1c(=O)c(O)nc2ccccc21
Yield: 55.5 %

Procedure:
In a solution containing 26.9 g of oxalyl chloride in 200 ml of o-dichlorobenzene at 60° C. under stirring, a solution containing 35.5 g of N-(3-ethoxypropyl)-o-phenylenediamine in 220 ml of o-dichlorobenzene is added for 42 minutes in several times. The mixture is then heated and stirred at 130° C. for 1.1 hours. The mixture is subjected to filtration during hot and the filtrate is cooled. Ether is added to the filtrate and the crystals are filtered, washed and dried, followed by combining second crystals to obtain 25.2 g of (1).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O1CCOCC1.[Br:18]N1C(=O)CCC1=O>COCCO>[Br:18][C:7]1[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]=1[CH2:10][OH:11]
Reactant: CCCCc1nc(CO)c[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: COCCO
Product: CCCCc1nc(CO)c(Br)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
10 g of 2-butyl-1H-imidazole-4-methanol (obtained by EP 0,253,310) were introduced into 150 ml of dioxane and 150 ml of 2-methoxyethanol with stirring and 12.7 g of N-bromo succinimide were added. The mixture was stirred at 40° C. for 2 hours and the reaction medium was allowed to cool down to ambient temperature for 90 minutes. After evaporation, the crystals were taken up in 250 ml of ethyl acetate and 150 ml of water and extraction was carried out with ethyl acetate. The extracts were washed with water, dried and filtered. Activated charcoal was added to the solution which was stirred for 10 minutes, followed by filtration and evaporation. The crystals were solubilized in 64 ml of hot ethyl acetate and then the solution stood for 90 minutes at 0° C. After separation, the crystals were washed with ethyl acetate, then with methylene chloride and separated and dried to obtain 4.39 g of the expected product melting at 160 ° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1ccccc1CN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C
Yield: 53 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-2-methoxybenzene. Yield 53%, white solid. 1H NMR (DMSO-d6, 400 MHz): .s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.83 (s, 3H), 4.50 (s, 2H), 5.20 (s, 2H), 6.91 (dt, J=1.2, 7.6 Hz, 1H) 7.00 (dd, J=0.8, 8.0 Hz, 1H), 7.27 (m, 2H), 7.82 (d, J=0.8 Hz, 1H), 8.20 (d, J=0.8 Hz, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an 1050 of 0.08 μm.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([Cl:36])[N:21]3[C@H:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[C:17]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:64][S:65](Cl)(=[O:67])=[O:66]>C(Cl)Cl>[Cl:36][C:20]1[N:21]([C@H:24]2[CH2:28][CH2:27][N:26]([S:65]([CH3:64])(=[O:67])=[O:66])[CH2:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[N:16]=[C:15]([C:12]1[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1)[N:23]=2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc4)nc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
tert-Butyl(3S)-3-(2-{2-[bis(tert-butoxycarbonyl)amino]pyrimidin-5-yl}-8-chloro-6-morpholin-4-yl-9H-purin-9-yl)pyrrolidine-1-carboxylate (1.32 g, 1.88 mmol) was dissolved in methylene chloride (5 ml) followed by the addition of trifluoroacetic acid (5 ml) and the resulting mixture was stirred for 0.5 hours. The solvent was removed azeotropically with toluene and evaporated under reduced pressure. The residue was dissolved in methylene chloride followed by the addition of triethylamine (1 ml) and methanesulfonyl chloride (170 μl, 2.26 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned with ethyl acetate and water, and the solid that was not dissolved in either layer was collected by filtration, washed with ethyl acetate and water, and dried. This solid was suspended in methylene chloride, and then the insoluble matter was collected by filtration and dried to give the title compound (0.38 g, 42%) as a pale grey solid.
Reaction SMILES: [C:1]([C@@:3]1([CH:32]2[CH2:34][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:23][N:22]([C:24](OC(C)(C)C)=[O:25])[CH2:21]4)[CH:19]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].Cl.O.C(#N)C.[C:40]([O:43][CH2:44]C)(=O)C>>[CH:32]1([C@:3]2([C:1]#[N:2])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:23][N:22]([C:24](=[O:25])[CH2:40][O:43][CH3:44])[CH2:21]5)[CH:19]=4)[N:9]=3)[C:4]2=[O:31])[CH2:34][CH2:33]1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COCC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (300 mg) obtained in Step C of Example 131 in ethyl acetate (5 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, to a suspension of the reaction mixture in tetrahydrofuran (10 mL) were added triethylamine (1.3 g) and methoxyacetyl chloride (77 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol). The obtained crude product was subjected to HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH4HCO3)), and the obtained fraction was concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (60 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:6]2[CH2:7][CH2:8][CH:3]1[CH:4]1[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:5]12.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C@@H:5]2[C@H:6]3[C:2]([CH3:1])([CH3:14])[C@H:3]([CH2:8][CH2:7]3)[C@@H:4]2[C:12]([OH:11])=[O:13])=[O:10])=[CH:18][CH:17]=1
Reactant: CC1(C)C2CCC1C1C(=O)OC(=O)C12
Reactant: Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@@H]2CC[C@H]1[C@@H](C(=O)Nc1ccc(Cl)cc1)[C@H]2C(=O)O

Procedure:
Following General Procedure A, Compound 3 (0.047 g, 0.24 mmol) and 4-chloroaniline (31 mg, 0.24 mmol) in chloroform (4 mL) was converted into the title compound, which was isolated as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][C:4]=1[O:23][CH3:24].OC1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35]C)=[O:34].[C:37](=O)([O-])[O-:38].[K+].[K+].Cl>CN(C)C=O>[CH3:37][O:38][C:21]1[CH:22]=[C:3]([CH:2]=[CH:5][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:12][C:13]=1[CH3:14])[CH2:4][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([OH:35])=[O:34]
Reactant: COC(=O)Cc1ccccc1O
Reactant: COc1cc(OCc2nc(-c3ccccc3)oc2C)ccc1CCl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(COc2ccccc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A mixture of 4-(4-chloromethyl-3-methoxyphenoxymethyl)-2-phenyl-5-methyloxazole (2.08 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (1.65 g) and N,N-dimethylformamide (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.36 g, 49%) of 2-[2-[3-methoxy-4-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless needle crystals. melting point: 165-166° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[CH:22][N:23]=3)[CH2:14][CH2:13]2)[CH2:2]1.[Cl:27][CH2:28][C:29]([NH2:31])=[O:30]>CS(C)=O>[ClH:27].[ClH:27].[NH:24]1[C:21]2=[CH:22][N:23]=[C:18]([N:15]3[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C@H:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[N:1]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:2]4)[CH2:13][CH2:14]3)[CH:19]=[C:20]2[CH:26]=[CH:25]1
Reactant: NC(=O)CCl
Reactant: c1ccc2c(c1)NC[C@H]2CCN1CCN(c2cc3cc[nH]c3cn2)CC1
Solvent: CS(C)=O
Product: Cl
Product: NC(=O)CN1C[C@@H](CCN2CCN(c3cc4cc[nH]c4cn3)CC2)c2ccccc21

Procedure:
from 5-{4-[(S)-2-(2,3-dihydro-1H-indol-3-yl)-ethyl]-piperazin-1-yl}-1H-pyrrolo[2,3-c]pyridine and 2-chloroacetamide. Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N>C1COCC1.CO>[CH3:29][O:30][CH2:31][C:32]([NH:12][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:3]=2[O:2][CH3:1])[CH:11]=[CH:10][N:9]=1)=[O:33]
Reactant: COCC(=O)Cl
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2OC)ccn1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a suspension of 4-(2-methoxy-4-nitrophenoxy)pyridin-2-amine (233 mg, 0.892 mmol) in THF (5.0 mL) and DIPEA (775 μL, 6.12 mmol) at 0° C. was added 2-methoxyacetyl chloride (325 μL, 3.57 mmol) in a single portion. The reaction mixture was warmed to RT for 1 hr and then a solution of NH3 in MeOH (7M, 2.0 mL) was added. After 30 min at RT the mixture was evaporated in vacuo and the residue was partitioned between DCM (50 mL) and brine (40 mL). The organic phase was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 2% MeOH in DCM, isocratic elution) to afford 2-methoxy-N-(4-(2-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide as an orange oil (234 mg, 78%); Rt 1.89 min (Method 2); m/z 334 (M+H)+ (ES+).