Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:44][CH3:45])=[C:11]([NH:13][C:14]2[N:15]=[C:16]([NH:33][C:34]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=3[C:36]([NH2:38])=[O:37])[C:17]3[CH:22]=[CH:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[N:19]=2)[CH:12]=1)=[O:5].[OH-].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][N:2]([CH3:46])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:44][CH3:45])=[C:11]([NH:13][C:14]2[NH:19][C:18]3=[N:20][CH:21]=[CH:22][C:17]3=[C:16]([NH:33][C:34]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=3[C:36]([NH2:38])=[O:37])[N:15]=2)[CH:12]=1)=[O:5]
Reactant: COc1ccc(NC(=O)CN(C)C)cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)CN(C)C)cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of 2-({2-{[5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (362 mg, 0.560 mmol) and a 1M aqueous KOH solution (5.60 mL, 5.60 mmol) in dioxane (20 mL) was heated at 80° C. for 7 h. The resulting mixture was allowed to cool to rt. EtOAc (50 mL) was added, followed by a saturated NaHCO3 solution (50 mL). The organic layer was washed with a saturated NaCl solution (50 mL), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (131 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 6H), 3.03 (s, 2H), 3.82 (s, 3H), 6.26 (dd, J=3.30, 1.83 Hz, 1H), 6.87-6.98 (m, 2H), 7.01 (dd, J=3.39, 2.29 Hz, 1H), 7.34 (dd, J=8.79, 2.56 Hz, 1H), 7.36-7.46 (m, 1H), 7.60 (s, 1H), 8.04 (s, 1H), 8.11 (s, 1H), 8.20 (d, J=2.56 Hz, 1H), 8.47 (d, J=8.42 Hz, 1H), 9.41 (s, 1H), 10.55 (s, 1H), 11.37 (s, 1H); ESIMS (M+H)+=493.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:13](\[CH:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.Cl.O.C([O-])(O)=O.[Na+]>CO>[OH:32][C:29]1[CH:28]=[CH:27][C:26](/[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][NH:2][CH3:1])=[CH:7][CH:8]=2)=[C:13](/[CH:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)\[CH2:14][CH3:15])=[CH:31][CH:30]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To a solution of (Z)-4-(1-(4-(2-(methylamino)ethoxy)phenyl)-2-(1,4-dioxaspiro[4.5]decan-8-yl)but-1-enyl)phenol (90 mg) in MeOH (10 mL) was added aqueous of HCl (3 M, 1.5 mL), the mixture was stirred at room temperature for 2 hours, 20 mL water was added, pH was adjusted to 7-8 by addition of aqueous NaHCO3, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated, and purified by column chromatography (CH2Cl2:MeOH=150:1) to give the desired product (22 mg, 27.5% yield). m/z=394[M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH2:2][C:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:4])[S:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])(=[O:22])=[O:23])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: CC(C)N1CCC(N(CC(=O)N2CCOCC2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(2-morpholin-4-yl-2-oxo-ethyl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 83 mg (2 equiv.) 2-chloro-1-morpholin-4-yl-ethanone and 100 mg (0.25 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(2-morpholin-4-yl-2-oxo-ethyl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material, which turned out to be hygroscopic with time.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)c3cn(-c4ccccn4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) in dry DMF was added NaH (1 eq) and the reaction mixture stirred at room temperature for 30 min and then treated with 2-fluoropyridine (1.5 eq) and heated at 140° C. under microwave irradiation for 15 min. Purification by preparative HPLC gave the desired product in 36% yield.
Reaction SMILES: C(O[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:10][C:9]=1[N+:25]([O-])=O)(=O)CC([O-])=O.Cl.[CH3:29][CH2:30][OH:31]>C(Cl)(Cl)Cl>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([C:11]2[CH:10]=[C:9]3[C:8]([CH2:29][C:30](=[O:31])[NH:25]3)=[CH:13][CH:12]=2)=[O:24])=[CH:20][CH:19]=1
Reactant: CCO
Reactant: O=C([O-])CC(=O)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Nitro-4-(4-nitrobenzoyl)phenyl] malonate (4.15 g, 9.61 mmol) was dissolved in EtOH (24 mL) after which Sn powder (9.16 g, 77 mmol) was added followed by dropwise addition of concentrated HCl(aq) (26 mL). The reaction mixture was allowed to reflux for 3 hours, filtered while hot and then allowed to cool to room temperature. The cooled reaction mixture was diluted with CHCl3 (400 mL) and then extracted once with H2O (400 mL). The aqueous layer was then neutralized with NaHCO3 (pH=7) and then extracted with a 95% EtOAc/5% i-prOH solution (3×400 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solution was then concentrated in vacuo affording the 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one in 51% yield (1.24 g, 4.90 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](Cl)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:16]([O:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][O:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(c1ccccc1)N(CCO)CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)c1ccccc1

Procedure:
N,N-bis(oleoyloxyethyl)benzamide was prepared by the procedue of example 1 from 19.5 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)benzamide and 60 gms. (0.2 mole) of oleoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:10]([Br:28])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
2,3-Dihydro-1-oxo-3-phenyl-1H-inden-6-yl acetate (10.1 g, 37.9 mmol) obtained in Step 3 was placed into a flask and dissolved in CCl4 (200 mL). To the resulting solution, NBS (14.8 g, 2.2 eq) and AIBN (0.62 g, 10 mol %) were added. The resulting mixture was allowed to reflux for 1 h. Then the mixture was further irradiated by a tungsten lamp (375W) for 1.5 h. After cooling to room temperature, the precipitate was collected using a Buchner funnel. The solid was dissolved in CH2Cl2 and washed with sat. Na2S2O3, H2O, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (12.0 g, 92%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8](=[O:19])[O:7][C:6]1=[O:20])C.CN>>[CH3:1][N:2]1[CH:4]=[C:5]([C:6]([OH:7])=[O:20])[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]1=[O:19]
Reactant: CN(C)C=C1C(=O)OC(=O)c2nc3ccccc3nc21
Agent: CN
Product: Cn1cc(C(=O)O)c2nc3ccccc3nc2c1=O

Procedure:
From 17d and methylamine, as for 18d except that, after reaction, the volatiles were removed at reduced pressure to leave the methylamine salt of 18z as a yellow-brown solid. This was suspended in a small amount of water and 10% sodium hydroxide was added dropwise, with stirring, until a solution was obtained. This was acidified with a minimum amount of concentrated hydrochloric acid and the solid which separated was filtered and washed with water to give the free acid as a yellow solid (52%), mp >300° C. (from dimethyl sulfoxide/1,4-dioxane). 1H NMR (d6-DMSO): δ 3.66 (s, 3H, NCH3), 7.97 (t, J=7.5 Hz, 1H), 8.08 (t, J=7.6 Hz, 1H), 8.25-8.32 (m, 2H), 8.79 (s, 1H), 14.03 (br s, 1H, COOH).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:41]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NCc1ccccc1)N1CCN(C(=O)Nc2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added benzyl isocyanate (0.103 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to give 157 mg (74.8%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[N+:39]([O-])([OH:41])=[O:40].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([N+:39]([O-:41])=[O:40])[CH:25]=[CH:24][C:23]=1[NH:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CN(CC(=O)OC)c1ccc(C)cc1OCCOc1ccccc1NC(C(=O)OC)C(=O)OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)CN(CC(=O)OC)c1ccc(C)cc1OCCOc1cc([N+](=O)[O-])ccc1NC(C(=O)OC)C(=O)OC
Temperature: 30 °C

Procedure:
50 g ((2-(2-(2-(Bis-methoxycarbonylmethyl-amino)-phenoxy)-ethoxy)-4-methyl-phenyl)-methoxycabonylmethyl-amino)-acetic acid methyl ester were dissolved in 600 ml glacial acetic acid. Under vigorous stirring 91.5 ml 1 molar nitric acid in glacial acetic acid was added and in a second step 28 ml of concentrated sulfuric acid was added. The temperature increased up to 30° C. The reaction mixture was directly poured in a 10 l ice/water mixture. The residue was filtered off, washed several times with water and dried under vacuum. The crude product was further purified by column chromatography on silica gel first with hexane/acetic acid ethyl ester (1:1) as eluent and a second time with toluene/acetonitrile (1:1) as eluent. The product was finally crystallized from propan-2-ol. Yield: 20 g.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH2:38][N:1]5[CH2:4][CH:3]([C:5]6[N:6]=[C:7]([C:10]7[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=7)[NH:8][N:9]=6)[CH2:2]5)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:19][CH2:18]1
Reactant: O=Cc1ccc(-c2nc3nc(C4CC4)nn3cc2-c2ccccc2)cc1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C7CC7)nn6cc5-c5ccccc5)cc4)C3)n[nH]2)n1

Procedure:
The compound is prepared in analogy to example 40.0. 211.6 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 250 mg (0.73 mmol) 4-(2-cyclopropyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (intermediate example 4.0) After the usual work-up and purification 97 mg (23.3%) of the desired compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:53]=[CH:52][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@@H:10]4[CH2:9][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:38]6[CH:53]=[CH:52][C:41]([CH2:42][N:43]7[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]7)=[CH:40][CH:39]=6)=[CH:7][N:6]=5)[CH2:13][CH2:12][O:11]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: CC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(Cc2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (50 mg, 0.11 mmol), 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl)piperazin-1-yl)ethanone (45 mg, 0.13 mmol), Pd(dppf)2Cl2 (4.5 mg, 0.005 mmol), and K2CO3 (45 mg, 0.33 mmol) were dissolved in dioxane (4 ml)+H2O (1 ml), and then degassed with N2 (gas), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-1-(4-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)ethanone (58 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][C:34](=[O:40])[NH:33][C:32]=2[CH:41]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:27][C:28]2[CH:29]=[CH:30][C:31]3[C:37]([CH3:38])([CH3:39])[CH2:36][CH2:35][C:34](=[O:40])[NH:33][C:32]=3[CH:41]=2)=[N:3][CH:4]=1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)ccc21
Yield: 76 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (88 mg, 0.22 mmol), 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mg, 0.22 mmol), and 10-Camphorsulfonic acid (7.8 mg, 0.033 mmol) in Isopropyl alcohol (2 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.25 mL satd. sodium bicarbonate, stirred for 10 min, then cooled for 1 h. The resultant solids were collected, washing with water, drying in vacuo to afford 3-{2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-5-morpholin-4-yl-phenoxy}-propionitrile as dark yellow solids (94 mg, 75%). MP: 150-156° C., LCMS 562 (M+H), 1H-NMR (CDCl3): 8.00 (d, 1H, J=8.9 Hz), 7.98 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.04 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.61 (d, 1H, J=8.8 Hz), 6.52 (s, 1H), 4.27 (t, 2H, J=6.2 Hz), 3.90 (t, 4H, J=4.7 Hz), 3.23 (t, 4H, J=4.7 Hz), 2.87 (t, 2H, J=6.2 Hz), 2.38 (t, 2H, J=7.0 Hz), 2.09 (t, 2H, J=7.0 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8]C)=O)=[N:2]1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>CO>[CH3:11][CH:10]([NH:13][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:8])[CH3:12]
Reactant: CC(C)N
Reactant: COC(=O)c1nc[nH]n1
Solvent: CO
Product: CC(C)NC(=O)c1nc[nH]n1
Temperature: 50 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
Methyl 1H-1,2,4-triazole-3-carboxylate (3.53 g, 27.8 mmol) and isopropylamine (11 ml, 128 mmol) were combined in a 20 ml vial to give a white suspension. The vial was sealed and heated to 50° C. After 6 days the reaction mixture had become a translucent solid. The vial was cooled to room temperature and unsealed. The solid was dissolved in methanol and transferred to a 200 ml flask. The solvent was evaporated under reduced pressure and the resulting residue was stripped several times with ethanol to removed excess isopropylamine. The residue was stripped with toluene and placed under high vacuum overnight to give the title compound (4.07 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc2c(n1)NCCC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 2-8 (1.4 g, 6.03 mmol) and 10% Pd/carbon (1 g) in EtOH (30 mL) was stirred under a balloon of hydrogen for 18 h. Filtration and evaporative removal of the solvent gave 2-9 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CO[C:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC1=CCCCCC1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC2=CCCCCC2)c1
Yield: 72.3 %

Procedure:
The compound 1 (401 mg, 1.20 mmol) was converted to the enol ether with 1-methoxy-1-cycloheptene (1.51 g, 12.0 mmol) in the same manner as the example 7 to give the compound 7 (372 mg, 77%) as oil. Rf 0.75 (Al2O3 60-type E, 2:1 hexane -EtOAc).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])=[N:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].[CH3:27][O:28][CH2:29][CH2:30]Br>O1CCCC1.CN(C)C=O>[C:1]([C:3]1[S:7]/[C:6](=[N:8]\[C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])/[N:5]([CH2:30][CH2:29][O:28][CH3:27])[CH:4]=1)#[N:2]
Reactant: COCCBr
Reactant: N#Cc1cnc(NC(=O)C23CC4CC(CC(C4)C2)C3)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1cc(C#N)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 183B (240 mg, 0.84 mmol) in N,N-dimethylformamide tetrahydrofuran (1:4, 10 mL) were added a solution of potassium tert-butoxide (Aldrich, 133 mg, 1.2 mmol) and commercially available, 2-bromoethyl methyl ether (Aldrich, 104 μL, 1.2 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL,). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.59-1.77 (m, 6 H), 1.84-1.91 (m, 6 H), 1.95-2.04 (m, 3 H), 3.26 (s, 3 H), 3.71 (t, J=5.3 Hz, 2 H), 4.36 (t, J=5.1 Hz, 2 H), 8.54 (s, 1 H); MS (ESI+) m/z 346 (M+H)+; Anal. Calculated for C18H23N3O2S: C, 62.58; H, 6.71; N, 12.16. Found: C, 62.15; H, 6.89; N, 11.95.