Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:25]1[C:28]2([CH2:31][NH:30][CH2:29]2)[CH2:27][O:26]1.C(O)(=O)C(O)=O>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[CH2:31][C:28]5([CH2:25][O:26][CH2:27]5)[CH2:29]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Reactant: C1NCC12COC2
Agent: O=C(O)C(=O)O
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CC5(COC5)C4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from Rac-(1S,3S)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 2-oxa-6-aza-spiro[3.3]heptane as oxalic acid salt (CAS [1045709-32-7]; Angew. Chem. Int. Ed. 2008, 47, 4512-4515) to afford the desired product as a light yellow oil. MS (EI): 450.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4].[CH2:19]=O>C(O)=O>[CH3:19][N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=O
Reactant: COC(=O)c1ccc(NCc2ccccc2)cn1
Solvent: O=CO
Product: CN(Cc1ccccc1)c1ccc(C(=O)O)nc1

Procedure:
The mixture of 4.84 g of 5-benzylaminopyridine-2-carboxylic acid methyl ester, 8 ml of 97% aqueous formic acid and 8 ml of 37% aqueous formaldehyde is heated on a steam bath for 22 hours. It is evaporated, the residue dissolved in water and the solution again evaporated. A third such cycle with acetonitrile-toluene yields a solid which is recrystallized from 90% aqueous acetonitrile, to yield the 5-(N-methyl-N-benzylamino)-pyridine-2-carboxylic acid melting at 168°-173°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@@H:19]1[CH2:41][C@@H:40]2[C@:35]([CH3:49])([CH2:36][CH2:37][C@@H:38]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH2:39]2)[C@@H:34]2[C@@H:20]1[C@H:21]1[C@:31]([CH3:50])([CH2:32][CH2:33]2)[C@@H:24]([C@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:11]([O:18][C@@H:19]1[CH2:41][C@@H:40]2[C@:35]([CH3:49])([CH2:36][CH2:37][C@H:38]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH2:39]2)[C@@H:34]2[C@@H:20]1[C@H:21]1[C@:31]([CH3:50])([CH2:32][CH2:33]2)[C@@H:24]([C@H:25]([CH3:30])[CH2:26][CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
DMSO (0.01 ml, 0.14 mmol) in CH2Cl2 (0.1 ml) was added dropwise to a stirred solution of oxalyl chloride (0.008 ml, 0.0917 mmol) in anhydrous CH2Cl2 (2 ml) at -78° C. under anhydrous conditions (drying tube). This solution was stirred at -78° C. for 15 minutes. Steroid 2008 (0.0234 g, 0.0423 mmol) in dry CH2Cl2 (0.5 ml) was then added dropwise and the solution stirred for 40 minutes at -780° C. Diisopropylethylamine (DIPEA) (0.08 ml, 0.458 mmol) was added and the solution allowed to warm to 0° C. with stirring over a 30-minute period. Aqueous saturated NaHCO3 solution (5 ml) was added and the solution extracted 3x with 5 ml CH2Cl2. The combined organic extracts were washed 2x with 5 ml of aqueous saturated NaCl solution, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2, 10:1 hexanes:EtOAc) gave compound 2009 (0.0226 g, 97%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 9.76 (s, 1H, C-24 H), 7.35-7.34 (m, 5H, benzyl Ar-H), 4.71-4.69 (m, 1H, THP ether methine H), 4.59 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.585 (d, J =11.8 Hz, 1/2H, benzyl-CH2), 4.30 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.29 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.95-3.89 (m, 1H, THP OCH2), 3.63-3.58 (m, 3H, C-24 H & THP OCH2) , 3.50-3.47 (m, 1H, C-3 H), 3.45 (s, 1H, 7-H), 2.49-2.42 (m, 1H, C-23H), 2.37-2.31 (m, 1H, C-23 H), 0.958 (d, J=6.5 Hz, 3H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 2900, 1700 cm-1 ; MS (CI/isobutane) m/z 552 (M+1, 0.4%), 465 (M+1-THP, 3%), 449 (M+1-THPO, 14%), 375 (M+1-THP-Bn, 7%), 359 (M+1-THP-HOBn, 68%), 341 (M+1-THP-HOBn-H2O, 100%); m.p. 50°-54° C.; Anal. calcd. for C36H54O4 : C=78.50, H=9.88; Found: C=78.11, H=10.04.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].C[O-].[Na+:26]>O1CCOCC1>[CH3:1][C:2]1[C:3]2[CH2:23][O:22][C:20](=[O:21])[C:4]=2[C:5]([OH:19])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([O-:18])=[O:17])\[CH3:13])[C:7]=1[O:8][CH3:9].[Na+:26]
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)[O-])C(=O)OC2

Procedure:
Mycophenolic acid (3.20 g, 10 mmol) was dissolved in 1,4-dioxane (64 ml). To this solution sodium methoxide (9 mmol, 1.67 ml of its 30% methanolic solution) was added under stirring. After 1 hour stirring at room temperature the solid was filtered off. The polymorphism was determined by X-ray diffraction from this wet sample. The obtained material was form M26.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[CH2:42]([N:49]=[C:50]=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(Cl)Cl.CO>C1COCC1>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:50]([NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:51]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)NCc1ccccc1

Procedure:
Analogously to Example 103, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71E) i) in 0.7 ml of THF are reacted with 21 μl (0.169 mmol) of benzyl isocyanate. Column chromatography (SiO2, methylene chloride/methanol 15:1) and digestion from DIPE yields the title compound: TLC Rf (A')=0.12; tRet (V)=15.5 min; FAB-MS (M+H)+ =694.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>C(Cl)Cl>[CH2:29]([NH:31][C:32]([NH:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][CH:8]=1)=[O:33])[CH3:30]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added TEA (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH:10]([CH2:18][CH2:19]Br)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:3][C:4]1[CH:5]=[N:6][N:7]([C:10]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:18]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnn(C2(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
Into a 25 mL round bottom flask were added sodium hydride (60% dispersion in mineral oil, 164.3 mg, 4.1 mmol) and anhydrous tetrahydrofuran (8 mL). The mixture was cooled with an ice-water bath before a solution of 4-methylpyrazole (204.2 mg, 2.487 mmol) in anhydrous tetrahydrofuran (2 mL) was added. The mixture was stirred in the ice-water bath for 30 minutes before tert-butyl 2,4-dibromobutanoate (0.48 mL, 2.2 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 18 h. The solvent was removed under reduced pressure and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford tert-butyl 1-(4-methyl-1H-pyrazol-1-yl)cyclopropanecarboxylate (218 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 9H), 1.45-1.51 (m, 2H), 1.61-1.67 (m, 2H)H), 1.98-2.01 (m, 3H)H), 7.21 (s, 1H), 7.23-7.26 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[CH3:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[Li]C(C)(C)C.CN([CH:30]=[O:31])C>C1COCC1>[CH3:21][C:16]1[N:15]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:7]=2[N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:30]=[O:31])[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)n1-c1cncc(Br)c1N1CCN(C)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cncc(C=O)c1N1CCN(C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-[3-bromo-5-(2,5-dimethylpyrrol-1-yl)-4-pyridyl]-4-methyl-piperazine (1250 mg, 3.579 mmol) in THF (35.79 mL) was cooled to −78° C. and t-BuLi (2.105 mL of 1.7 M, 3.579 mmol) was added dropwise. The mixture was stirred for 30 mins at −78° C. before DMF (261.6 mg, 277.1 μL, 3.579 mmol) was added dropwise. The mixture was stirred for 2 h at −78° C. The reaction was quenched with MeOH (5 mL) and allowed to warm to room temperature. The reaction was washed with an aqueous saturated solution of ammonium chloride (50 mL) and extracted with EtOAc (100 mL and 50 mL). The combined organics were dried (MgSO4) and evaporated to leave an orange oil. Purification by column chromatography (EtOAc to EtOAc:MeOH 20%) yielded 5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(4-methylpiperazin-1-yl)nicotinaldehyde as a pale yellow crystalline solid. MS (ES+) 299.2.
Reaction SMILES: O[CH2:2][C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:2][C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11]
Reactant: CN1CCCCC(CO)(c2cccc(O)c2)C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCCCC(CBr)(c2cccc(O)c2)C1=O
Reaction time: 16 h

Procedure:
3-Hydroxymethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (as described in Example 6, Step B) (0.60 g, 2.40 mmol), triphenylphosphine (0.94 g, 3.60 mmol), and carbon tetrabromide (1.19 g, 3.60 mmol) were dissolved in CH2Cl2 (15 mL), stirred under Ar for 16 h, then the solution was concentrated in vacuo and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH:17]=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1C=Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 66.7 %

Procedure:
A solution of [(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate prepared in Example 35, step 7 (250 mg, 0.542 mmol) and sodium azide (141 mg, 2.17 mmol) in anhydrous dimethyl sulfoxide (10 mL) was heated at 70° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (20 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 120 mg (67%) of (2R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-2H-chromene as a colorless syrup that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]3[O:39][C:40]4[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:41]=4[N:42]=3)=[CH:33][CH:32]=2)O1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13]3)[N:9]=[C:10]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38]4[O:39][C:40]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:41]=5[N:42]=4)=[CH:35][CH:36]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CN(C)CC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)CN(C)C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-1-[3-(4-Amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone was prepared from rac-1-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone (0.278 g, 0.669 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.305 g, 0.837 mmol) in a manner similar to that used for the preparation of cis-N-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.219 g, 62%). 1H NMR (DMSO-d6, 400 MHz) 2.17 (s, 3H), 2.23 (s, 3H), 2.3-2.50 (m, 4H), 2.34 (s, 3H), 2.40 (s, 3H), 2.99-4.26 (m, 4H), 5.44-5.49 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.65 (d, 2H), 7.92 (d, 2H), 8.26 (s, 1H), 10.86 (s, 1H); RP-HPLC Rt 10.765 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 526 (MH+).
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]([NH:7][C:8]([C@@H:10]([NH:15]C(C2C=CC3SC4C(=CC=CC=4)NC=3C=2)=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[CH2:5][CH2:4][O:3]1.[C:32]1([C:46]([OH:48])=O)[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[S:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:1][CH:2]1[C@@H:6]([NH:7][C:8]([C@@H:10]([NH:15][C:46]([C:32]2[C:45]3[NH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:37][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[O:48])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: O=C(O)c1cccc2c1Nc1ccccc1S2
Reactant: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@H]1CCOC1O
Product: CC(C)C[C@H](NC(=O)c1cccc2c1Nc1ccccc1S2)C(=O)N[C@H]1CCOC1O

Procedure:
The experimental protocol used is identical to that described for compound 17, with 10H-phenothiazine-1-carboxylic acid replacing 10H-phenothiazine-2-carboxylic acid. Yellow powder. Melting point: 99-101 ° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:13]=1)=[O:11].C(N(CC)CC)C.[C:36](Cl)(=[O:39])[O:37][CH3:38]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][N:25]([C:36]([O:37][CH3:38])=[O:39])[CH2:24]2)[CH:13]=1)=[O:11]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](n2cc(C(=O)Nc3c(Cl)cncc3Cl)c(=O)c3cccnc32)C1
Reaction time: 0.67 h
Yield: 88 %

Procedure:
Then, to a 4 ml anhydrous methylene chloride solution of (S)-N-(3,5-dichloropyridin-4-yl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide hydrochloride, 43.6 μl (0.31 mmol) of triethylamine and 9.7 μl (0.125 mmol) of methyl chlorocarbonate were added at room temperature and stirred for 40 minutes. The reaction solution was concentrated under vacuum and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=1/3) to obtain 45 mg (88%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COCCOc1ccc2ncnc(O)c2c1
Product: COCCOc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1
Yield: 18.8 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (138 mg, 0.5 mmol) and 4-chloro-6-(2-methoxyethoxy)quinazoline from Example 40A Step 5 (119 mg, 0.5 mmol) using the procedure of Example 16C. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (45 mg, 0.094 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.62 (s, 1H), 7.94 (d, 1H), 7.74-7.64 (m, 3H), 7.60 (s, 1H), 7.42 (t, 1H), 7.27 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 4.37-4.31 (m, 2H), 3.78-3.71 (m, 2H), 3.34 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>ClCCl>[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 11.6 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (125 mg, 0.53 mmol) in dichloromethane (5 ml) at 0° C. was added sodium carbonate (167 mg, 1.58 mmol) and propionyl chloride (58 mg, 0.63 mmol). The resulting mixture was stirred at RT for 13 h before volatiles were removed under reduced pressure. Purification by silica FCC (using a gradient of eluents; 100:0 to 98:2 DCM:2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (18 mg, 12% yield) as pale yellow oil. LCMS data: Calculated MH1(294). Found 86% (MH1) m/z 294, Rt=3.18 min (Method D).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=[N:56][C:51]3[CH:52]=[CH:53][CH:54]=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CCC1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:56][CH:51]4[CH2:52][CH2:53][CH2:54]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NC1CCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added cyclobutanamine (6.5 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of cyclobutanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobutylacetamide. (36 mg, 0.077 mmol, 55%).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([S:15]([C:18]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:32])=[CH:23][N:24]=[C:25]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[C:34]([C:38]([OH:40])=[O:39])([F:37])([F:36])[F:35]>>[F:35][C:34]([F:37])([F:36])[C:38]([OH:40])=[O:39].[Cl:32][C:22]1[C:21]2[C:26](=[CH:27][C:18]([S:15]([N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][C:6]([OH:33])=[O:5])(=[O:16])=[O:17])=[CH:19][CH:20]=2)[C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-phenylglycine t-butyl ester (25 mg, 0.05 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 2 h. The mixture was concentrated in vacuo, azeotroping with PhMe, and the residue triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-phenylglycine trifluoroacetate (13 mg, 0.23 mmol) as a pale yellow powder.