Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH2:19][CH2:18]1.C[Al](C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)=[O:26])[CH2:19][CH2:18]1
Reactant: COC(=O)CCN1CCOCC1
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CCN1CCOCC1)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 160 °C

Procedure:
To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) and methyl 3-morpholinopropanoate (63 μL, 0.39 mmol) in toluene (2.5 mL) was added a 2M solution of trimethylaluminum in toluene (0.22 mL, 0.43 mmol). The resulting solution was heated twice for 5 min at 160° C. in the microwave. After cooling, sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with brine and the combined organic layers were dried over anhydrous MgSO4. After evaporation, the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v and the desired product was obtained by elution with methanol to afford 17.5 mg (14%) of the title compound (LCMS RT=5.54 min, MH+ 352.0)
Reaction SMILES: C[Mg]Br.Br[C:5]1[CH:6]=[C:7]([C:18]#[N:19])[N:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1.C([Li])CCC.CCCCCC.[CH2:31]=[O:32]>C1COCC1>[C:13]([O:12][C:11](=[O:17])[NH:10][N:8]1[CH:9]=[C:5]([CH2:31][OH:32])[CH:6]=[C:7]1[C:18]#[N:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Agent: C[Mg]Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nn1cc(CO)cc1C#N
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Under argon, a 1 M solution of methylmagnesium bromide in THF (13.3 ml) was added over 15 min to a solution of tert-butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (3.7 g, 12.09 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883, Intermediate AAE, Step 3) in THF (37 ml) cooled to −60° C. After 30 min, a 1.6 M solution of n-butyllithium in hexane (15.1 ml, 24.2 mmol) was added over 10 min to the reaction, and the resulting mixture was stirred between −60° C. and −40° C. for 1 h. Then, paraformaldehyde (1.09 g, 36.3 mmol) was added to the reaction, and the reaction mixture was slowly warmed to rt and stirred overnight. After quenching with sat. aq. ammonium chloride solution, the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1→1:1) afforded 2.04 g (69% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22](=O)[CH2:23][C:24]([O:26]CC)=O)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:37]=[N:36][C:24](=[O:26])[CH:23]=2)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(COCC2=CC(=O)N=N2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 38.7 %

Procedure:
A solution of ethyl 4-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.50 g) and hydrazine hydrate (0.50 g) in ethanol (20 ml) was kept at room temperature for 4 days and then evaporated. The residue was purified by chromatography on silica gel (1.0 g) using dichloromethane plus 0-5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ethyl acetate to give the title compound (0.18 g), m.p. 207° C. Found: C,57.11; H,5.15; N,9.19. C22H24ClN3O6 requires: C,57.20; H,5.24; N,9.10%.
Reaction SMILES: [C:1]([C:3]([C:15]#[N:16])=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)#[N:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[F:17][C:18]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([NH:22][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:15]#[N:16])[CH:6]=[CH:7][C:8]=2[OH:14])[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:25]=1
Reactant: N#CC(C#N)=Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#CC(C#N)=Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 9.1 %

Procedure:
Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:53]=[C:52]2[C:47]([CH2:48][CH2:49][CH:50]([NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:51]2)=[CH:46][CH:45]=1>>[F:59][C:56]([F:57])([F:58])[C:55]([NH:54][CH:50]1[CH2:49][CH2:48][C:47]2[C:52](=[CH:53][C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:29]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)=[CH:45][CH:46]=2)[CH2:51]1)=[O:60]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)CC2
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)CC4)n2)c1
Yield: 40.8 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (99 mg, 0.22 mmol) (see Example 2, Step B) and N-(7-amino-1,2,3,4-tetrahydro-2-naphthalenyl)-2,2,2-trifluoroacetamide (69 mg, 0.26 mmol) following the protocol outlined in Example 54, Step C. Purification provided 60 mg (41%) of the coupled adduct as an oil. ES-LC/MS m/z=668 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:7][C:6]2[CH:21]=[CH:22][CH:3]=[CH:4][CH:5]=2)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 147.2 %

Procedure:
4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (Example 5-1b) (450, mg, 1.4 mmol), benzyl bromide (770 mg, 4.5 mmol), and cesium carbonate (1.5 g, 4.5 mmol) in DMF (10 mL) were stirred at 80° C. for 2 hours. The solution was cooled to room temperature, diluted with H2O (200 mL) and extract with ethyl acetate (3×, 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromotography (10% ethyl acetate in hexanes) to afford benzyl 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoate (517 mg, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 4.28 (s, 2H), 4.32 (s, 2H0, 5.40 (s, 2H), 6.79 (d, J=8 Hz, 2H), 6.96 (d, J=8 Hz, 2H), 7.04-7.07 (m, 2H), 7.21-7.23 (m, 3H), 7.35-7.47 (m, 5H), 7.85 (d, J=8 Hz, 2H), 8.17 (d, J=8.4 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH:36]=[C:35]1[C:43](O)=[O:44].Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43]([C:35]3[O:34][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH:36]=3)=[O:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc5ccccc5o4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 2-benzofuran carboxylic acid (0.39 g, 2.4 mmol) were added. To the reaction, was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 30% EtOAc in CH2Cl2 for 10 min, then 40% EtOAc in CH2Cl2 for 10 min) to afford benzofuran-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.59 g, 63%): mp, 292-295° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.3 min. (98%); 1H NMR (DMSO-d6): δ 2.09-2.10 (m, 1H), 2.55-2.65 (m, 2H), 2.84-2.93 (m, 1H), 4.97 (d, J=6.0 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.33-7.84 (m, 8H), 9.40 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 37.90, 48.87, 109.90, 111.79, 121.95, 122.81, 123.74, 126.96, 127.09, 127.15, 131.54, 133.02, 134.83, 138.71, 148.71, 154.27, 158.52, 166.94, 167.51, 169.82, 172.74. Anal Calcd for C23H17N3O6+0.2H2O: C, 63.51; H, 4.03; N, 9.66. Found: C, 63.45; H, 3.76; N, 9.52.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])O1.Br[C:28]1[O:32][C:31]([C:33]2[CH:34]=[CH:35][C:36]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37]([CH:40]=2)[C:38]#[N:39])=[N:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(O)C(O)C.O>>[C:38]([C:37]1[CH:40]=[C:33]([C:31]2[O:32][C:28]([C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH2:11][CH2:12][C@H:13]4[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:29][N:30]=2)[CH:34]=[CH:35][C:36]=1[O:41][CH:42]([CH3:44])[CH3:43])#[N:39]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)o2)cc1C#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)o2)cc1C#N
Yield: 67 %

Procedure:
Prepared using General Procedure 13. A 20 mL microwave vial was charged with (R)-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-32 (58.4 mg, 0.16 mmol), 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile INT-40 (50 mg, 0.16 mmol), potassium carbonate (68 mg, 0.5 mmol) and a 3:1 mixture of dimethylethylene glycol/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 ((3.9 mg, 0.004 mmol) was added and the solution degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 30 min. The solvent was removed and the residue dissolved in EA (10 mL), washed with brine, and then dried over MgSO4. The product was purified by chromatography (EA/hexanes) to afford 50 mg (67%) of (R)-tert-butyl 4-(2-(3-cyano-4-isopropoxyphenyl)oxazol-5-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-42 as an off-white solid. LCMS-ESI (m/z) calculated for C27H29N3O4: 459.5; found 460.2 [M+H]+, tR=4.1 min. 1H NMR (400 MHz, CDCl3) δ 8.32-8.03 (m, 2H), 7.60 (dd, J=8.6, 4.1 Hz, 1H), 7.32-7.22 (m, 3H), 7.00 (d, J=8.9 Hz, 1H), 5.19 (dd, J=15.5, 7.5 Hz, 1H), 4.82-4.56 (m, 2H), 3.12 (ddd, J=16.3, 9.0, 3.5 Hz, 1H), 2.95 (dt, J=16.3, 8.1 Hz, 1H), 2.70-2.51 (m, 1H), 1.83 (dq, J=13.1, 8.2 Hz, 1H), 1.43 (s, 9H), 1.41-1.35 (m, 6H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH3:11][NH+:12]1[C@@H:17]2[CH2:18][C:19]([CH2:21][C@H:13]1[CH2:14][CH2:15][CH2:16]2)=O.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:15]1[CH2:16][CH:17]3[N:12]([CH3:11])[CH:13]([C:14]2=1)[CH2:21][CH2:19][CH2:18]3
Reactant: C[NH+]1[C@@H]2CCC[C@H]1CC(=O)C2
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Temperature: 80 °C

Procedure:
In a 100 mL round-bottom flask were combined p-tolylhydrazine hydrochloride (1.58 g, 10 mmol; Aldrich), pseudopelletierine hydrochloride (2.0 g, 10.5 mmol; Acros), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5 hours, then cooled to room temperature. The solvent was decanted, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to pH ˜12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the resulting solid was recrystallized from ether to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.21-1.41 (m, 2H), 1.60-1.71 (m, 2H), 1.90-2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H), 2.42-2.52 (m, 1H), 3.16-3.27 (m, 2H), 4.09 (t, J=3 Hz, 1H), 6.86 (dd, J=8, 1 Hz, 1H), 7.10 (s, 1H), 7.17 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([C:10]([CH3:20])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.CN1CCOCC1.CCN=C=[N:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])C.Cl.C1C=C2N=NN(O)C2=CC=1.O.Cl.N1CC(C#N)C1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][C:2]([CH3:21])([CH3:1])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([C:10]([CH3:20])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:38]1[CH2:37][CH:36]([C:35]#[N:34])[CH2:40]1)=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cnc2[nH]cc3c2c1CN([C@@H](C(=O)O)C(C)(C)C)C3=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#CC1CNC1
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2[nH]cc3c2c1CN([C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C)C3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
(R)-3,3-Dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (10 mg, 0.033 mmol), DMAP (6 mg, 0.05 mmol), 4-methylmorpholine (0.015 mL, 0.13 mmol), EDC hydrochloride (10 mg, 0.050 mmol), HOBt hydrate (8 mg, 0.050 mmol) and azetidine-3-carbonitrile hydrochloride (6 mg, 0.050 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred under nitrogen at room temperature for 3 h. The solution was concentrated and purified by preparative HPLC (10-30% AcCN/H2O with 0.035% TFA) to give the title compound (1.4 mg, 12%). 1H NMR (500 MHz, CD3OD) δ 1.18 (s, 9H), 2.35 (d, J=8.8 Hz, 3H) 4.17-4.18 (m, 1 H), 4.29-4.31 (m, 2 H), 4.52-4.62 (m, 1 H), 4.64-4.69 (m, 1 H), 5.19-5.23 (m, 2 H), 5.45 (s, 1 H), 7.83 (d, J=16.1 Hz, 3 H), 8.19 (s, 1 H). [M+H] calc'd for C20H23N5O2, 366; found, 366
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:16][O:17][N:18]([CH3:25])[C:19](N(OC)C)=[O:20].Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([N:18]([O:17][CH3:16])[CH3:25])=[O:20])=[C:4]([O:8][CH3:9])[C:3]=1[F:10]
Reactant: CON(C)C(=O)N(C)OC
Reactant: COc1cccc(Cl)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(=O)N(C)OC)ccc(Cl)c1F
Temperature: -70 °C
Yield: 38.4 %

Procedure:
1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 10 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After 1.5 hours at −70° 1 g (6.9 mmol) N,N′-dimethoxy-N,N′-dimethyl urea in 6 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 7.5 ml of a 2 M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 30%) to yield 0.59 g 4-chloro-3-fluoro-2, N-dimethoxy-N-methylbenzamid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[N:16]=[C:15]1[CH:26]=CN(C)C>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[N:16]=[C:15]1[CH:26]=[O:2]
Reactant: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Yield: 101.1 %

Procedure:
To a well stirred mixture of sodium periodate (2.24 g, 10.47 mmol) in pH 7 buffer (10 mL) and tetrahydrofuran (10 mL) was added 3-(2-chloro-phenyl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.90 g, 2.62 mmol) all at once. The mixture warmed slightly to the touch and was stirred 1 h at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ethyl acetate. The phases were separated from the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated to afford 0.802 g (97%) of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as a 1:2 mixture of free aldehyde and hydrate which had: 1H NMR δ 9.52 (s,) [CHO], 8.20-7.45 (m, 7 H), 6.75 (d, J=7.4 Hz) [hydrate OH] and 6.49 (d, J=8 Hz) [hydrate OH], 5.14 (t, J=7.5 Hz) [hydrate methine CH].
Reaction SMILES: [ClH:1].O1CCOCC1.C(O[C:13]([N:15](C)[C@:16]([CH3:25])([C:21]([NH:23][CH3:24])=[O:22])[C:17](=[O:20])[O:18][CH3:19])=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:24][NH:23][C:21](=[O:22])[C@:16]([CH3:25])([C:17](=[O:20])[O:18][CH3:19])[NH:15][CH3:13]
Reactant: CNC(=O)[C@](C)(C(=O)OC)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@@](C)(NC)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 4.0 mol/L-hydrochloric acid-dioxane solution (5.0 mL) was added to a dioxane (5.0 mL) solution of N2-(t-butoxycarbonyl)-N,N2,O,2-tetramethyl-3-oxoserinamide (Intermediate 8-2, 1.5 g) under ice cooling, and the mixture was stirred for 18 hours at room temperature. Then, the reaction mixture was concentrated to obtain N,N2,O,2-tetramethyl-3-oxoserinamide hydrochloride (Intermediate 9-2, white solid) (1.1 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[C:15]([NH:25][C:26]3[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=3)[N:14]=[C:13]2[O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(NC(C)=O)cc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 404(MH+).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:30][CH3:31])=[C:21]([O:26][C:27](=[O:29])[CH3:28])[CH:22]=2)[CH:17]1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH3:41])[CH:34]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O.C(OCC)(=O)C.CCCCCC>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:30][CH3:31])=[C:21]([O:26][C:27](=[O:29])[CH3:28])[CH:22]=2)[CH:17]1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH3:41])[CH:34]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1C=Cc2cc(OC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)N1C=C(C=O)c2cc(OC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To anhydrous N,N-dimethylformamide (3.46 mL, 43.5 mmol) at 0° C. was added phosphorus oxychloride (1.83 mL, 19.2 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, and 6-acetoxy-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (3.7 mg, 8.70 mmol) in dichloromethane (8 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (5.26 g, 52.2 mmol) in water (10 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 mL). The organic layer was washed water (2×80 mL), saturated aqueous sodium bicarbonate solution (50 mL), saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded 6-acetoxy-1-(3-ethoxy-benzyl)-4-formyl-7-methoxy-1H-isoquinoline-2-carboxylic acid ethyl ester as a colorless oil (1.0 g, 25% yield).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7]2[CH:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH:31]=[CH:30][C:8]=2[C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:10])[CH2:2]1.C=O.O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:29])[CH:25]=1)[CH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:11][C:9](=[O:10])[C:8]1[CH:30]=[CH:31][C:32]([N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[CH:33][C:7]=1[NH:6][CH2:5][CH:3]1[CH2:2][N:1]([CH3:44])[CH2:4]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C)C3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a solution of 2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide (100 mg, 0.14 mmol) in dichloromethane (2 mL) were added formaldehyde 37 wt. % in water (0.014 mL, 0.168 mmol), TEA (0.4 mmol) and sodium triacetoxyborohydride (45 mg, 0.21 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with aqueous NaHCO3 sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 100:10:1 as the eluant, affording 5 mg of the title compound.