Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH2:31])=[N:23]1>C(O)C>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Reactant: Nc1n[nH]c2ccccc12
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2n[nH]c3ccccc23)n1
Yield: 26.5 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and 1H-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 mL) was heated at 160 C and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 C for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol:dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, 27%). 1H NMR (500 MHz, d6-DMSO) δ 9.78 (br s, 1H), 8.62 (d, 1H), 7.9-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.70-7.68 (m, 1H), 7.65-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.45 (m, 3H), 7.41-7.38 (m, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 6.95-6.92 (m, 1H), 5.76 (s, 1H); LC-MS (ES+) m/e=405.18 (M+H); HPLC-Method D Rt 2.74 min.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2occ(C(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
Methyl 3-isopropyl-1-benzofuran-5-carboxylate (1.20 g, 5.51 mmol) is dissolved in MeOH (20 ml) and water (4 ml), treated drop-wise with 2N NaOH (3.3 ml, 6.6 mmol) and stirred at RT for 2 days, then at 40° C. for 4 h. The volatiles are removed in vacuo, the residue is dissolved in water (10 ml) and the pH is adjusted to 3 with concentrated HCl. The resulting precipitate is isolated via filtration and dried overnight to afford 1.08 g (97%) of 3-isopropyl-1-benzofuran-5-carboxylic acid as a white solid. MS (ESI−) for C12H12O3 m/z: 203.0 (M−H)−.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nsc(N)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1cccc(-c2c[nH]c3ccc(-c4nsc(N)n4)cc23)n1
Temperature: 100 °C
Yield: 20.3 %

Procedure:
To a solution of 3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.25 g, 0.49 mmol) in 1,4-dioxane (10 mL) was added 10% aq NaOH (5 mL) and the reaction was heated at 100° C. for 2 h. The reaction was quenched with ice cold H2O to give a pale yellow precipitate. The precipitate was filtered, washed with ice cold H2O and dried under vacuum. The crude product was purified with preparative HPLC (eluent: 30-100% MeCN in H2O with 5 mM NH4OAc) to give 3-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (35 mg, 20.2%). MS (ESI, pos. ion) m/z: 352.3 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ 11.65 (brs, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.91 (dd, J=8.4, 1.6 Hz, 1H) 7.85 (brs, 2H), 7.66 (t, J=8, 1H) 7.46 (d, J=8.8, 1H), 7.39 (d, J=7.6, 1H), 6.50 (d, J=8, 1H), 5.58-5.55 (m, 1H), 1.42 (d, J=6 Hz, 6H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[C:2]1([C:1]2[O:20][C:18](=[O:19])[CH:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2)=NC1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 85.5 %

Procedure:
A suspension of N-benzoyl-DL-phenylalanine (5.39 g) and acetic anhydride (12.3 g) is stirred at 80° C. for 40 minutes under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure to give the titled reference compound (4.30 g).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pd]>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]2)=[CH:15][C:16]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[N:17][CH:18]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ncc2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (121 mg, 0.309 mmol) in EtOH (5 mL) and EtOAc (3 mL) was added 10% palladium on carbon (32.9 mg, 0.031 mmol). The reaction was stirred under a hydrogen atmosphere (H2 balloon) at RT. After 3 hours, the reaction mixture was filtered through Celite® brand filter aid (washed with MeOH and DCM), and concentrated to afford cis-4-(5-amino-2-morpholinopyridin-4-ylamino)-N-isopropylcyclohexane-carboxamide as a dark oil. The diamine was dissolved in THF (3 mL), and 4-fluorobenzoyl isothiocyanate (61.8 mg, 0.341 mmol) was added. The reaction was stirred at 0° C. for 15 minutes, and then EDC (89 mg, 0.465 mmol) and DIPEA (0.081 mL, 0.465 mmol) were added. The reaction was stirred at 60° C. for 2 hours and then overnight at RT. After 16 hours, the reaction mixture was concentrated, and adsorbed onto a plug of silica gel. The residue was purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as a light-yellow powder (38 mg, 24.11% yield). MS, m/z (C27H33FN6O3): calcd, 508.3. found, 509.1 [M+H].
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.CN(C=O)C.[Cl-].[Na+].O>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[CH2:26][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3ccccc3N2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of phenol (1.715 g, 18.22 mmol, 1.2 eq) in THF (100 mL) was slowly added sodium hydride (0.915 g, 22.87 mmol, 1.5 eq) and the reaction was stirred at rt 1 hour. (S)-2-(Toluene-4-sulfonyloxymethyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6.077 g, 15.14 mmol, 1 eq) (J. Org. Chem, 62, 7679, 1997) in THF (50 mL) and DMF (50 mL) were added and the mixture was heated at reflux overnight. After cooling, it was poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The crude residue purified by column chromatography using ethyl acetate/hexanes (15/85) as an eluent to give the title compound as a colorless oil (3.371 g, 74%). NMR (400 Mz, DMSO-d6): consistent
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH2:7][CH3:8])[CH2:5][OH:6].Cl[CH2:10][C:11](OCC)=[O:12].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:7]([C@@H:4]1[NH:3][C:11](=[O:12])[CH2:10][O:6][CH2:5]1)[CH3:8]
Reactant: CCOC(=O)CCl
Reactant: CC[C@H](N)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC[C@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To an ice cold, stirred suspension of NaH(60% in oil, 1.6 g, 39.0 mmol) in toluene (50 mL) was added dropwise a solution of (S)-2-aminobutan-1-ol (1.5 g, 17.0 mmol) in toluene (36 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (9 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid NH4Cl (2.0 g, 38.7 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 methylene chloride/CH3OH) to give (S)-5-ethylmorpholine-3-one (1.9 g, 88%) as an off-white semi-solid: 1H NMR and MS consistent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A solution of m-nitrophenol (1.8 g, 13 mmol) in dichloromethane (13 mL) was treated with dihydropyran (1.7 mL, 19 mmol) followed by pyridinium p-toluenesulfonate (0.32 g, 1.2 mmol) and stirred at 25° C. for 16 h. The reaction mixture was diluted with dichloromethane and washed with 1:1 brine/water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude oil. This material was purified by flash column chromatography to give the desired product (2.5 g, 88%) as a clear oil.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([C:30](=O)[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:16]([C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:17][CH:18]([CH3:20])[CH3:19])(C)(C)C>CO>[CH:23]1([NH:22][C:21](=[O:29])[CH:16]([N:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:30]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)CC(C(=O)NC1CCCCC1)N(C(=O)c1ccc(Cl)cc1)c1ccccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)CC(C(=O)NC1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Temperature: 145 °C

Procedure:
Concentrated HCl (25% in water, 0.5 mL) was added to a solution of crude {2-[(4-chloro-benzoyl)-(1-cyclohexylcarbamoyl-3-methyl-butyl)-amino]-phenyl}-carbamic acid tert-butyl ester (83 mg, 0.12 mmol) in methanol (2.0 mL). The reaction mixture was heated in a focussed microwave (CEM Discovery) at 145° C., for 3 minutes with stirring. The reaction mixture was then evaporated, purified by preparative HPLC (gradient elution: water/acetonitrile with 0.1% trifluoroacetic acid) and evaporated under vacuum. This was then re-dissolved in dichloromethane (2 mL), PS-carbonate resin (4 mmol/g, 100 mg) was added and the mixture shaken for 2 hours. The mixture was filtered and evaporated to afford 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-4-methyl-pentanoic acid cyclohexylamide, 30 mg (46%) as a white solid. MS (ES+): 424 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=O)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].N>CO.C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:15]([C@H:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:23][N:19]4[CH2:20][CH2:21][CH2:22][C@H:18]43)=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)CN2CCCC2c2cccc(OCC3CCN(C(C)C)CC3)c2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCC4CCN(C(C)C)CC4)ccc32)cc1
Yield: 70 %

Procedure:
2-{2-[3-(1-Isopropyl-piperidin-4-ylmethoxy)-phenyl]-pyrrolidin-1-yl}-(4-methoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.31 mmol scale, to give 1.04 g (70%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H36N2O3, 450.3; m/z found, 451.5 [M+H]+. 1H NMR (MeOH-d4): 7.84 (m, 2H), 7.20 (m, 1H), 7.01 (d, J=1.5, 1H), 6.96 (d, J=7.5, 1H), 6.92 (m, 2H), 6.81 (m, 1H), 4.89 (s, 1H), 3.96 (d, J=16.6, 1H), 3.86 (m, 5H), 3.46 (m, 3H), 3.29 (m, 3H), 2.80 (t, J=12.3, 2H), 2.33 (m, 1H), 2.18 (m, 1H), 2.02 (m, 4H), 1.87 (m, 1H), 1.75 (m, 1H), 1.64 (m, 2H), 1.28 (d, J=6.7, 6H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OCCN1CCc2ccccc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1SC(Cc2ccc(OCCN3CCc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 240 mg of 2-(indolin-1-yl)ethanol (prepared as described in Preparation 9), 690 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 370 mg of 1,1'-(azodicarbonyl)dipiperidine and 5 ml of anhydrous tetrahydrofuran were used, to give 530 mg of the title compound having Rf=0.88 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[C:14]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:15]4[C:16](=[O:31])[NH:17][C:18]5[CH:24]=[C:23]([N:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:22]=[CH:21][C:19]=5[C:20]=4[C:11]=3[C:10]([CH3:40])=[N:9]2)=CC=1.C(OC(C)C)(C)C.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:14]2[C:15]3[C:16](=[O:31])[NH:17][C:18]4[CH:24]=[C:23]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:22]=[CH:21][C:19]=4[C:20]=3[C:11]3[C:10]([CH3:40])=[N:9][NH:8][C:12]=3[N:13]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(Cn2nc(C)c3c4c(c(-c5ccc(OC)cc5)nc32)c(=O)[nH]c2cc(N3CCNCC3)ccc24)cc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nc3[nH]nc(C)c3c3c2c(=O)[nH]c2cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4.5 g (8.03 mmol) of 3-(4-methoxybenzyl)-5-(4-methoxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one dissolved in 70 ml of trifluoroacetic acid is carried at 70° C. for 4 hours and then cooled to room temperature before the addition of isopropyl ether (150 ml). The reaction medium is stirred at room temperature for 30 minutes and then the precipitate obtained is filtered to yield 5-(4-methoxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one trifluoroacetate. The solid is dissolved in 180 ml of anhydrous dichloroethane. The reaction medium is cooled to 0° C. before the slow addition of 43.3 ml (43.3 mmol) of a 1 M solution of boron tribromide in dichloromethane. The reaction medium is carried at reflux for 7 hours and then cooled again to 0° C. Methanol (approximately 200 ml) is added and then the reaction medium is stirred for 2 hours. The solid obtained is filtered and then triturated several times in hot methanol. A final filtration yields 2.6 g (47%) of 5-(4-hydroxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one hydrobromide in the form of an orange solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[Na].[C:23]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br)#[N:24]>CS(C)=O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[C:23]#[N:24])=[CH:16][CH:17]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1CBr
Reactant: CCCCc1cccc(=O)n1Cc1ccc(O)cc1
Agent: CO[Na]
Solvent: CS(C)=O
Product: CCCCc1cccc(=O)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.57 g of 6-butyl-1-p-hydroxybenzyl-1,2-dihydro-2-oxopyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH3ONa and 40 ml of DMSO is stirred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of DMSO is added dropwise and the mixture is stirred for 16 hours at 20° and evaporated to give 6-butyl-1-(4-o-cyanobenzyloxybenzyl)-1,2-dihydro-2-oxopyridine after conventional working-up.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22](=O)[C:23]#[C:24][CH2:25][O:26]C)C>C(O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:25](=[O:26])[CH:24]=[C:23]([CH2:22][O:21][CH3:19])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C#CCOC
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: CCO
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)C)cc1)O2
Yield: 69.6 %

Procedure:
To a solution of (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine (2.3 g, 9.26 mmol) (prepared according to the procedures employed in Step 1 through 2 of Example 1) in ethanol (35 mL) was added 1.7 g (12.04 mmol) of 4-methoxy-but-2-ynoic acid ethyl ester (prepared in accordance with the procedures as described in Larock, J Org Chem 2002, 67, 9318). This mixture was stirred at reflux for 6 hours and cooled. The reaction mixture was concentrated and loaded onto a silica gel column. Chromatography with 1-10% EtOH/CH2Cl2 provided 2.22 g of the title compound. [α]D25 −18.00 (c 0.5, CHCl3)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:26]=1[CH2:27][NH:28][C:29]1[C:30]([NH2:36])=[CH:31][CH:32]=[C:33]([F:35])[CH:34]=1>C(#N)C.[Cl-].[Na+].O>[CH3:23][O:24][C:25]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:26]=1[CH2:27][NH:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: COc1ccc(CNc2cc(F)ccc2N)c(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNc2cc(F)ccc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Temperature: 65 °C
Yield: 37.7 %

Procedure:
A mixture of (R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine (32 mg), N1-(2,4-dimethoxybenzyl)-5-fluorobenzene-1,2-diamine (28 mg) and KCO3 (41 mg) in ACN was heated at 65° C. for 3 hr, cooled to RT, diluted with brine and extracted with EtOAc (2×). The combined organics were evaporated, and purified by column chromatography (eluted with 30% EtOAc/Hex) to yield the titled product (21 mg). 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.6 (br d, 1H), 7.2-6.8 (m, 6H), 6.5-6.3 (m, 4H), 4.4-4.2 (m, 4H), 3.8 (s, 6H), 2.3-2.2 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11](N(OC)C)=[O:12])[C:8]([Br:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:17][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][C:9]=1[CH:11]=[O:12]
Reactant: CON(C)C(=O)c1nc(NC(C)=O)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)c(C=O)n1
Reaction time: 1 h

Procedure:
To the crude material from last step (1B, 2.6 g, 8.6 mmol) in THF (tetrahydrofuran)(30 mL) was added DIBAL-H (diisobutylaluminium hydride)(13 mmol, 1.5 equiv) dropwise at 70° C. The reaction was stirred for 1 h and was then quenched with NH4Cl solution. The reaction mixture was partitioned between EtOAc and saturated NH4Cl solution. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was used in the next step without further purification. MS (m/z) 244.1 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[Cl:24])=[O:16].[OH-].[Na+]>COCCOC>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH2:14][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
A reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 5.0 g, 125 mmol), DME (40 ml) and 2-chloro-5-trifluoromethylpyridine (6.93 g, 38.2 mmol). 2-Chloro-4-fluoroacetophenone (6.8 g, 39.4 mmol) in DME (10 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45° C. overnight. Upon the completion of the reaction, the mixture was cooled to 5° C. and 10% aqueous sodium hydroxide solution (20 ml) was slowly added to the reaction mixture. The mixture was partitioned between diethylether (300 ml) and water (300 ml). The layers were separated, the organics dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3). Concentration of the appropriate fractions afforded 8.10 g (67%) of the title compound.
Reaction SMILES: [Na:1].CO[CH:4]1[O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:6][O:5]1.[CH2:31]1[C:35]2(OCC(CO)CO2)C[CH2:33][CH2:32]1>>[Na:1].[CH2:35]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)=[O:20])[C:13]=3[CH3:30])[CH2:6][O:5]2)[CH2:33][CH2:32][CH2:31]1
Reactant: OCC1COC2(CCCC2)OC1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCC2COC3(CCCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.1 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 6,10-dioxaspiro[4.5]dec-8-ylmethanol obtained in the step (21a) to obtain the title compound (180 mg, total yield: 8.1%) as a light yellow solid.