Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][C:36]([F:41])([F:40])[CH2:35]1)(=[O:33])=[O:32]>>[F:41][C:36]1([F:40])[CH2:37][CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC(F)(F)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(F)(F)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-difluoropiperidine. MS (ESI): mass calcd. for C21H19F3N4O2S, 448.12; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35-8.27 (m, 2H), 8.12-8.05 (m, 1H), 8.01-7.94 (m, 1H), 7.74-7.67 (m, 1H), 7.65-7.58 (m, 1H), 7.44-7.38 (m, 1H), 7.32-7.24 (m, 2H), 3.04-2.96 (m, 2H), 2.95-2.88 (m, 2H), 1.96-1.82 (m, 2H), 1.69-1.61 (m, 2H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:16])=[C:6]([CH3:15])[C:7]2[N:8]([C:10]([CH2:13][NH2:14])=[N:11][N:12]=2)[N:9]=1.O.ClCCl.[CH3:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([CH:23]([O:26][C:4]1[C:5]([CH3:16])=[C:6]([CH3:15])[C:7]2[N:8]([C:10]([CH2:13][NH2:14])=[N:11][N:12]=2)[N:9]=1)[CH2:24][CH3:25])[CH3:21]
Reactant: CCC(O)CC
Reactant: Cc1c(Cl)nn2c(CN)nnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(CN)nnc2c(C)c1C
Reaction time: 8 h

Procedure:
3-Pentanol (1.2 ml) was initially charged at RT with stirring. Thereafter, sodium hydride (77 mg) was added while cooling with ice. After stirring at 55° C. for 3 h, (6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamine (W2.169; 50 mg), dissolved in 3-pentanol (1 ml) and DMF (2 ml), was added dropwise. After stirring for 2 h, the reaction mixture was left to stand at RT overnight, admixed with water and dichloromethane and then extracted three times more with dichloromethane. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 44 mg of the title compound were obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[F:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[OH:9]
Reactant: Oc1cnccc1F
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1nccc(F)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 500 mg (3.43 mmol) of 4-fluoropyridin-3-ol hydrochloride were dissolved carefully in 3.2 ml of concentrated sulphuric acid, and 0.21 ml of concentrated nitric acid was added carefully at 0° C. The reaction was warmed to RT and stirred overnight. The mixture was added to 10 g of ice, and 6 ml of 45% strength aqueous sodium hydroxide solution were added dropwise with ice cooling. The solid formed was filtered off and then dried under reduced pressure overnight. This gave 191 mg (36% of theory) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O[NH:13][C:14](=[NH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:15]([C:14]1[N:13]=[C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[O:3][N:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC(=N)NO
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Yield: 34 %

Procedure:
The same procedure as employed in the preparation of Example 277 (step a) but using 4-carboxybenzaldehyde and N-hydroxynonanimidamide gave the title compound as a beige solid (34%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 8.29 (d, 2H, J=8.3 Hz), 8.03 (d, 2H, J=8.3 Hz), 2.81 (t, 2H, J=7.4 Hz), 1.86-1.75 (m, 2H), 1.46-1.21 (m, 10H), 0.87 (m, 3H). HPLC (Condition A), Rt: 5.16 min (HPLC purity: 95.4%).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[S:10][C:9]=1[C:16]([O:18]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[S:10][C:9]=1[C:16]([NH2:2])=[O:18])[CH3:5]
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc([N+](=O)[O-])sc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (35 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-5-nitrothiophene-2-carboxylate (400 mg) in THF (10 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (50:50) as eluents to give the product as a yellow color solid (90 mg, 26%), mp 240-246° C. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (1H, s), 8.05 (1H, s), 7.91 (1H, s), 3.63 (3H, s), 3.26 (3H, s); LC-MS (positive ion mode): m/z 266 (M+Na)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([CH:7]2[C:12](=O)[CH2:11][C:10]([CH3:15])([CH3:14])[CH2:9][C:8]2=[O:16])=O)[CH2:3][CH2:2]1.Cl.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)#[N:19].CC(O)=O>CCO>[CH:1]1([CH2:4][C:5]2[C:7]3[C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][C:12]=3[N:26]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:27]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc(C#N)cc3)c2C1
Yield: 51.2 %

Procedure:
2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione (111.1 mg, 0.5 mmol) and 4-cyanophenylhydrazine hydrochloride (84.8 mg, 0.5 mmol, 1.0 eq) were suspended in 4 mL of 3:1 EtOH:AcOH and microwaved at 100° C. for 10 minutes. The solvent was removed in vacuo and the resultant residue purified by column chromatography to yield 81.8 mg (51% yield) of 4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile as an off-white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16](SCC4C=CC(OC)=CC=4)=[CH:15][N:14]=3)[CH2:8]2)=[CH:3][CH:2]=1.[NH4+].[OH-].C(Cl)Cl>>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH2:10][C@@H:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]4[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=4)[N:14]=3)[CH2:8]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(CSc2ccc(OC3CCN(c4ccncc4)C3)nc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc2nc(O[C@@H]3CCN(c4ccncc4)C3)ccc2c1

Procedure:
Rf=0.37 (10%MeOH/1%NH4OH/CH2Cl2)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH:8]([C:5]1[N:6]=[CH:7][C:2]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=Cc1ccc(Br)cn1
Reactant: CNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(C=O)nc1
Temperature: 110 °C
Yield: 51.3 %

Procedure:
A mixture of 5-bromo-2-pyridinecarbaldehyde (1.5 g, 8.064 mmol), 1,1-dimethylethyl methylcarbamate (D83) (1.267 g, 9.677 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.148 g, 0.161 mmol), xantphos (0.373 g, 0.645 mmol) and cesium carbonate (3.678 g, 11.289 mmol) in dioxane (35 mL) was heated at 110° C. overnight under an argon atmosphere. On cooling, the solvent was removed in vacuo and the residue partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-50% ether/petroleum ether gave the title compound as a brown oil (0.977 g). δH (CDCl3, 400 MHz) 10.01 (1H, s), 8.79 (1H, d), 7.94 (1H, dd), 7.86 (1H, dd), 3.40 (3H, s), 1.53 (9H, s). MS (ES+): 259.1 (MNa+), 181.2, no molecular ion (MH+) observed.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pt]>[OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C:3]=12
Reactant: [H][H]
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)CC3
Yield: 52.9 %

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (5 g, 14.60 mmol) and sulfided platinum (5% on carbon, 1 g) in toluene/isopropyl alcohol (200/50 mL) was hydrogenated 16 h at room temperature under atmospheric pressure of hydrogen. The catalyst was filtered off and the filtrate concentrated under vacuum. The solid residue was crystallized from ethanol and re-crystallized from acetone to provide 2.66 g of 44a (53% yield). 1H NMR (CDCl3): 1.03 (t, J=7.5 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.42 (s, 6H), 1.64 (m, 2H), 1.84 (t, J=6.5 Hz, 2H), 2.70 (t, J=6.5 Hz, 2H), 2.90 (m, 2H), 3.34 (q, J=7.0 Hz, 2H), 5.98 (s, 1H), 14.61 (s, 1H); 13C NMR (CDCl3): 8.45, 13.89, 16.42, 23.37, 26.62, 31.20, 38.13, 39.38, 77.60, 102.77, 103.43, 105.30, 110.22, 156.41, 157.29, 158.94, 159.76, 165.77, 206.67; IR: 1730 cm−1; MS (ACPI+): 345 (M+1); Anal. Calcd. for C20H24O5: C 69.75, H 7.02; Found C 70.03, H 7.18.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=O)[NH2:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>C1COCC1>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[S:47])[NH2:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=S
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
A mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-piperidine-1-carboxylate (2.2 g, 4.0 mmol) and Lawesson's reagent (1.3 g, 3.2 mmol) in dry THF (40 mL) was heated at 50° C. under N2 atmosphere for 1 h. The solvent was removed, and the residue was dissolved in DCM (100 mL). NaOH solution (0.1 N, 100 mL) was added and the mixture was stirred at rt for 10 minutes. The organic phase was separated, dried, and concentrated. The residue was purified by silica gel column chromatography (2:1 petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamothioylpiperidine-1-carboxylate (1.6 g, 75%) as white solid. ESI-MS (EI+, m/z): 573 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:34]([CH:36]([CH2:39][CH3:40])[CH2:37][NH2:38])[CH3:35]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH2:37][CH:36]([CH2:39][CH3:40])[CH2:34][CH3:35])=[O:23])(=[O:15])=[O:16])[CH2:12]2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CCC(CC)CN
Product: CCC(CC)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Yield: 42.7 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 19 mg of 2-ethylbutylamine. 47 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide are thus obtained in the form of a pale yellow powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.86 (t, J=7 Hz, 6H), from 1.20 to 1.40 (mt, 4H), 1.50 (mt, 1H), 2.98 (s, 3H), 3.19 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.42 (t, J=6 Hz, 1H)].
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([NH:20][C@H:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=O)=[O:19]>C(OC(C)C)(C)C>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([NH:20][C@@H:21]1[C:27](=[O:28])[O:29][C:24](=[O:26])[CH2:23][CH2:22]1)=[O:19]
Reactant: O=C(O)CC[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C1CC[C@H](NC(=O)c2ccc3ccccc3c2)C(=O)O1

Procedure:
30.6 g (0.3 moles) of acetic anhydride with 60 ml of isopropyl ether are added to 30.1 g (0.1 moles) of 2-naphthoyl glutamic acid. The mixture is heated under reflux (73°-77° C.) for 2 hours. It is cooled, filtered, washed with a little ether to remove residual acetic anhydride and dried. 24.8 g are thus obtained. Yield 88%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:51]([CH3:55])([CH3:54])[CH2:52][OH:53])[C:10]([NH:12][C@@H:13]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:14]([OH:43])[CH2:15][C@@H:16]([NH:30][C:31](=[O:42])[C@H:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:33][C:34]([O:36][CH3:37])=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1)=[O:11])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C.ClC(OC)=O>ClCCl.O>[CH3:1][O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:51]([CH3:55])([CH3:54])[CH2:52][OH:53])[C:10](=[O:11])[NH:12][C@@H:13]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C@@H:14]([OH:43])[CH2:15][C@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1)[NH:30][C:31](=[O:42])[C@H:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:33][C:34](=[O:35])[O:36][CH3:37]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)CO)C(C)(C)C
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)CO)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of the product of Example 175A (0.025 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the reaction mixture was partitioned between ethyl acetate and dilute NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in tetrahydrofuran (0.25 mL) and diisopropylethylamine (0.015 mL, 0.086 mmol) and methyl chloroformate (0.002 mL, 0.026 mmol) were added at room temperature. After 2 hours water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.006 g, 34% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (2s, 6 H), 0.79 (s, 9 H), 1.45-1.56 (m, 2 H), 2.71-2.80 (m, 3 H), 3.08 (dd, J=5.4, 10.9 Hz, 1 H), 3.18 (dd, J=5.4, 10.9 Hz, 1 H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.59-3.67 (m, 1 H), 3.81 (d, J=9.6 Hz, 1 H), 4.02 (d, J=9.2 Hz, 1 H), 4.04-4.21 (m, 2 H), 4.62 (m, 1 H), 4.90 (d, J=5.5 Hz, 1 H), 6.61 (d, J=9.6 Hz, 1 H), 6.92 (d, J=9.2 Hz, 1 H), 7.10-7.21 (m, 7 H), 7.29-7.31 (m, 1 H), 7.47 (d, J=8.8 Hz, 1 H), 7.78 (d, J=8.8 Hz, 1 H), 7.82-7.89 (m, 4 H), 8.64 (m, 1 H).
Reaction SMILES: [C:1]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]#[N:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].CCOC(C)=O>[Pt]=O.CCO>[ClH:19].[CH:2]1([C:1]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:15])[CH2:16][CH2:17][N:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc(CC#N)c1C(=O)c1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc2c1C(C1CCCCC1)=NCC2
Reaction time: 72 h

Procedure:
To (2-benzoyl-3-methylphenyl)acetonitrile (4.6 g) were added EtOH (70 mL), 4 M HCl/EtOAc (15 mL), and platinum oxide (IV) (0.40 g), followed by stirring under a hydrogen atmosphere for 3 days. The reaction liquid was filtered through celite and then concentrated. Toluene was added to the concentrate, followed by extraction with an aqueous 1 M HCl solution. A 28% aqueous ammonia solution was added to the aqueous layer, which was then extracted with toluene and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in toluene. 4 M HCl/EtOAc (7 mL) was added to the mixture, followed by concentration under reduced pressure. iPrOH and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected to obtain 1-cyclohexyl-8-methyl-3,4-dihydroisoquinoline hydrochloride (2.2 g).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:28])[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(N(C)C)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C21H19N5O2, 373.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.F[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]1([NH:20][C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7](=[O:15])[C:6]=3[CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:18]=1
Reactant: Nc1ccccc1F
Reactant: O=c1[nH]c2ncccc2c2ccc(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]c2ncccc2c2ccc(Nc3ccccc3)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
8-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (50 mg, 0.22 mmol), 2-fluoroaniline (48 mg, 0.43 mmol), palladium(II) acetate (2 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8 mg, 0.02 mmol), and sodium tert-butoxide (63 mg, 0.65 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane plug, and purified via prep-LC-MS to provide 17 (25 mg, 38% yield) as a tan solid. LC-MS (M+H=306, obsd.=306). 1H NMR (400 MHz, d6-DMSO): δ 11.92 (s, 1H), 8.66 (dd, 1H), 8.58 (s, 1H), 8.39 (m, 2H), 7.75 (d, 1H), 7.44 (m, 2H), 7.32 (dd, 1H), 7.28 (dd, 1H), 7.21 (dt, 1H), 7.11 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C@@H:19]1[CH2:23][C:22](=[O:24])[O:21][C:20]1=[O:25]>>[CH3:17][O:18][C@@H:19]([C:20](=[O:25])[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)[CH2:23][C:22]([OH:24])=[O:21]
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CO[C@@H]1CC(=O)OC1=O
Product: CO[C@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 1a from 6-bromo-2-phenyl-benzoxazole and (R)-3-methoxy-dihydro-furan-2,5-dione.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:12][CH2:13][CH2:14][N:15]([CH2:20][CH2:21][OH:22])[C:16](=[O:19])[CH2:17]O>N1C=CC=CC=1>[C:1]([O:22][CH2:21][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:16](=[O:19])[CH2:17][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(CO)N(CCO)CCO
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)CC(=O)N(CCOC(=O)CCCCCCCC)CCOC(=O)CCCCCCCC

Procedure:
106 g (0.6 mole) of pelargonoyl chloride was added dropwise with stirring to a solution of 32.6 g (0.2 mole) of N,N-bis(hydroxyethyl)hydroxyacetamide in 60 ml of pyridine. The precipitated pyridine hydrochloride was filtered, washed with benzene, and discarded. The benzene solution of product was water washed, dried over sodium sulfate, and passed through an activated alumina column to remove any acid. The benzene was stripped off an a rotary evaporator. The yield of product was essentially quantitative. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It had nD30 1.4537 and d430 0.9745.