Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of N-(3,5-dichlorobenzyl)-5-fluoro-2-(methylsulfonyl)benzenamine (2.1 mmol), t-butyl piperazine-1-carboxylate (2.2 mmol), N,N-diisopropylethylamine (4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (23%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1H), 7.67 (d, 1 H), 7.31 (s, 1H), 7.21 (s, 2H), 6.13 (dd, 1H), 5.70 (d, 1H), 4.42 (d, 2H), 3.54 (m, 4H), 3.38 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z: Calculated: 514.47; Observed: 515.6 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[N:5]([CH2:18][CH3:19])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH3:19])[C:4]([CH2:3][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])([CH3:20])[CH3:21])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-amino-2-methylpropyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (609 mg, 2.15 mmol) in dichloromethane (60 mL) was cooled to 0° C. Triethylamine (326 mg, 3.22 mmol) and methanesulfonyl chloride (246 mg, 2.15 mmol) were sequentially added. The reaction was stirred at 0° C. for five hours and then allowed to warm to room temperature slowly and stirred overnight. Water was added, and the aqueous layer was separated and extracted four times with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by IFC (silica cartridge) followed by recrystallization from acetonitrile. The crystals were dried overnight on the vacuum filter funnel to provide 363 mg of N-[2-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white solid, mp 229-230° C.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:31]4[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
To 10 mL of 1,4-dioxane was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (100 mg, 0.31 mmol), 4-formylphenylboronic acid (56 mg, 0.37 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (1.2 mL, 1.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 100 mL of water. The mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as orange/red solid. Yield: 100 mg, 93%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][OH:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+].C(O)(=[O:31])C>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:21]([OH:31])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(CO)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(CC)(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cooled mixture of chromic anhydride (8.5 g, 85,2 mmole) in 100 ml acetic acid was added dropwise a solution of 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl-butan-1-ol (10.4 g, 28.4 mmole) in 50 ml acetone and the mixture was stirred 24 hours at room temperature. The mixture was added to 1000 ml 10% sodium chloride solution and extracted four times with ethyl acetate. The organic phase was washed twice with brine, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 7 g=65%. The product can be activated and esterified directly to a drug or further modified as described below.
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Cl.C(=O)(O)[O-].[Na+].[CH3:14][O:15][C:16](=[O:27])[CH:17]=[C:18]([C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[CH3:19]>O>[CH3:14][O:15][C:16](=[O:27])[CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]2[N:22]([CH:3]=[CH:4][N:26]=2)[CH:21]=1)[CH3:19]
Reactant: COC(=O)C=C(C)c1ccc(N)nc1
Reactant: COC(CBr)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)C=C(C)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetaldehyde dimethyl acetal (0.692 mL, 5.85 mmol) was refluxed in a solution of water (10 mL) and concentrated HCl (0.1 mL) for 30 min. The reaction was cooled to ambient temperature, and sodium bicarbonate (629 mg, 7.49 mmol) was added in several portions. After the addition was complete, 3-(6-amino-pyridin-3-yl)-but-2-enoic acid methyl ester (900 mg, 4.68 mmol) was added, and the reaction stirred overnight. During this time, the reaction became homogenous. After extracting the reaction mixture with ethyl acetate (3×20 mL), the organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 4μ plate, 50% ethyl acetate in hexanes) to yield 3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester as an off white solid (223.3 mg, 22%). 1H NMR (250 MHz, CDCl3): δ 8.32 (bs, 1H), 7.58-7.70 (m, 3H), 7.35 (dd, 1H, J=7.5, J=3.1), 6.24 (d, 1H, J=0.62), 3.31 (s, 3H), 2.64 (d, 3H, J=0.62). MS [EI+] 217 (M+H)+.
Reaction SMILES: C(OC(CSC(=O)C)C(O)=O)(=[O:3])C.C(SCC(CSC(=O)C)C(O)=O)(=O)C.C([O:32][C:33](=[O:60])[C@H:34]([CH2:48][CH2:49][CH2:50][CH2:51][NH:52]C(OC(C)(C)C)=O)[NH:35][C:36](=[O:47])[CH:37](OC(=O)C)[CH2:38][S:39]C(=O)C)(C)(C)C.C(OC(CSC(=O)C)C(N[C@H](C(O)=O)CCCCN)=O)(=O)C>>[OH:3][C@@:34]([C:33]([OH:32])=[O:60])([CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])[NH:35][C:36](=[O:47])[CH2:37][CH2:38][SH:39]
Reactant: CC(=O)OC(CSC(C)=O)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(CSC(C)=O)C(=O)O
Agent: CC(=O)OC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: CC(=O)SCC(CSC(C)=O)C(=O)O
Product: NCCCC[C@](O)(NC(=O)CCS)C(=O)O

Procedure:
By substituting 2-acetoxy-3-(acetylthio)propanoic acid for the 2-(acetylthiomethyl)-3-(acetylthio)propanoic acid in the procedure of Example 38 and then submitting the product to the procedures of Examples 39 and 40, Nα -[2-acetoxy-3-(acetylthio)propanoyl]-Nε -tert.butyloxycarbonyl-L-lysine tert.butyl ester, Nα -[2-acetoxy-3-(acetylthio)propanoyl]-L-lysine and Nα -(2-hydroxy-3-mercaptopropanoyl-L-lysine are obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:5][N:4]=1.Br[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:2][C:3]1[O:7][C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:5][N:4]=1
Reactant: Cc1nnc(C2CCNCC2)o1
Reactant: Brc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(C2CCN(c3ncccn3)CC2)o1
Temperature: 60 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
4-(5-Methyl-[1,3,4]oxadiazole-2-yl)-piperidine hydrochloride (203 mg, 1 mmol) (see reference WO 0039125, preparation 43) was added to a solution of 2-bromopyrimidine (207 mg, 1.3 mmol) and potassium carbonate (207 mg, 1.5 mmol) in N,N-dimethylformamide (0.5 mL). The solution was heated to 60° C. for 4 hours, before cooling and stirring at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, before being dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (25 g) eluting with dichloromethane and methanol (97.5:2.5) to give the title compound as a crystalline solid (75 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[N+](=[CH:30][Si](C)(C)C)=[N-].CO>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[C:17]([O:19][CH3:30])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C1CCC(C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CC1CCC(=O)CC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(4-oxocyclohexy)propanoic acid (45 mg), diazomethyltrimethylsilane (2.0 M diethyl ether solution, 0.1 mL), methanol (0.2 mL), and toluene (0.8 mL) was stirred at room temperature for 10 minutes. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain methyl (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(4-oxocyclohexyl)propanoate (29 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9](B(O)O)=[CH:10][C:3]=12.I[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][C:3]=12
Reactant: Ic1cccnc1
Reactant: C[Si](C)(C)CCOCn1c(B(O)O)cc2c(Cl)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Cl)ccnc21
Yield: 52.3 %

Procedure:
Argon was bubbled through a mixture of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-ylboronic acid (5.55 g, 17 mmol), 3-iodopyridine (6.97 g, 34 mmol), Pd(OAc)2, 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (405 mg, 0.85 mmol), and K3PO4 (2 M in H2O, 34 mmol) in DME (50 mL) for 10 min and then heated at reflux overnight. The reaction mixture was diluted with EtOAc and washed with saturated aq. K2HPO4 solution. The title compound was purified by flash column chromatography (silica gel, 20% EtOAc/CH2Cl2) to afford the desired product (3.2 g, 52% yield) as an oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:52]1([C:58]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C=O)C.O>[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[N:55]2[CH2:56][CH2:57][N:52]([C:58](=[O:59])[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[C:66]([F:69])([F:67])[F:68])[CH2:53][CH2:54]2)=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
HOBt (19 mg, 0.14 mmol) and DIPEA (0.017 mg, 0.14 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (40 mg, 0.14 mmol) in DMF (3 mL). The mixture was cooled to 10° C. and EDCI.HCl (40 mg, 0.2 mmol) followed by piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (45 mg, 0.15 mmol) were added. The mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered and the residue was purified by column chromatography using silica gel 60-120 mesh and 90% ethyl acetate in hexane as eluant to afford 20 mg (30%) of N-biphenyl-4-yl-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 496.18 (M+1)+, 97.3%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.76 (d, 1H), 7.6 (m, 7H), 7.44 (t, 2H), 7.35 (t, 2H), 4.0 (m, 2H), 3.7 (m, 4H), 3.5 (m, 4H), 3.25 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10](CC=C)[CH2:9]1.B(F)(F)F.CCOCC>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:14])(=[O:15])[NH:10][CH2:9]1
Reactant: C=CCN1CC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CCS1(=O)=O
Agent: [Pd]
Agent: FB(F)F
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Yield: 58.9 %

Procedure:
N-[[(5S)-3-[3-Fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (350 mg, 0.82 mmol), 10% palladium on carbon (500 mg), boron trifluoride etherate (179 mg, 1.26 mmol) and absolute ethanol (8 ml) are heated under reflux for 5 hr. Upon cooling the suspension is filtered and evaporated. Chromatography over silica gel (55 g) eluting with 2-6% methanol-chloroform affords the title compound as a foam (186 mg, 59%). HRMS(FAB): calcd for m+H=386.1186; Found: 386.1194.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][NH:8][C:7]1=[O:21])([O:3][CH2:4][CH3:5])=[O:2].F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:27][O:21][C:7]1[CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][N:8]=1
Reactant: C[O+](C)C
Reactant: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CNC1=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CN=C1OC
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of 14.9 g 3carboethoxy-5-[t-butyl(dimethyl)silyloxymethyl]-2 -piperidone in 400 ml anhydrous dichloromethane at 4° C. were added 7.7 g of trimethyloxonium tetrafluoroborate. The mixture was first stirred for 90 minutes at 4° C. and then for 1 hour at 22° C. The resulting solution was poured into a saturated solution of sodium bicarbonate and extracted with three portions of dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to give 13.8 g of the title compound: 300-MHz 1H NMR (CDCl3) δ0.04 (s, 6H), 0.88 (s, 9H), 1.25 (t, J=7 Hz, 3H), 1.51-2.18 (m, 3H), 3.11-3.32 (m, 2H), 3.48-3.56 (m, 2H), 3.60-3.76 (m, 4H), 4.19 (t, J=7 Hz, 2H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH:27][CH3:28])=[N:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C>[CH3:28][N:27]([CH2:26][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([CH3:16])[N:18]=1)[C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNCc1nn(C)c2ccccc12
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(Cc1nn(C)c2ccccc12)C(=O)c1ccccc1-c1ccccc1
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A solution of 2-biphenylcarboxylic acid (198 mg, 1 mmole), 1-methyl-3-(methylaminomethyl)-1H-indazole (210 mg, 1.2 mmole), EDC (230 mg, 1.2 mmole), HOBt.H2O (162 mg, 1.2 mmole), and triethylamine (0.28 mL, 2.0 mmole) in DMF (5 mL) was stirred at RT. After 18 hr, the reaction was concentrated to dryness, and the residue was purified by flash chromatography on silica gel (45% EtOAc/hexanes). The title compound (221 mg, 62%) was obtained as a white solid: MS (ES) m/e 356 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[CH2:15][C:16](O)=[O:17])[CH2:12]2.[NH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]1[CH:31]([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C>>[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[CH2:15][C:16]([NH:19][N:20]1[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]1[CH:31]([CH3:33])[CH3:32])=[O:17])[CH2:12]2
Reactant: O=C(O)CC1C2CC3CC(C2)CC1C3
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC1C2CC3CC(C2)CC1C3
Temperature: 80 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
Thionyl chloride (1.72 mL, 23.5 mmol) was added to adamant-2-yl acetic acid (241 mg, 1.24 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in a 25 mL round-bottom flask with stir bar. The resulting solution was heated at 80° C. for 1 hour, and then concentrated under vacuum. The residue was taken up in CH2Cl2 (3 mL) and concentrated under vacuum. This process was repeated twice more to ensure removal of excess thionyl chloride. The residue was taken up in fresh CH2Cl2 (2 mL) and 3-amino-2-isopropyl-4(3H)-quinazolinone (252 mg, 1.24 mmol) was added. The mixture was stirred at 20-25° C. After 18 hours, diisopropylethylamine (0.40 mL) was added and the solution was stirred for 1 hour longer, and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 90:10-70:30). Unreacted quinazolinone (80 mg, 31% recovered) eluted first, followed closely by a second fraction from which crystals precipitated on standing at room temperature for 1 hour. The crystals were collected by filtration and dried at 50° C. under vacuum to provide the title compound (102 mg, 22% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (2 d, J=6.7 Hz, 6H), 1.58-1.96 (m, 14H), 2.41 (br. t, J=7.3 Hz, 1H), 2.64 (d, J=7.5 Hz, 2H), 3.16 (hept, J=6.7 Hz, 1H), 7.43 (td, J=7.3, 1.2 Hz, 1H), 7.68 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 8.21 ppm (d, J=7.5 Hz, 1H); MS (DCI) m/z 380 (M+H)+; Elemental Analysis calculated for C23H29N3O2.0.3H2O: C, 71.77; H, 7.75; N, 10.92. Found: C, 71.70; H, 7.68; N, 10.76.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.CN(C)C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH:13]([O:12][C:10]1[C:9]([O:16][CH3:17])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:11]=1)([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc(OC)c(OC(C)C)cc1N
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OC(C)C)cc1NCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A mixture of methyl 2-amino-4-isopropoxy-5-methoxybenzoate (12.67 g), 4-methoxybenzaldehyde (7.90 g), N,N-dimethylformamide (150 ml) and acetic acid (3 ml) was stirred for 8 hours. After stirring, the sodium triacetoxyborohydride (13.4 g) was added thereto. The reaction mixture was stirred for 1 night. To the reaction mixture was added 4-methoxybenzaldehyde (1.98 g) and sodium triacetoxyborohydride (3.35 g) and stirred for 1 day. The reaction mixture was concentrated under reduced pressure until the amount was concentrated to a half, adjusted to pH 8˜9 by adding 5% sodium carbonate. Water was added thereto, the precipitated solid was collected by filtration, washed with water and dried to obtain the target compound (18.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[O:5][CH2:6][C:7](O)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:7][CH2:6][O:5][C:4]2[CH:10]=[CH:11][C:12]([CH3:13])=[C:2]([CH3:1])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc(OCC(=O)O)cc1C
Reactant: NC1CC1
Product: Cc1ccc(OCCNC2CC2)cc1C

Procedure:
Synthesized according to typical procedures C and D from (3,4-dimethylphenoxy)acetic acid and cyclopropylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[O:13][CH3:14])[NH2:10])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(N)ccc1OC
Yield: 77.4 %

Procedure:
Leave under hydrogen pressure (Patm) for 12 hours, 5 g of 2-ethoxy-1-methoxy-4-nitrobenzene (XIXaa), 500 mg of 10% palladium on charcoal (10% by weight of product to reduce), in 200 ml of methanol. Filter on celite, rinse several times with methanol. Evaporate to dryness. Take up in ether and evaporate. One obtains 3.28 g of the abovenamed product as a pinkish white powder. Yield: 79%. 1H-NMR (CDCl3, 300 MHz): d 1.46 (t, 3H, —CH3), 3.33 (s, 2H exchangeable, —NH2), 3.81 (s, 3H, OCH3), 4.05 (q, 2H, OCH2), 6.22(d, 1H Ar), 6.28 (dd, 1H Ar), 6.71 (d, 1H Ar).