Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16]Br)=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)/C=C(\CBr)c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(\Cn1cccn1)c1cccc(C#N)c1
Yield: 71.1 %

Procedure:
To a solution of ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (103 mg, 0.35 mmol) in 5 ml anhydrous di-methylformamide was added pyrazole (24 mg, 0.35 mmol) and cesium carbonate (228 mg, 0.7 mmol). Reaction mixture was stirred for 1.5 hours at room temperature after which 25 ml ethyl acetate was added. Organic was washed with 3×25 ml water, 3×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to give ethyl (Z)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (70 mg, 71%) as a brown residue which was sufficiently pure to be used without further purification. ES-MS (M+H+): 282.1
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH3:10])[C:5]2[N:15]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)[CH:16]=[N:17][C:4]=2[CH:3]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[Br:40]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:40][C:16]1[N:15]([CH2:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:5]2[C:6]([O:8][CH:9]([CH:11]3[CH2:12][CH2:13][CH2:14]3)[CH3:10])=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:17]=1
Reactant: CC(Oc1nc(Cl)cc2ncn(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(Oc1nc(Cl)cc2nc(Br)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (3.5 g, 11.73 mmol) in THF (20 mL) was added 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1.0 M in THF/Toluene, 29.8 mL, 29.84 mmol) at −78° C. The resulting solution was stirred 2.5 hours and then 1,3 dibromo-5,5 dimethyl hydantoin (8.5 g, 29.84 mmol) in THF (20 mL) was added dropwise at −78° C. The reaction was stirred for 30 minutes then slowly warmed to room temperature over a period of 2 hours. The reaction was quenched with saturated NH4Cl solution (50 mL) at 0° C. and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 8-10% EtOAc/petroleum ether) to yield 2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ES/APCl calc'd. for C20H27BrClN3O [M+H]+ 440. found 440.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1(C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Methanesulfonyl chloride (0.29 mL, 3.7 mmol) is added to a solution of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 4, step 2; 1.36 g, 3.37 mmol), triethylamine (0.52 mL, 3.7 mmol) and CH2Cl2 (8 mL) at 0° C. The mixture is stirred for 2 hours, washed with saturated NaHCO3 (2×10 mL), water (10 mL), dried (MgSO4), filtered, and concentrated to give 1.22 g (75%) of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(N(CC)CC)C>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCCCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 36 h
Yield: 58.2 %

Procedure:
6-Aminocaproic acid (26 g, 0.2 mole) was dissolved in dichloromethane (200 mL) by the addition of triethylamine (100 mL). Trityl chloride (120 g, 0.45 mole) was added and the solution stirred for 36 hr. The resulting solution was extracted with 1N HCl and the organic layer evaporated to dryness. The residue was suspended in 2-propanol/1N NaOH (300 mL/100 mL) and refluxed for 3 hr. The solution was evaporated to a thick syrup and added to dichloromethane (500 mL). Water was added and acidified. The phases were separated, and the organic layer dried over sodium sulfate and evaporated to dryness. The residue was suspended in hot 2-propanol, cooled, and filtered to give 43.5 g (58%) of 6-(trityl-amino)caproic acid, useful as an intermediate compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(Oc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenoxyacetophenone (2.00 g, 9.43 mmol), lithium bis(trimethylsilyl)amide (2.36 g, 14.15 mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 114°-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.76 (t, 2 H), 2.99 (t, 2 H), 6.76 (s, 1 H), 7.09 (m, 7 H), 7.34 (s, 1 H), 7.44 (t, 2 H), 7.56 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)(O)[CH3:13])([CH3:9])[C:5]([F:8])([F:7])[F:6].C[Si]([N:27]=[N+:28]=[N-:29])(C)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])[C:4]([O:10][CH2:11][C:12]([N:27]=[N+:28]=[N-:29])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[CH3:13])([CH3:9])[C:5]([F:8])([F:7])[F:6]
Reactant: COC(=O)C(C)(OCC(C)(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C(C)(OCC(C)(N=[N+]=[N-])c1cccc(Br)c1)C(F)(F)F
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[2-(3-bromo-phenyl)-2-hydroxy-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid methyl ester (5.1 g, 11.92 mmol) in toluene (50 ml) was added trimethylsilyl azide (3.95 ml, 29.8 mmol) and at 0° C. BF3-Et2O (4.53 ml, 35.8 mmol). The reaction mixture was stirred for 2 days at 25° C. and for another day at 40° C. The reaction was carefully quenched by slow addition of the reaction mixture to a cold aqueous NH4OH solution. The product was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (toluene to toluene/EtOAc 10:1) to provide a diastereomeric mixture of the title compound as a light yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.69; HPLC RtH5=1.560 min; 1H NMR (360 MHz, CDCl3): δ 7.65 (s, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 7.27 (t, 1H), 3.87 and 3.85 (s, 3H), 3.76 (m, 2H), 1.78 and 1.75 (s, 3H), 1.65 and 1.61 (s, 3H); ESIMS: 427, 429 [(M+NH4)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[CH:38]=2)=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([NH:26][C:27]2[CH:28]=[C:29]([NH:34][C:35]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[CH:38]=3)=[O:36])[CH:30]=[CH:31][C:32]=2[CH3:33])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 26, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzoic acid was reacted with N-(3-amino4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give N-{3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)4-methoxybenzamido]-4-methylphenyl}-2-morpholinopyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.72 (m, 2H), 1.85 (m, 2H), 2.21 (s, 3H), 3.15 (m, 2H), 3.5 (t, 4H), 3.76 (m, 6H), 3.83 (s, 1H), 4.41 (m, 1H), 6.84 (d, 1H), 6.87 (d, 1H), 7.01 (s, 1H), 7.16 (d, 1H), 7.37 (m, 1H), 7.44 (d, 1H), 7.57 (m, 2H), 8.03 (d, 1H), 8.21 (d, 1H), 9.8 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M+H+ 646.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: C=Cc1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
An oven dried Schlenk flask was charged with Pd(OAc)2 (2.2 mg, 0.01 mmol, 1 mol %) and tethered ligand 2 (45.8 mg, 0.0044 mmol, 0.44 mol %). The flask was evacuated and backfilled with nitrogen and then capped with a rubber septum. Dry dimethylformamide (5 ml) was added and the mixture was stirred for 60 min at room temperature under nitrogen. 4′-Bromoacetophenone (0.199 g, 1.0 mmol), styrene (0.137 ml, 1.2 mmol), and triethylamine (0.195 ml, 1.4 mmol) were added successively. The rubber septum was replaced with a glas stopper, the flask was sealed, and the mixture was stirred at 120° C. for 20 h. After cooling to room temperature, the mixture was filtered, and the solid was washed with methyl-t-butyl ether (MTBE), water, MeOH, acetone, and once more with MTBE. The phases of the filtrate were separated and the aqueous phase was extracted with MTBE (2×30 ml). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc, 10/1 to 1/1) to give E-4-acetylstilbene (0.192 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8](CC=C)[CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].C1([SiH3])C=CC=CC=1.C(O)(=O)C>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20]
Reactant: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]cnc21

Procedure:
1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.45 g, 1.63 mmol), phenylsilane (0.25 ml, 2.03 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.3 mmol) was dissolved in DCM (10 ml) containing acetic acid (6 ml). The air in the flask was replaced by nitrogen by evacuating the flask then filling with nitrogen (×3) and the reaction mixture heated to 45 C for 4 h. The solution was allowed to cool diluted with DCM then washed with water then saturated sodium bicarbonate solution. The organics were isolated, dried and concentrated to yield crude product. Purification by SPE (silica) eluting with ether provided the product, 0.06 g, 16%. m/z 237 [MH+].
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[C:4]#[C:5][CH3:6].[CH2:8]([NH:10][NH2:11])[CH3:9]>C(O)CCC.O>[CH2:8]([N:10]1[C:5]([CH3:6])=[CH:4][C:3]([CH2:2][CH3:1])=[N:11]1)[CH3:9]
Reactant: CC#CC(=O)CC
Reactant: CCNN
Solvent: O
Solvent: CCCCO
Product: CCc1cc(C)n(CC)n1
Temperature: 25 °C

Procedure:
A solution of 18.9 g (0.2 mol) of hex-4-yn-3-one (from Step B) in 120 mL of n-butanol was treated with 40 mL (0.227 mol) of ethyl hydrazine, 34% solution in water. The resulting mixture was heated at reflux for 1.5 h, then cooled to rt. The mixture was concentrated to ˜150 μL volume; this was partitioned between 1 L of ether and 250 mL of water. The layers were separated and the organic layer was dried and concentrated to afford the title compound, which was used without further purification. 1H-NMR (400 MHz) δ 1.22 (t, J=7.6, 3H), 1.37 (t, J=7.2, 3H), 2.23 (s, 3H), 2.59 (q, J=7.6, 2H), 4.01 (q, J=7.2, 2H), 5.81 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)=[CH:4][CH:3]=1.[NH:25]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]2)[NH2:26].C(O)C.[O-]CC.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]2[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:26][N:25]2[C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=Cc1ccc(F)cc1)C2=O
Reactant: NNc1ccc2c(c1)CCNC2=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)CCC1C2=NN(c2ccc3c(c2)CCNC3=O)C1c1ccc(F)cc1
Temperature: 80 °C
Yield: 63 %

Procedure:
To ethyl 6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Preparation 16; 303 mg, 1.07 mmol) and 6-hydrazinyl-3,4-dihydroisoquinolin-1(2H)-one (240 mg, 1.3 mmol) (U.S. Pat. No. 6,432,974, Kelly et al., Aug. 13, 2002, intermediate 2) was added ethanol (8 mL) and 21% sodium ethoxide in ethanol (1.5 mL, 4 mmol) in a vial. The vial was flushed with argon and heated at 80° C. overnight with stirring. The reaction was quenched with 1M hydrogen chloride (8 mL) and diluted with water to give a precipitate. The precipitate was collected by vacuum filtration to give a yellow solid. The solid was dissolved in of dimethylformamide (3 mL) and purified by reverse phase chromatography with 45-75% acetonitrile/water to give (±)-3-(4-fluorophenyl)-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid as a 25/75 mixture of the cis/trans-diastereomers (290 mg, 0.68 mmol, 63% yield). ES-MS m/z 430 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[N+:19]([CH:10]1[CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]1([CH3:13])[CH3:12])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC([N+](=O)[O-])C(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (20.0 g, 106.2 mmole) in 85 ml of acetic anhydride at 0° C. was treated with 12.2 mL of acetic acid followed by 11.1 mL of nitric acid (70%) and was allowed to warm to room temperature. After 24 hours the reaction mixture was poured onto 300 mL of ice-water and extracted with three 150 mL portions of ether. The combined organic extracts were washed with four 100 mL portions of 15% aqueous sodium hydroxide solution, two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated in vacuo to provide 23.93 g (97%) of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39](Cl)=[O:40]>C1COCC1.CO>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:40]
Reactant: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.1 %

Procedure:
To a solution of N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-5-fluoro-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (50 mg, 0.11 mmol) in THF (5 mL) was added 2,6-difluorobenzoyl chloride (20 mg, 0.11 mmol) and the reaction mixture stirred at rt for 20 min. The reaction was diluted with MeOH, adsorbed to silica gel, and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (15.4 mg, 24%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.52 (s, 1H), 8.86 (d, J=7.69 Hz, 1H), 8.45-8.46 (m, 1H), 8.06 (s, 1H), 7.89 (d, J=8.61 Hz, 1H), 7.71-7.73 (m, 1H), 7.54-7.58 (m, 1H), 7.30-7.47 (m, 4H), 7.20-7.24 (m, 3H), 7.08-7.12 (m, 1H), 6.86 (d, J=8.42 Hz, 1H), 3.26 (s, 2H), 2.66-2.69 (m, 2H), 2.49-2.51 (m, 2H), 2.26 (s, 3H); ESIMS (M+H)+=606.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A mixture of 37.4 g (0.20 mole) of 4-bromoanisole, 170 g (0.25 mole) of imidazole, 26 g (0.2 mole) of potassium carbonate, and 1.2 g of cuprous bromide in 150 ml of N-methylprryolidinone was heated at reflux under a blanket of nitrogen for 4 hr. The mixture filtered and concentrated to remove the solvent. The residue was partioned between dilute sodium hydroxide solution and methylene chloride. After filtration, the organic fraction was chromatographed. The desired fractions were concentrated and the crystalline residue was recrystallized from toluene/cyclohexane to give 17.4 g (50%) of the title compound as white plates, mp 63.0-64.0° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[N:48]1([CH2:53][CH2:54][CH2:55][CH2:56][C:57](Cl)=[O:58])[CH:52]=[N:51][N:50]=[N:49]1>C(Cl)Cl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:57](=[O:58])[CH2:56][CH2:55][CH2:54][CH2:53][N:48]2[CH:52]=[N:51][N:50]=[N:49]2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCCCn1cnnn1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CCCCn1cnnn1
Reaction time: 0.5 h

Procedure:
1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are dissolved in 30 ml of methylene chloride, and, at 0°, 0.41 ml of pyridine, 50 mg of 4-dimethylaminopyridine and then, dropwise, a solution of 0.87 g of 5-(tetrazol-1-yl)-valeric acid chloride in 15 ml of methylene chloride are added. After stirring for 30 minutes at 0°, the solid material is filtered off over Hyflo and the filtrate is washed with aqueous sodium bicarbonate solution and then with brine. After drying over MgSO4, the solution is concentrated by evaporation. The residue is purified by chromatography over silica gel (eluant toluene/ethyl acetate: 9:1 to 1:1). TLC (ethyl acetate) Rf =0.33; IR (CH2Cl2): 1750, 1690, 1620 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.C(=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2ccc(OC)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 4-anisaldehyde (16.7 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(4-Methoxybenzyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 10 as a colorless oil (18.7 mg, 59%). LRMS 366.