Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:46])[C@H:3]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:4](=[O:40])[N:5]1[C@H:10]([C:11]2[NH:12][C:13]([C:16]3[CH:29]=[CH:28][C:27]4[C:26]5[C:21](=[CH:22][C:23](B6OC(C)(C)C(C)(C)O6)=[CH:24][CH:25]=5)[CH2:20][CH2:19][C:18]=4[CH:17]=3)=[CH:14][N:15]=2)[C@@H:9]2[CH2:39][C@H:6]1[CH2:7][CH2:8]2.Br[C:48]1[N:49]=[C:50]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[NH:51][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:44][O:43][C:42]([NH:41][C@@H:3]([CH:2]([CH3:46])[CH3:1])[C:4]([N:5]1[C@H:10]([C:11]2[NH:12][C:13]([C:16]3[CH:17]=[C:18]4[C:27]([C:26]5[CH:25]=[CH:24][C:23]([C:48]6[NH:49][C:50]([CH:53]7[CH2:57][CH2:56][CH2:55][N:54]7[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:51][CH:52]=6)=[CH:22][C:21]=5[CH2:20][CH2:19]4)=[CH:28][CH:29]=3)=[CH:14][N:15]=2)[C@@H:9]2[CH2:39][C@H:6]1[CH2:7][CH2:8]2)=[O:40])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Br)c[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1)C(C)C
Temperature: 85 °C
Yield: 37 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate (˜0.67 mmol), (S)-tert-butyl 2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (266 mg, 0.84 mmol), tetrakis(triphenylphosphine) palladium(0) (23 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (30 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (10.0 mL) and dimethylformamide (2 mL) was added a solution of potassium carbonate (2M in water, 1.0 mL, 2.0 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield S)-tert-butyl 2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (182 mg, 56%)
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=2)[N:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(O)C.C1C=CC=CC=1.O.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>[F:1][C:2]1[C:7]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:29][CH:28]=2)=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=2)[N:3]=1
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCCCC)cc3)c(F)n2)cc1
Yield: 49.4 %

Procedure:
3.35 g (10.00 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine-3-boronic acid in 45 ml of ethanol are refluxed together with 2.85 g (10.00 mmol) of 1-bromo-4-octyloxybenzene and 0.37 g (0.31 mmol) of tetrakis(triphenylphosphine)palladium in 60 ml of benzene and 3.18 g (30.00 mmol) of sodium carbonate in 12 ml of water for 20 hours. After distributing the reaction mixture between water and dichloromethane, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, dichloromethane) and recrystallization from acetonitrile give 2.5 g of 2-fluoro-3,6-di(4-octyloxyphenyl)pyridine. ##STR30##
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][C:8]([N:12]=O)=[C:9]([OH:11])[CH:10]=1)[CH3:3].[OH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH2:2]([N:4]([CH2:14][CH3:15])[C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:12]=[C:20]1[C:19](=[CH:18][C:17](=[O:16])[C:26]3[CH:25]=[CH:24][C:23]([C:27]([OH:29])=[O:28])=[CH:22][C:21]=31)[O:11]2)[CH3:3]
Reactant: O=C(O)c1ccc2c(O)cccc2c1
Reactant: CCN(CC)c1ccc(N=O)c(O)c1
Agent: Cl
Product: CCN(CC)c1ccc2nc3c4cc(C(=O)O)ccc4c(=O)cc-3oc2c1

Procedure:
This was made similarly to the hydroxy derivative above except that the starting materials were 5-diethylamino-2-nitrosophenol hydrochloride and 1-hydroxynaphthalene-6-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:9]2)=[CH:5][CH:4]=1.[C:15](O)(=O)[C@@H:16]([C@H:18]([C:20](O)=[O:21])O)O.C(N)(=O)CCC.CCCC(Cl)=O.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH2:12][CH2:13][NH:14][C:20](=[O:21])[CH2:18][CH2:16][CH3:15])[CH2:8][CH2:9]2)=[CH:5][CH:4]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: COc1ccc2c(c1)CCC2CCN
Agent: CCCC(=O)Cl
Agent: CCCC(N)=O
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CCCC(=O)NCCC1CCc2cc(OC)ccc21

Procedure:
N-[2-(2-,3-dihydro-6-methoxy-1H-inden-3-yl)ethyl]amine was resolved according to the procedure described using L-tartaric acid and was shown to have an enantiomeric excess of ≤90 by 1H NMR. The amine was then converted to the butanamide using n-butyryl chloride according to General Procedure A. m.p. 79°-80° C.; 1H NMR (300 MHz, CDCl3) δ7.08 (d, J=8Hz, 1H), 6.72-6.67 (M, 2H), 5.57 (bs, 1H), 3.76 (s, 3H), 3.86-3.66 (bm, 2H), 3.08 (bm, 1H), 2.89-2.69 (bm, 2H), 2.35-2.27 (m, 1H), 2.13 (t, J=7.5 Hz, 2H), 2.06-2.00 (m, 2H), 1.7-1.54 (bm, 4H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ172.0, 158.8, 148.11, 135.8, 124.9, 112.27, 109.18, 55.48, 42.67, 38.71, 37.98, 34.83, 32.47, 30.55, 19.21, 13.76; IR (KBr) 1632, 1546, 1290 cm-1 ; MS (DCI) 276m/e (MH); Analysis calc'd for C16H21NO1 : C, 78.97; H, 8.70; N, 5.76; found: C, 78.73; H, 8.90; N, 5.76. Analysis calc'd for C16H23N1O2 : C, 73.53; H, 8.87; N, 5.36; found: C, 73.47; H, 8.77; N, 5.13; [α] (25° C., 589 nm, CHCl3)=+4.24.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]=[C:15]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[Li+].[OH-]>CCO.O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]=[C:15]([O:24][CH2:25][C:26]([OH:28])=[O:27])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: COC(=O)COc1nc([C@H](C)Nc2ncnc3[nH]cnc23)cc2cccc(Cl)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(OCC(=O)O)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-methyl 2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)acetate 127 (200 mg, 0.47 mmol, 1.0 eq) in EtOH (5 mL) and H2O (2 mL), LiOH (78 mg, 3.25 mmol, 6.9 eq) was added in one portion. The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The residue was suspended in ice-water (15 mL) and the resulting mixture was neutralized with acetic acid at 0-5° C. to adjust pH to 7-8. The precipitate was collected by filtration and dried in vacuo to afford the product (S)-2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)acetic acid 128. ESI-MS m/z: 399.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]2[C:17](=[O:19])[O:16][C:15]([CH2:20][C:21]#[N:22])=[CH:14][C:13]=2[CH:12]=[C:11]([O:23][CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[F-].[CH2:28]([N+](CCCC)(CCCC)CCCC)CCC.CI>C(Cl)Cl>[Si:1]([O:8][C:9]1[C:18]2[C:17](=[O:19])[O:16][C:15]([CH:20]([C:21]#[N:22])[CH3:28])=[CH:14][C:13]=2[CH:12]=[C:11]([O:23][CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(CC#N)cc2c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: ClCCl
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(C(C)C#N)cc2c1
Temperature: 0 °C
Yield: 155.2 %

Procedure:
2.50 g (7.24 mmol) of the 8-tert-butyldimethylsilyloxy-3-cyanomethyl-6-methoxy-1-oxo-1H-2-benzopyran obtained in Example 5 was dissolved in 80 ml of methylene chloride. 100 ml of a 1M aqueous solution of sodium hydroxide was added thereto, and the resulting mixture was cooled to 0° C. While this mixture was being vigorously stirred, 584 mg (1.81 mmol) of tetrabutylammonium fluoride and then 10 ml of methylene chloride containing 0.92 ml (14.47 mmol) of methyl iodide were added thereto, followed by stirring at 0° C. for 1 hour. Moreover, 10 ml of methylene chloride containing 0.92 ml (14.47 mmol) of methyl iodide was added thereto, followed by stirring for 30 minutes. After completion of the reaction, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [using 130 g of Wako Gel C-200 and hexane/ethyl acetate (5:1)]. Thus, 1.01 g of the title compound was obtained in a 39% yield.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1>CN(C)C=O>[CH3:24][C:17]1[CH:16]=[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.7 %

Procedure:
Sodium hydride (60% in mineral oil; 0.599 g) was suspended in dimethylformamide (10 mL), and to this was added dropwise a solution of diethyl malonate (2.00 g) in dimethylformamide (10 mL) under ice-cooling. After the foam generation was finished, a solution of 4-fluoro-2-methylnitrobenzene (1.94 g) in dimethylformamide (5 mL) was added thereto. The reaction temperature was raised to 100° C., the mixture was stirred for 6 hours. The resulting reaction mixture was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give the title compound (1.65 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[O:15][C:14](=[O:19])[CH2:13]1>C1COCC1>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:18])[CH2:17][CH:12]([CH3:11])[CH2:13][C:14]([OH:19])=[O:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(Cl)c1
Yield: 124.1 %

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (500 mg, 3.28 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (420 mg, 3.28 mmol) in THF (15 mL) was stirred at 90° C. for 14 hr. The reaction solution was concentrated to give 5-(3-chloro-4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (1143 mg, 4.07 mmol, 124%) as a crude product.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35])=[CH:28][CH:27]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:7]4[N:3]([CH3:2])[N:4]=[N:5][N:6]=4)[CH:9]=3)=[O:16])[CH2:20]2)=[O:35])=[CH:30][CH:31]=1
Reactant: CC(C)(Cc1ccc(F)cc1)C(=O)O
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCNC2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(C(=O)C(C)(C)Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (100 mg, 284 μmol), 3-(4-fluorophenyl)-2,2-dimethylpropionic acid (56 mg, 284 μmol) and triethylamine (158 μL, 1.14 mmol) in dichloromethane (2 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (177 mg, 341 μmol) and the mixture was stirred at room temperature for 17 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and then with 1.0 N aqueous hydrochloric acid, dried (sodium sulfate) and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% hexane in ethyl acetate, to provide an amorphous white solid. 1H NMR (300 MHz, CDCl3) δ7.83 (s, 1H), 7.58 (d, J=7 Hz, 1H), 7.38 (t, J=8 Hz, 1H), 7.28 (m, 1H), 7.05 (m, 2H), 6.90 (t, J=9 Hz, 2H), 4.18 (s, 3H), 4.10 (m, 2H), 3.31 (m, 2H), 3.00 (m, 2H), 2.90 (s, 2H), 1.90 (m, 1H), 1.77 (m, 2H), 1.56 (m, 1H), 1.40 (m, 1H), 1.23 (s, 6H). Mass spec (AP+) m/z 494.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].B.B.O1CCCC1>O1CCCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCC1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 0 °C
Yield: 87 %

Procedure:
1-(4-Nitrobenzoyl)piperidine (0.1125 gms.) is then dissolved in tetrahydrofuran (1 mL) and slowly added dropwise to a 0° C., 1.0 M solution (4 mL) of Borane in tetrahydrofuran. The reaction mixture is maintained at 0° C. for 20 minutes following the completion of the addition to the Borane/tetrahydrofuran solution. The reaction mixture is then allowed to warm to room temperature, and is subsequently heated to 60° C. using an oil bath. The reaction mixture is maintained at 60° C. overnight, then is cooled to room temperature, and quenched with the addition of concentrated HCl (added until gas evolution stops). The quenched reaction mixture is then extracted with ethyl acetate and water. The organic layer is separated, and concentrated in vacuo, while the aqueous layer is separated and made basic with the addition of aqueous 1M NaOH. The basic aqueous layer is then extracted with ethyl acetate and the ethyl acetate layer from this extraction is concentrated in vacuo. The solids isolated from both concentrated ethyl acetate layers are combined to yield 92 mg of 1-(4-nitro-benzyl)-piperidine as a white-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][C:10]1(C)[C:14](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[CH2:9]=[C:10]([C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1)[CH3:14]
Reactant: Nc1cncc(Br)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cncc(N)c1
Temperature: 90 °C
Yield: 230.4 %

Procedure:
5-Bromopyridin-3-amine (0.433 g, 2.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.630 g, 3.75 mmol), Cs2CO3 (3.10 g, 9.5 mmol) and Pd(PPh3)4 (0.289 g, 0.25 mmol) were suspended in DMF/H2O (3:1, 20 mL). The reaction mixture was degassed with N2 and heated at 90° C. for 16 h. Solvent was removed under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried, concentrated in vacuo and purified by chromatography to afford 5-(prop-1-en-2-yl)pyridin-3-amine (0.773 g, 230%) as a dark yellow oil. MS (ESI) m/z: 135.0 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])[NH:30][CH3:31])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[N:29]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:30]1[CH3:31]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CNN(C(=O)OC(C)(C)C)c1c(F)cccc1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1c(F)cccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.9 %

Procedure:
Triethylamine (300 μL, 2.15 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 220 mg, 1.03 mmol) in 1,2-dichloroethane (3 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N-(2,6-difluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (167 mg, 0.65 mmol) in 1,2-dichloroethane (6 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated successively with methanol and diethyl ether. The residue was dried overnight under high vacuum at 70° C. to give (4S,7R)-2-(2,6-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (97 mg, 47%) as an off-white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:20])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1cccc(Nc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of N-(3-aminophenyl)-2-(3-nitrophenyl)acetamide-hydrogen chloride (0.11 g, 0.35 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was then added an stirred overnight again. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The resulted mixture was purified by column chromatography to give the desired product (0.080 g, 53%). LCMS for C18H13Cl2N5O3 (M+H)+: m/z=418.0, 419.9. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 9.53 (s, 1H), 8.35 (s, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.12 (ddd, J=8.2, 2.4, 1.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 7.78 (dt, J=7.8, 1.4 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.36 (dt, J=8.0, 1.7 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.25 (dt, J=8.0, 1.7 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:22][C@H:23]([CH2:27][CH3:28])[C:24]([NH2:26])=[O:25])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:26][C:24](=[O:25])[C@H:23]([NH:22][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:27][CH3:28]
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3cccnc3)cc2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3cccnc3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound (R)-2-(5-cyano-6-(4-(pyridin-3-yl)phenylamino)pyrazin-2-ylamino)butanamide (90 mg, 0.241 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. To the residue, CH3CN (6 mL) and H2O (8 mL) were added to induce precipitation. The precipitate was collected by filtration, and dried on vacuum to give the titled compound (40 mg). The filtrate was purified by HPLC to give additional titled compound (11 mg). MS 392.3 (M+H); UV 202.3, 235.8, 274.4, 336.1 nm; t 0.404 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](OC)=[CH:13][C:12](B(O)O)=[C:11]([O:20][CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:42])[C:25]1[CH:30]=[C:29]([C:31](=[O:33])[CH3:32])[CH:28]=[CH:27][C:26]=1OS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>[Cl-].[Na+].O.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.C(OCC)(=O)C>[CH3:22][O:23][C:24]([C:25]1[C:26]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:20][CH3:21])=[CH:27][CH:28]=[C:29]([C:31](=[O:33])[CH3:32])[CH:30]=1)=[O:42]
Reactant: COc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Reactant: COC(=O)c1cc(C(C)=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)ccc1-c1ccc(OCc2ccccc2)cc1OC
Yield: 115.6 %

Procedure:
4-Benzyloxy-2,5-dimethoxyphenylboronic acid 5b (4.15 g, 14.4 mmol), 5-Acetyl-2-trifluoromethanesulfonyloxy-benzoic acid methyl ester 6 (4.69 g, 14.4 mmol) and K2CO3 (3.98 g, 28.8 mmol) were added and the flask was flushed with Ar. Absolute ethanol (83 mL) and DME (94 mL) were added followed by Pd (PPh3)4 (0.87 g, 0.785 mmol) and the reaction mixture refluxed for 4 h. After cooling, water (100 ml), ethyl acetate (100 mL) and brine (50 mL) were added. The organic layer was washed with brine (2×50 mL) and the combined aqueous fraction was back extracted with ethyl acetate. The combined organic fraction was dried, concentrated and recrystallized from ethyl acetate/hexanes to give 6.5 g (99%) of 7b as a yellow solid. 1H-NMR (400 MHz, CDCl3) dH 2.65 (3H, s, COCH3), 3.58 (3H, s, OCH3), 3.68 (3H, s, OCH3), 3.88 (3H, s, OCH3), 5.21 (21H, s, CH2Ph), 6.55 (1H, s, ArH), 6.86 (1H, s, ArH), 7.30-7.48 (6H, m, ArH+CH2Ph), 8.10 (1H, d, ArH),8.37(1H,s,ArH),