Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:13]2[C@H:17]([C:18]#[N:19])[CH2:16][N:15]([CH3:20])[CH2:14]2)=[C:7]([CH:12]=1)[C:8](OC)=[O:9]>CO.[Ni]>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:13]3[CH2:14][N:15]([CH3:20])[CH2:16][C@H:17]3[CH2:18][NH:19][C:8](=[O:9])[C:7]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)ccc1[C@@H]1CN(C)C[C@H]1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1C[C@H]2CNC(=O)c3cc(Cl)ccc3[C@@H]2C1
Reaction time: 2 h

Procedure:
To a 2 gallon Parr vessel was charged Raney®-nickel (77 g, Grace 2800 (water decanted)) and 7 M ammonia in methanol (3 L) and trans-methyl 5-chloro-2-(4-cyano-1-methylpyrrolidin-3-yl)benzoate (152.7 g). The reactor was sealed, purged with nitrogen, then purged with hydrogen and pressurized to 30 psi with hydrogen. After 2 hours, the reaction mixture was filtered through a polypropylene cartridge and rinsed with methanol (1 L). The solvent was removed under vacuum to provide the title compound (crude) used as is in Example 199.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A suspension of tert-butyl(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.05 g, 4 mmol) and 5% palladium carbon (0.6 g) in tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(6-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (1.56 g, 92.3%) as crystals.
Reaction SMILES: [OH:1][B:2]1[CH2:7][CH:6]=[CH:5][CH:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[O:3]1>CCOC(C)=O.[Pd]>[OH:1][B:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[O:3]1
Reactant: CC(C)(C)OC(=O)CC1C=CCB(O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1CCCB(O)O1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)acetate XLVII (670 mg, 3.16 mmol) in EtOAc (45 mL) was added 10% Pd/C (135 mg). The vessel was evacuated by applying vacuum and flushed with hydrogen gas. The reaction was stirred under hydrogen for 2 h. The mixture was filtered through a Celite pad and which was washed with additional EtOAc (15 mL). Concentration of the filtrate gave pure tert-butyl 2-(2-hydroxy-1,2-oxaborinan-6-yl)acetate XLVIII (641 mg, 3.00 mmol, 94.8% yield).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=1.CC(C)([O-])C.[Na+].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:40]1([NH:39][C:15]2[CH:32]=[CH:31][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[CH:16]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc2c3ccccc3c3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3c4ccccc4c4ccccc4c3c2)cc1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
Palladium acetate (0.01 g, 0.06 mmol) and 1.0 M tri(t-butyl)phosphine solution in toluene (0.02 mL, 0.02 mmol) were added to a three-neck flask under nitrogen. 100 mL of toluene was then added. The solution was stirred under nitrogen until the color disappeared. To the solution was added 2-bromotriphenylene (2 g, 6.5 mmol), sodium tert-butoxide (0.94 g, 9.8 mmol), and aniline (1.8 g, 20 mmol) in sequence. The mixture was then heated up to reflux overnight. After cooled to room temperature, the mixture was filtered through a celite bed and washed thoroughly with dichloromethane. The product was purified by column chromatography using 1:7 dichloromethane and hexanes as eluent. 0.8 g of desired product was obtained after purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[NH:13]([CH2:17][CH2:18]O)[CH2:14][CH2:15]O>>[F:1][C:2]1[CH:3]=[C:4]([B:10]2[O:11][CH2:18][CH2:17][NH:13][CH2:14][CH2:15][O:12]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OCCNCCO
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Fc1cc(B2OCCNCCO2)cc(F)c1F
Yield: 70 %

Procedure:
The title compound (70%, crystals) was prepared from 3,4,5-trifluorophenylboronic acid and diethanolamin.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([Cl:17])=[C:5]([C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.[OH-].[Na+]>C(Cl)(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:20]1([CH2:23][O:9][N:8]=[C:6]([NH2:7])[C:5]2[C:10]([C:13]([F:15])([F:14])[F:16])=[CH:11][CH:12]=[C:3]([C:2]([F:18])([F:1])[F:19])[C:4]=2[Cl:17])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: NC(=NO)c1c(C(F)(F)F)ccc(C(F)(F)F)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(=NOCC1CC1)c1c(C(F)(F)F)ccc(C(F)(F)F)c1Cl
Yield: 56.7 %

Procedure:
In 10 ml of chloroform was dissolved 0.60 g of 3,6-bistrifluoromethyl-2-chlorobenzamidoxime and 0. 50 g of cyclopropylmethylbromide, and to the solution was added 0.1 g of tetrabutylammonium bromide at room temperature with stirring, and then 1.2 ml of 10% aqueous solution of sodiumhydroxide, then stirred for 3 hours at 30-40° C. The solution was washed with water, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 0.40 g of the objective compound.m.p. 75-80° C.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:24]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[F:8][C:7]1[CH:6]=[C:5]([OH:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[C:20]1[CH:21]=[N:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(Br)c(F)cc1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C(=O)OC(C)(C)C)c2)c(F)cc1O
Temperature: 50 °C
Yield: 100.5 %

Procedure:
To a reaction flask was added 4-bromo-5-fluoro-2-methoxyphenol (500 mg, 2.26 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (998 mg, 3.39 mmol), potassium phosphate (1.4 g, 6.79 mmol), and XPhosPalladacycle (178 mg, 0.23 mmol), followed by addition of DMF (11 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 50° C. in the microwave for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel to afford tert-butyl 4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-1H-pyrazole-1-carboxylate (700 mg) MS [M+H+]=307.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([CH3:20])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][C@H:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:48]12[CH2:53][CH2:52][CH:51]([CH2:50][CH2:49]1)[C@H:46]([NH:45][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:20])=[N:12][C:11]=13)=[O:19])[CH2:47]2
Reactant: Cc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
A mixture of 2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxylic acid (59 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (51 mg, 0.26 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.11 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide (16 mg, 19%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.47 (d, J=7.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.20-8.10 (m, 2H), 7.83 (d, J=1.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.45-4.35 (m, 1H), 3.93 (s, 3H), 3.55-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.75 (m, 1H), 2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI+) m/z 396 (M+H); HPLC 99.0% (AUC), tR=14.57 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
A mixture of 12 g (0.027 mol) of 2,6-dimethyl-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained as described in A), and 98 g (0.082 mol) of pyridinium chlorochromate adsorbed on alumina, was suspended in 270 ml of CH2Cl2, and the suspension was maintained under stirring at room temperature for 6 hours. The remaining solid was eliminated by filtration, and the liquid was washed with water (3×300 ml), drive over anh. Na2SO4, and concentrated at reduced pressure, to dryness. The product was obtained as an oil, which was purified by column chromatography (Silicagel, n-hexane:EtAcO, 8:2) with a yield of 65%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:12]3[C:21]4[N:17]([C:18]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:19][N:20]=4)[C:16]4[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=4[N:14]([CH2:32][C:33]([N:35]([CH:44]([CH3:46])[CH3:45])[C:36]4[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)=[O:34])[C:13]3=[O:47])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH:12]3[C:21]4[N:17]([C:18]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[N:19][N:20]=4)[C:16]4[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=4[N:14]([CH2:32][C:33]([N:35]([CH:44]([CH3:45])[CH3:46])[C:36]4[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)=[O:34])[C:13]3=[O:47])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4cc(F)ccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3c[nH]c4cc(F)ccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 69.3 %

Procedure:
To a solution of 2-[4-(6-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (158 mg, 0.252 mmol) in MeOH (20 mL) was added ammonium formate (463 mg, 7.34 mmol) and 10% palladium on charcoal (112 mg). The reaction was heated at reflux for 24 hours. The suspension was filtered hot, rinsing with 10% MeOH in CH2Cl2 (3×) and with CH2Cl2 (3×). The combined organic filtrates were concentrated and the residue was purified by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) to yield 110 mg of 2-[4-(6-fluoro-1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.08 (d, 1H), 7.39-7.62 (m, 9H) 7.15 (m, 2H), 6.93 (m, 3H), 6.68 (m, 1H), 4.80 (m, 1H), 4.55 (m, 1H), 4.20 (m, 1H), 3.95 (s, 3H), 3.88 (t, 1H), 3.77 (m, 1H), 3.67 (m, 1H), 1.01 (m, 6H); MS 630 (M+1), 628.5 (M−1).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH3:23])=O.Cl>O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:8]=[C:7]([CH3:23])[C:6]([NH2:5])=[C:11]([CH3:12])[CH:10]=2)=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)cc(C)c1NC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2)cc(C)c1N
Temperature: 25 °C
Yield: 69 %

Procedure:
A 250 ml round bottom flask was charged with 5.06 mmol (1.768 g) of 2,2,2-trifluoro-N-(4′-tert-butyl-3,5-dimethyl-biphenyl-4-yl)-acetamide, water (10 ml), and concentrated hydrochloric acid (10 ml). The mixture was heated to reflux for 17 h. The solution was allowed to cool to ambient temperature before it was evaporated to dryness. The residue was refluxed with Ba(OH)2.8H2O (9 g) in 100 ml of water for 1.5 h and then cooled to room temperature. This aqueous solution was extracted three times with 20 ml of CHCl3. The organic layer was dried over MgSO4, filtered, evaporated and dried under vacuum. The resulting brown precipitate of 4′-tert-butyl-3,5-dimethyl-biphenyl-4-ylamine was obtained in 69% yield. 1H NMR (CDCl3): δ=1.37 (s, 9H, C(CH3)3); 2.27 (s, 6H, ortho-CH3); 7.30-7.31 (d, 2H, CHar); 7.44-7.50 (m, 4H, CHar), 13C NMR (CDCl3): δ=18.3 (ortho-CH3); 31.4 (CH3); 34.6 (C(CH3)3); 125.8 (CHar); 126.8 (CHar); 127.2 (CHar); 135.5 (CHar); 137.3 (CHar); 141.4 (CHar); 150.7 (CHar).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[C:13]([O:17][C:18](=[O:26])[N:19]([CH3:25])[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[C:13]([O:17][C:18](=[O:26])[N:19]([CH:20]1[CH2:24][CH2:23][N:22]([C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])[CH2:21]1)[CH3:25])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)c2cc3ccccc3[nH]2)C1
Reaction time: 18 h
Yield: 82.3 %

Procedure:
To a solution of indole-2-carboxylic acid (388 mg, 2.40 mmol) and methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (401 mg, 2.00 mmol) in THF (16 mL) was added CDI (356 mg, 2.20 mmol). After 18 h at rt, the mixture was concentrated, diluted with CH2Cl2, washed with satd. aq. Na2CO3 and water, dried (Na2SO4), and concentrated. The residue was purified by FCC to give the title compound (565 mg, 69%). MS (ESI): mass calcd. for C19H25N3O3, 343.19; m/z found, 344 [M+H]+. 1H NMR (CDCl3): 9.73 (s, 1H), 7.67 (d, J=8.0, 1H), 7.46 (dd, J=8.3, 0.8, 1H), 7.29 (t, J=8.2, 1H), 6.89 (d, J=1.3, 1H), 4.89 (br s, 1H), 4.26-3.49 (m, 4H), 2.85 (s, 3H), 2.36-1.96 (m, 2H), 1.76 (s, 1H), 1.49 (s, 9H). Anal. Calcd for C19H25N3O3: C, 66.45; H, 7.34; N, 12.24. Found: C, 66.42; H, 7.55; N, 12.10.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>O1CCOCC1.FC(C1C=CC=CC=1)(F)F>[NH2:1][C:2]1[C:7]([N:20]2[CH2:21][CH2:22][N:17]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@@H:18]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19]2)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Temperature: 210 °C
Yield: 67.8 %

Procedure:
To a solution of 2-amino-3,5-dibromopyrazine 106 (0.2 g, 0.79 mmol.) and (S)-1-Boc-2-benzylpiperazine 107 (0.44 g, 1.59 mmol) in dioxane (2 mL) and trifluoromethylbenzene (2 mL) was added diisopropylethylamine (0.31 g, 2.4 mmol). The reaction mixture was heated in a microwave reactor at 210° C. for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (0.24 g, 0.536 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=[O:15])[CH2:6]1)[CH2:12]2)=[O:4]>[Li+].[OH-].CO>[O:15]=[C:8]1[CH:9]2[CH2:14][C:5]3([C:3]([OH:4])=[O:2])[CH2:12][CH:11]([CH2:13][CH:7]1[CH2:6]3)[CH2:10]2
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
1.64 g of 4-Oxo-adamantane-1-carboxylic acid methyl ester (10) were dissolved in 4 mL of 2M aq. LiOH/MeOH (1:1) and stirred overnight at room temperature. Additional 5 ml of the MeOH/LiOH mixture were added and stirring was continued until conversion was complete. The reaction mixture was acidified and extracted three times with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to dryness to give 1.4 g of (11) as a solid. Rt=0.87 min (Method 3). Detected mass: 195.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1C(=O)CCC1=O.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>[Co].[Re].[Mo].[Ni].CN1CCCC1=O>[C:12]1(=[O:13])[O:14][C:9](=[O:15])[CH:10]=[CH:11]1.[CH3:1][NH2:2]
Reactant: CN1C(=O)CCC1=O
Agent: [Co]
Agent: [Mo]
Agent: [Ni]
Solvent: CN1CCCC1=O
Product: CN

Procedure:
U.S. Application No. 4,731,454 describes the preparation of N-methylpyrrolidone (NMP) by hydrogenating N-methylsuccinimide on a cobalt/rhenium/molybdenum catalyst. U.S. Application No. 3,109,005 discloses a process for the preparation of NMP by hydrogenating maleic anhydride (MAA)/methylamine mixtures on a Raney nickel catalyst. At reaction times of 10 hours, NMP yields of 70% are achieved in this process. According to the process of DE-A 22 00 600, NMP is obtained in a yield of 44% under the most favorable conditions by hydrogenating MAA/methylamine mixtures on palladium supported catalysts.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#C.C(O)CC#CCCCC>NCCCN>[CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: C#CCCCCCCCO
Agent: CCCCC#CCCO
Agent: NCCCN
Product: C#CCCCCCCO

Procedure:
The same procedure for 8-nonyn-1-ol was followed with 3-octyn-1-ol (6.89 g, 54.6 mmol), KH (6.57 g, 16.4 mmol), and 1,3-diaminopropane (60 mL). This produced 6.09 g of clear yellowish liquid (88%): IR (neat)ν 3360, 2896, 2116 cm−1; 1H—NMR δ 3.44 (t, 2H, J=6.6 Hz), 3.27 (bs, 1H), 2.04 (td, 2H, J=2.6 Hz, 6.6 Hz), 1.83 (t, 1H, J=2.6 Hz), 1.39 (m, 4H), 1.25 (m, 4H); 13C NMR δ 84.5, 68.3, 62.2, 32.3, 28.3, 25.2, (2C), 18.2; MS m/z 136.00 (m++Li). Anal. Calcd for C8H14O: C, 76.14; H, 11.18. Found: C, 76.04; H, 11.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:28][C:29]1[C:33](C(N)=O)=[CH:32][NH:31][N:30]=1.NC1[C:42]([C:43]([NH2:45])=[O:44])=CNN=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:28][C:29]4[N:30]([C:14]=2[CH2:15]3)[N:31]=[CH:32][C:33]=4[NH:45][C:43](=[O:44])[CH3:42])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC(=O)c1c[nH]nc1N
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cnn2c3c(cnc12)C1CCCC(C3)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-4-pyrazolecarboxamide hemisulfate salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a solution of tert-butyl 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (780 mg, 2.15 mmol) in ethyl acetate (50 ml) was added a 4N solution (25 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (487 mg, 86.3%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH:16]([OH:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:38])[CH3:37])[CH3:36]
Reactant: Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Temperature: 55 °C
Yield: 65 %

Procedure:
4-Benzyloxy-2-(hydroxy-phenyl-methyl)-phenol (690 mg, 2.25 mmol) and Cs2CO3 (734 mg, 2.25 mmol) in DMF (7 mL) was treated with ethyl bromoisobutyrate (0.66 mL, 4.5 mmol) and heated at 55° C. for 16 h. Additional bromo ester (0.40 mL, 1.23 mmol) and Cs2CO3 (400 mg, 1.23 mmol) were added and the reaction mixture was heated for 40 h. The mixture was cooled and partitioned between ethyl acetate (30 mL) and H2O (10 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography using hexanes:ethyl acetate to give a pale yellow oil (615 mg, 65%): 1H NMR (400 MHz, CDCl3) δ1.21 (t, 3H, J=7.3 Hz), 1.39 (s, 3H), 1.43 (s, 3H), 4.19 (q, 2H, J=7.3 Hz), 4.97 (s 2H), 6.00 (s, 1H), 6.61 (d, 1H, J=8.8 Hz), 6.74 (dd, 2H, J=3.2, 9.0 Hz), 6.96 (d, 1H, J=2.9 Hz), 7.22-7.39 (m, 10).