Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([N:16]1[C:23](=[O:24])[C:20]2([CH2:22][CH2:21]2)[NH:19][C:18](=[O:25])[CH:17]1[CH2:26][OH:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:9]([N:16]1[C:23](=[O:24])[C:20]2([CH2:21][CH2:22]2)[NH:19][C:18](=[O:25])[CH:17]1[CH2:26][O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1NC2(CC2)C(=O)N(Cc2ccccc2)C1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1C(=O)NC2(CC2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4-dimethylaminopyridine (660 mg, 5.00 mmol) and tert-butyldimethylchlorosilane (4.90 g, 32.0 mmol) were added to a dimethylformamide (100 ml) solution of the compound (7.15 g, 27.0 mmol) obtained in Step 4 above and triethylamine (4.5 ml, 32.0 mmol). The resulting mixture was stirred at room temperature for 16 hours, then ice water (200 ml) was added to the reaction mixture and the precipitated solid was collected by filtration. The solid obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=3:1 (v/v)] to give the title compound (8.63 g, 85%) as a colorless solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C>[CH:1]1([O:6][C:7]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[N:18][OH:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1cccc(C=O)c1OC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C=NO)c1OC1CCCC1
Yield: 97.2 %

Procedure:
To the stirred solution of 2-(cyclopentyloxy)-3-methoxybenzaldehyde (3 g, 13.636 mmol) in ethanol was added hydroxylamine hydrochloride (1.758 g, 27.277 mmol) and aqueous solution of sodium hydroxide (18 ml, 34.091 mmol). The reaction mixture was refluxed for 6 h under nitrogen atmosphere. The solvent was evaporated under reduced pressure and the reaction mixture diluted with water. The product was extracted using chloroform (3×200 ml), combined organic layers washed with water (3×100 ml), brine (50 ml), dried (Na2SO4), filtered and concentrated under vacuum to yield 3.12 g of the product. 1H NMR (300 MHz, CDCl3) δ 1.58-1.64 (m, 4H), 1.66-1.72 (m, 4H), 3.84 (s, 3H), 4.86 (br s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.99 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 8.43 (s, 1H).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH3:27][O:28][C:29]([C:31]1([CH2:46]O)[CH:35]([CH3:36])[C:34](=[O:37])[N:33]([C:38]2[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:45])[CH2:32]1)=[O:30]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:27][O:28][C:29]([C:31]1([CH2:46][I:25])[CH:35]([CH3:36])[C:34](=[O:37])[N:33]([C:38]2[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:45])[CH2:32]1)=[O:30]
Reactant: II
Reactant: COC(=O)C1(CO)CN(c2c(C)cccc2C)C(=O)C1C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1(CI)CN(c2c(C)cccc2C)C(=O)C1C
Temperature: 100 °C
Yield: 83.1 %

Procedure:
Imidazole (261.5 mg, 3.84 mmol), triphenyiphosphine (670.7 mg, 2.56 mmol) and I2 (487.3 mg, 1.92 mmol) were added sequentially to a solution of 1-(2,6-dimethylphenyl)-3-hydroxymethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step c, 373 mg, 1.28 mmol) in toluene (15 mL) and resulting reaction mixture was heated at 100° C. with stirring for an hour. The reaction mixture was then cooled to room temperature and diluted with EtOAc (50 mL), washed with water (30 mL), saturated NH4Cl (30 mL), dried (Na2SO4) and evaporated. The residue was then purified by flash chromatography (SiO2, 20→70% EtOAc/hexanes) to obtain 1-(2,6-dimethylphenyl)-3-iodomethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (427 mg, 83% yield). LC-MS: Rt (retention time): 2.32 min, MS: (ES) m/z 402.2 (M+H+).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4]>C(O)CCC>[CH2:3]([C:2](=[CH:1][CH2:2][CH2:3][CH3:4])[CH:1]=[O:5])[CH3:4]
Reactant: CCCC=O
Solvent: CCCCO
Product: CCCC=C(C=O)CC
Reaction time: 2 h

Procedure:
The experiment in this example was carried out as described in Example 7 except that the first catalyst charged to the reactor was 5.02 g (6.8 mL) charge of Catalyst D; the reaction time was two hours. These results correspond to 94% butanol conversion and 57.3% conversion of theoretical butyraldehyde. Selectivities based on molar conversion of butyraldehyde: 5.6% selectivity to butylbutyrate, 54.8% selectivity to oxygenated 2-EH products and 7.0% selectivity to dehydrated 2-EH products. This example demonstrates that the Catalyst A forms only a slight amount of ester while generating butyraldehyde which undergoes aldol self-condensation over Catalyst D to form primarily 2-ethyl-2-hex-enal along with other 2-EH related compounds.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:14]([CH3:15])=[CH:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C.[OH-].[Na+]>O>[CH3:15][C:14]1[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)=[N:11][N:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=1
Reactant: COc1ccc(Nc2nn(-c3ccccc3)cc2C)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn(-c2ccccc2)nc1Nc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A 50 ml round bottom flask was charged with N-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine (0.37 g, 1.33 mmol), hydrobromic acid (2.16 ml, 39.74 mmol), and acetic acid (2.27 ml, 39.74 mmol). The reaction mixture was stirred at 110° C. for 4 h, then cooled to RT and diluted with water. The solution was neutralized with 6 N NaOH until a pH of about 6, upon which the product precipitated out of solution. The solid was filtered and dried under high vacuum to afford 4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol as a dark solid. MS m/z=266.1 [M+H]+. Calc'd for C16H15N3O: 265.31.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:6]1=2>C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:6]2[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:10](=[O:11])[CH2:9][O:8][C:7]=2[CH:12]=1
Reactant: CN(C)CCN1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN1C(=O)COc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of 4-(2-(dimethylamino)ethyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 1.884 mmol) in dry ethanol (5 mL) was treated with Pd—C (˜0.05 g) and purged with hydrogen gas. The flask was evacuated and purged with hydrogen gas (twice) and stirred at room temperature under hydrogen atm. (balloon pressure) for 2 hours. The reaction was filtered through a Celite bed and washed with methanol (3×10 mL). The combined organic layers were evaporated to obtain the crude title compound (0.44 g, quantitative) as a solid. 1H NMR (DMSO-d6) δ 2.16 (s, 6H), 2.36 (t, 2H, J=6.9 Hz), 3.88 (t, 2H, J=6.9 Hz), 4.47 (s, 2H), 5.01 (s, 2H), 6.21 (d, 1H, J=2.1 Hz), 6.25 (dd, 1H, J=2.7, 8.5 Hz), 6.84 (d, 1H, J=8.4 Hz); ESI-MS (m/z, %): 236 (MH+, 31), 191 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@@H:10]4[CH2:9][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:42]6[CH:41]=[CH:40][C:39]([C:37]([N:34]7[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]7)=[O:38])=[CH:44][CH:43]=6)=[CH:7][N:6]=5)[CH2:13][CH2:12][O:11]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (50 mg, 0.11 mmol), (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)methanone (45 mg, 0.13 mmol), Pd(dppf)2Cl2 (4.5 mg, 0.0054 mmol), and K2CO3 (45 mg, 0.33 mmol) were dissolved in dioxane (4 ml)+H2O (1 ml), and then degassed with N2(gas), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)phenyl) (4-methylpiperazin-1-yl)methanone (62 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:21])(O)[C:18]#[N:19].[O-]S([O-])(=O)=O.[Mg+2]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:17]([C:18]#[N:19])([CH3:21])[CH3:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)(C#N)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
The mixture of 2a (0.83 g, 4 mmol), acetone cyanohydrin (4 ml) and MgSO4 (2 g) was heated to 80° C. and stirred over 2.5 h. After cooling down to room temperature, compound 2b was crystallized into water (30 ml). The solid was filtered and dried to yield {4-[(1-cyano-1-methylethyl)amino]phenyl}carbamic acid tert-butyl ester, 2b (1.08 g, 3.9 mmol, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:18]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 91.3 %

Procedure:
A solution prepared by adding 20 g of 4-cyano-4′-hydroxybiphenyl, 20 g of allyl bromide and 25 g of potassium carbonate to 250 ml of 2-butanone was refluxed for 7 hours. Water was added to the reaction solution for liquid-liquid separation, and the organic layer was washed with water and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel column chromatography using toluene as an eluent solvent and then further recrystallized from ethanol to obtain 22 g of 4-allyloxy-4′-cyanobiphenyl.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=CC=2N=N1.[NH2:25][C:26]1[N:34]=[C:33]([C:35](O)=[O:36])[N:32]=[C:31]2[C:27]=1[NH:28][CH:29]([O:45][CH3:46])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.NCC1CC1>CC(N(C)C)=O>[NH2:25][C:26]1[N:34]=[C:33]([C:35]([NH:8][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[O:36])[N:32]=[C:31]2[C:27]=1[NH:28][CH:29]([O:45][CH3:46])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC1Nc2c(N)nc(C(=O)O)nc2N1Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC1Nc2c(N)nc(C(=O)NCC3CC3)nc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (89 mg, 0.235 mmol) was added to a solution of 6-amino-9-benzyl-8-methoxy-8,9-dihydro-7H-purine-2-carboxylic acid (Example 246) (64 mg, 0.214 mmol) and diisopropylethylamine (75 μl, 0.428 mmol) in dimethylacetamide (0.5 ml) and the reaction mixture stirred at room temperature for 1 hour. Aminomethylcyclopropane (28 μl, 0.321 mmol) was added and the reaction mixture stirred at room temperature for a further 20 hours. The reaction mixture was concentrated in vacuo and water added. The resultant precipitate was collected by filtration, azeotroped with toluene and triturated with methanol to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:38]/[O:39]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:21]([O:23][CH:24]([O:26][C:27]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:28])[CH3:25])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(O)=O.[OH-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:38]/[OH:39])/[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:21]([O:23][CH:24]([O:26][C:27]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:28])[CH3:25])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of the product of Procedure 13 (62.7 g, 0.076 mol) and 90% aqueous formic acid (110 ml) was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc (600 ml) and ice-water (300 ml) and the lower layer was adjusted to pH 3.3 with 30% aq. NaOH under vigorous stirring. The upper layer was diluted to 2 L, separated, washed with water (500 ml×3) and brine, dried over MgSO4 and concentrated under diminished pressure. The residue was dissolved in toluene (300 ml) which was carefully transferred to the top surface of a silica gel column (Wakogel C-200, 800 g). The column was eluted with CH2Cl2, 0.5%, 1.0%, 1.5%, 2.0% and 3.0% MeOH in CH2Cl2, successively. The fractions which exhibited approximately Rf: 0.12 on TLC (SiO2, 5% MeOH-CH were combined and concentrated in vacuo to give 30.0 g (68%) of the desired product as an amorphous powder. The starting material was recovered (8.4 g, 14%) from the fractions which showed Rf 0.55 on TLC.
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])C)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.Cl>>[C:13]([NH:12][CH2:11][CH2:10][N:8]([C:41]([CH2:40][CH2:39][C:38]([OH:43])=[O:44])=[O:42])[CH3:1])([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]
Reactant: CN(CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
Boc-NMe-CH2CH2—NH-Fmoc (520 mg, 1.31 mmol) was treated with TFA-water (15 ml, 95:5, v/v) for 1 hour at ambient temperature, when TLC analysis showed complete Boc-deprotection. TFA-water was removed under reduced pressure and the resulting oil dissolved in DCM (30 mL). To this solution, succinic anhydride (131 mg, 1.31 mmol) was added followed by DIPEA (to pH ˜10 by moist pH paper). The mixture was then stirred for 30 min. The reaction mixture was then acidified (pH=1) with HCl (1 M) and extracted with EtOAc (100 mL×3). The combined EtOAc layers were washed with brine (100 mL×2) and dried over Na2SO4. The EtOAc was removed under reduced pressure to give the title compound as a colorless oil. ES-MS (MeOH-direct infusion) Calculated MH+ (C23H26N2O5H+)=411.10, Observed MH+411.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=O)=[CH:9]2)=[CH:5][CH:4]=1.[N+:21]([CH3:24])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](/[CH:17]=[CH:24]\[N+:21]([O-:23])=[O:22])=[CH:9]2)=[CH:5][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(Cn2cc(C=O)c3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(Cn2cc(/C=C\[N+](=O)[O-])c3ccccc32)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
1-(4-Methoxybenzyl)-1H-indole-3-carbaldehyde (I-61a: 22 g, 83.01 mmol) was refluxed overnight with nitromethane (146 g, 2407 mmol) and ammonium acetate (3.26 g, 42.33 mmol) to afford the crude product. The reaction mass was cooled to room temperature and filtered. The solid collected was washed with water and dried under reduced pressure to afford 20 g of the product (76% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:28]1([CH:27]=[CH:26][C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1
Yield: 67.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (4.8 mL), cinnamic acid (2.6 g), WSC.HCl (3.3 g), and methylene chloride (150 mL), to give the captioned compound (3.7 g, 67%) as an oily product.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C@H:14]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([O:42]C)[CH:36]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C@H:14]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([OH:42])[CH:36]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A solution of boron tribromide in dichloromethane (1M solution, 3.7 ml) was added dropwise over 20 minutes to an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbenzyl)-piperazine (0.68 g) in dichloromethane (5 ml). After being stirred at the same temperature for 2 hours, followed by further stirring at room temperature for 12 hours, the mixture was poured into aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (0.56 g) as a red foam.
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.CC1NC2C=CC(OC)=CC=2C=1CCNC(C)=O>C1COCC1>[CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH:6][C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20]
Reactant: COc1ccc2[nH]c(C)c(CCN)c2c1
Reactant: O=C(Cl)C1CC1
Agent: COc1ccc2[nH]c(C)c(CCNC(C)=O)c2c1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(CCNC(=O)C3CC3)c2c1

Procedure:
A solution of the crude 2-methyl-5-methoxytryptamine (from 5 mmol of 3a), in THF (15 mL) and TEA (0.7 mL) was acylated with cyclopropanecarbonyl chloride (0.45 mL) at room temperature for 1.5 h using the procedure described for 4a. The desired product 4e was obtained as white solid (0.615 g, 45% overall yield), mp 102°-103° C. IR νmax : 3460, 3300, 1650. 1H NMR: 0.70(m, 2H, CH2cyclopropyl), 0.97(m, 2H, CH2 cyclopropyl), 1.24(m, 1H, cyclopropyl-CH), 2.36(s, 3H, 2-CH3), 2.90(t, 2H, β -CH2), 3.51(q, 2H, α-CH2), 3.85(s, 3H, OCH3), 5.75(br s, 1H, NH), 6.75-7.25 (m, 3Harom), 8.00(br s, 1H, NHindole).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Product: Cc1nnc2n1-c1ccc(C#C[Si](C)(C)C)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was similarly prepared by coupling of 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with trimethylsilylacetylene as described in Example 56. The product was isolated by chromatography and was crystallized from ethyl acetate/ hexane to give colorless crystals of the title compound with m.p. 243°-245° C.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+]>CO>[Cl:20][C:17]1[N:16]=[C:15]([CH3:21])[C:14]([C:12]2[N:11]=[N:10][NH:9][CH:13]=2)=[CH:19][CH:18]=1
Reactant: Cc1nc(Cl)ccc1-c1cn(COC(=O)C(C)(C)C)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(Cl)ccc1-c1c[nH]nn1

Procedure:
[4-(6-Chloro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl]methyl pivalate (350 mg, 0.96 mmol) was taken up in methanol (3.9 ml) at room temperature. Aqueous sodium hydroxide (1.0M, 4.8 ml, 4.8 mmol) was added, and the mixture was allowed to react for 2 hours. The reaction was then extracted three times with diethyl ether. The combined organic fractions were washed with water. The combined aqueous layers were adjusted to pH 7.0 via dropwise addition of 6 M aqueous hydrochloric acid. The neutralized mixture was saturated with solid sodium chloride and extracted three times with ethyl acetate. All the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound.