Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17]=[C:18]([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:18]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
In 612 ml of methylene chloride was suspended 45.0 g of 4-cyanobenzoic acid and 3.1 ml of conc. sulfuric acid. To the suspension was added, while stirring at 0° C., 310 ml of isobutene. The mixture was stirred for 13 days. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting precipitate was collected by filtration and washed with hexane. The filtrate and the washings were combined and concentrated under reduced pressure. The concentrate was purified by silica gel chromatography (hexane/ethyl acetate=10/1), followed by crystallization from methylene chloride/petroleum ether to afford 43.1 g of the title compound as a white crystalline product.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH:26]1([C:30]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#N)c(N)c(OC(=O)C2CCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (250 mg, 1.03 mmol) was dissolved in acetonitrile (0.10 ml), and cooled to 0° C. Triethylamine (244 μl, 1.75 mmol) and cyclobutanecarbonyl chloride (177 μl, 1.55 mmol) were dropwise added to the solution, followed by stirring at room temperature for 1 hour. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under, reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate/hexane (1:4, v/v) gave the entitled compound (283 mg, 85%) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24]O)[CH:16]=4)[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]4[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=4[CH3:36])=[O:27])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:59].O>C(Cl)Cl>[Br:59][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]3[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=3[CH3:36])=[O:27])[C:9]3[CH:8]=[N:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:14]=3[CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCO)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCBr)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxamide (0.35 g, 0.68 mmol) in DCM (5 mL), triphenyl phosphine (0.285 g, 1.08 mmol) was added and the reaction mixture stirred at room temperature for 10 min. Finally CBr4 (0.36 g, 1.08 mmol) was added portion wise and resulting solution was stirred at room temperature for 4 h. On completion, water was added to the reaction mixture and extracted with 5% MeOH/DCM. The combined organic layer was dried over sodium sulfate and concentrated to give crude material which was purified by column chromatography over silica gel to afford 6-(3-(3-bromopropoxy)phenyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.28 g, 71%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].N1CCCCC1>C(O)(=O)C>[C:7](/[C:9](=[CH:1]\[CH2:2][CH:3]([CH3:5])[CH3:4])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)CC=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)/C(C#N)=C/CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a mixture of 3.00 mL (28.0 mmoles) of isovaleraldehyde and 3.00 mL (28.1 mmoles) of ethyl cyanoacetate in 4.0 mL of glacial acetic acid was added a solution of 0.10 mL of piperidine in 1.0 mL of glacial acetic acid. This mixture was subsequently stirred at room temperature for 18 hours, after which the product was isolated by diluting the mixture with 50 mL of 10% aqueous sodium chloride and extraction with ether. The combined extracts were washed thoroughly with 50 mL portions of 10% aqueous NaCl, followed by washes with 50 mL of 1:1 (v/v) 1M aqueous NaOH:saturated brine and saturated brine. The organic extracts were then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether by evaporation at reduced pressure, followed by distillation, afforded 3.91 g (77% yield) of cyanoester 5: bp 78°-90° C. (bath temperature, 0.07 mm).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
8.77 g of 4-nitrobenzoic acid (52.5 mM) were dissolved in 400 ml of THF and 53.1 g of triethylamine (525.0 mM). The solution was cooled to −30° C. and 6.01 g of methansulfochloride (52.5 mM) were added dropwise. The mixture was stirred for 1 h at this temperature, then 6.95 g of 4-nitrophenol (50.0 mM) were added at once, followed by 250 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, the reaction mixture was filtered, the cake was washed with THF and the filtrate was evaporated to dryness. The residue was purified by chromatography using silica gel and dichloromethane to give 11.0 g (38.2 mM, 76%) of 4-nitrophenyl 4-nitrobenzoate as white crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:4]([OH:6])=[O:5].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O>[CH2:24]([O:23][C:21]([NH:2][C@@H:3]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:4]([OH:6])=[O:5])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Reaction time: 4 h
Yield: 115.3 %

Procedure:
The (2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid hydrochloride (20 g) was dissolved in 100 ml water at 25-30° C. The pH of the solution was adjusted to 8.5-9.5 with aqueous sodium hydroxide solution at 5° C. To the mixture benzyl chloroformate (10.7 g) was added and set aside for 4 h at 25-30° C. The reaction mass was washed with MTBE (25 ml) and the pH of the aqueous phase adjusted to 2-3 with dilute hydrochloric acid. Aqueous phase was extracted with ethyl acetate, the organic phase dried and evaporated to yield 26 g (95%) of the title product. M.P 55-58° C., H1NMR (300 MHz, CDCl3): 1.39-1.58 (m, 12H), 2.04-2.07 (s, 2H), 3.86-3.89 (dd, 1H), 4.98 (s, 2H), 5.11 (s, 1H), 7.0 (d, 1H), 7.16-7.27 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.N1C=CC=CC=1.ClCCl.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Oc2cccc3ncnc(NC(C)=O)c23)cc1
Temperature: 4 °C
Reaction time: 96 h
Yield: 43.7 %

Procedure:
To a stirred solution of 4-amino-5-(4-methoxyphenoxy)quinazoline (1.0 g, 3.7 mmol) in 30 ml of dichloromethane pyridine (0.3 g, 3.7 mmol) and acetic anhydride (0.38 g, 3.7 mmol) were added at room temperature and stirring continued for 4 days. After evaporation under reduced pressure, 30 ml of 2-propanol was added and after cooling to 4° C. the solid was collected by filtration, washed, recrystallized from ethanol, filtrated again and dried at 50° C. in vacuo. to give 4-acetamido-5-(4methoxyphenoxy)quinazoline (0.5 g, 45.4%, m.p. 174-175° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](I)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: ICc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.2 %

Procedure:
To 1 ml of a DMF solution containing 55.5 mg (0.1438 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 21.82 μl (0.1798 mmol) of benzyl iodide, there was added 27.43 μl (0.1798 mmol) of DBU and the resulting mixture was agitated for 4.5 hours at room temperature. After the solvent in the reaction mixture was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 5 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 52.8 mg (0.111 mmol, 77%) of 2-benzyloxy-2'-hydroxy-5,5'-bis (2-ethyoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.23 (6H, t, 2CH3), 2.5-2.8 (4H, m, 2CH2), 2.8-3.1 (4H, m, 2CH 2), 4.13 (4H, q, 2CH2), 5.06 (2H, s, CH2), 6.27 (1H, s, OH), 6.8-7.4 (11H, m, arom-H) MS (FAB): 475 (M-H)-
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cnc(CON)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cnc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added tert-butyl 4-[(aminooxy)methyl]-1H-imidazole-1-carboxylate 122 (0.289 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 123 (0.40 g, 94%) as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:13][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)s1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of methyl 5-(hydroxymethyl)thiophene-2-carboxylate (375 mg, 2.17 mmol) in methylene chloride (9.0 mL) is added phosphorus tribromide (100 μL, 1.08 mmol) and the reaction mixture is stirred at 0° C. for 0.5 h. Saturated sodium bicarbonate (10 mL) is carefully added to the reaction mixture and the phases are separated. The organic phase is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield the title compound in pure form. ESI MS m/z 235 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14](OCC)(OCC)OCC)[CH3:12]>C(OC(C)C)(C)C>[CH2:11]([O:13][C:14]1[NH:1][C:2]2=[N:3][C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1)[CH3:12]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Cc1cc(C)c(N)c(N)n1
Solvent: CC(C)OC(C)C
Product: CCOc1nc2c(C)cc(C)nc2[nH]1
Temperature: 155 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
2,3-Diamino-4,6-dimethylpyridine (U.S. Pat. No. 5,332,744; 2.70 g, 19.7 mmol) and tetraethoxymethane (16.5 mL, 78.7 mmol) were mixed, and the mixture was stirred at 155° C. for 2 hr. The mixture was cooled to room temperature, and diisopropyl ether (30 mL) was added. The precipitated solid was collected by filtration to give the title compound (2.42 g, 64%).
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([Br:13])[CH:12]=1)=O)C.S(O)(O)(=O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([NH2:28])=[NH:27])[CH2:22][CH2:21]1.CC([O-])(C)C.[K+]>O1CCOCC1>[Br:13][C:11]1[CH:12]=[C:8]([C:6]2[N:28]=[C:26]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[N:27]=[CH:4][N:5]=2)[S:9][CH:10]=1
Reactant: CN(C)C=NC(=O)c1cc(Br)cs1
Reactant: CN1CCN(C(=N)N)CC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2ncnc(-c3cc(Br)cs3)n2)CC1

Procedure:
To a solution of 4-bromo-thiophene-2-carboxylic acid dimethylamino-methyleneamide (261 mg, 1.0 mmol) in anhydrous 1,4-dioxane (8 mL) was added 4-methyl-piperazine-1-carboxamidine sulfate (95.6 mg, 0.25 mmol) and KOtBu (56.1 mg, 0.5 mmol). The resulting suspension was heated at reflux overnight under argon. After cooling, the reaction mixture was passed through a pad of diatomaceous earth, the filtrate was concentrated and the residue was purified by preparative TLC (2 M NH3 in MeOH/CH2Cl2) to yield the title compound as a yellowish solid.
Reaction SMILES: O.[C:2]1([CH:8]([CH3:11])[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:12].[H][H]>C(O)C>[ClH:12].[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(C#N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(CN)c1ccccc1
Temperature: 57 °C
Yield: 76.2 %

Procedure:
To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5% starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ˜400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitated solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 9, 76.2%) as a white powder.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:31])[C:21]=1[CH2:22][OH:23].N1C=CN=C1.O>CN(C)C=O>[Si:1]([O:23][CH2:22][C:21]1[C:24]([CH3:31])=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=1[CH3:19])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of tert-butyldiphenylsilyl chloride (30.7 g) in N,N-dimethylformamide (90 ml) were added 2,6-dimethyl-3-nitrobenzyl alcohol (18.4 g) and imidazole (8.99 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 3 hours at ambient temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (46.67 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:21][C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:21][C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(Cc2ccccc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(Cc2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-I), the title compound was prepared as a solid having a melting point of 106-107° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10]CC)=[O:9])=[N:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[N:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-(pyrimidin-4-yl)acetate (Example 33b, 450 mg, 2.71 mmol) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 24 hours, concentrated under reduced pressure and suspended in ethanol. The solid was removed by vacuum filtration, and the filtrate was concentrated under reduced pressure, triturated with ethanol, concentrated again and carried onto the next step without further purification. MS 139 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:9]([CH3:10])=[N:20][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[C:6]=1[CH3:7])=[O:12])[CH3:2]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
Dissolve 2-acetyl-3-oxobutyric acid ethyl ester (20.74 g, 0.120 mol) and 2-pyridylhydrazine (14.5 mL, 0.133 mol) in acetic acid (160 mL) and stir the mixture for 18 hr. Concentrate, dilute with DCM, wash with saturated sodium bicarbonate, dry (sodium sulfate), filter and concentrate to give 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester as an oil (28.6 g, 97%). MS (APCI): m/z=246 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4Br)=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12>C1(C)C=CC=CC=1.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>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:20]4[CH:19]=[CH:18][CH:17]=[CH:22][N:21]=4)=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1)c1ccccc1-c1ccccn1
Yield: 83 %

Procedure:
A mixture of 484 mg of N-[5-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-pyridinyl]-2-bromobenzamide, 814 mg of 4-(N,N-dimethyl)anilino-tri-n-butyl stannane and 100 mg of tetrakis(triphenylphosphine)palladium (O) is refluxed in degassed toluene for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with ethyl acetate to give 200 mg of the desired product: M+1=528.
Reaction SMILES: C(OCC)(=O)C.[CH:7]1([NH:10][C:11](=[O:26])[C@@H:12]([OH:25])[C@@H:13]([NH:17]C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]1.[ClH:27].C(O)(C)C>C(O)(C)C>[ClH:27].[CH:7]1([NH:10][C:11](=[O:26])[C@@H:12]([OH:25])[C@@H:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
The ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (92.2 g, 10.8 wt. %) obtained in the above Example 2 was used. The solvent was changed from ethyl acetate to isopropyl alcohol, thereby to prepare an isopropyl alcohol solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (69.63 g). The solution was heated up to 60° C., and 10.5 wt % hydrogen chloride/isopropyl alcohol solution (18.2 g) was dropwise added, taking 1 hour. After stirred for 8 hours, the reaction solution was cooled down to 0° C. at a constant rate, taking about 6 hours. The slurry had no solid aggregation therein, and had good flowability. The precipitated crystals were collected by filtration under reduced pressure, using a kiriyama funnel (diameter 6 cm, filter pore size 4 μm). At the time, the filterability was good, and the time taken for separation of the crystals from the mother liquid was about 30 seconds. The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (30 mL). Next, the washed wet crystals were dried in vacuum at 60° C., to obtain (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (7.06 g, isolation yield: 90 mol %, chemical purity: 100.0 area %, optical purity: 100% ee).