Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>CN(C)C=O>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reaction time: 0.83 h
Yield: 70 %

Procedure:
A 300 ml glass-made three-neck flask was charged with 0.134 mol of p-vinylphenol, 0.343 mol of imidazole and 90 ml of dimethylformamide as a solvent, and a solution prepared by dissolving 0.174 mol of triisopropylsilyl chloride in 90 ml of dimethylformamide was dropwise added thereto at 0° C. in 50 minutes. Then, the reaction temperature was elevated up to room temperature to carry out reaction for 10 hours in the same condition. Water was added thereto, and the reaction product was extracted with chloroform. The solvent was distilled off, and the residue was dissolved in diethyl ether and washed with a sodium hydroxide aqueous solution and water. The product was dried on magnesium sulfate and filtered, and then it was further dried on a calcium hydride. Then, the reaction product was distilled at a reduced pressure under nitrogen flow to obtain aimed p-triisopropylsilyloxystyrene at a yield of 70%.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)CCCCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)CCCCCCNC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C

Procedure:
A solution of 72 mg (0.18 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxa-diazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2), 30 mg (0.15 mmol) of methyl 7-amino-heptanoate hydrochloride, 87 mg (0.23 mmol) of HATU and 0.8 ml of pyridine in 3.2 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was poured into ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and, after filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative RP-HPLC. This gave 13 mg (0.02 mmol, 13% of theory) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].F[C:17]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:18]=1[CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:17]=1[C:5]([CH2:3][CH3:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:31])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
To a flask with sodium hydride (207 mg, 8.64 mmol) was added DMSO (5 mL). The mixture was stirred at rt for 5 min. Diethyl 2-ethylmalonate (1626 mg, 8.64 mmol) in DMSO (5 mL) was added. After 20 min stirring, 13A (550 mg, 1.728 mmol) in DMSO (5 mL) was added. The reaction mixture was heated at 65° C. over night. The reaction was quenched with water, extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography to give 13B (820 mg, 98% yield). MS (ESI) m/z: 486.9 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.00-8.12 (m, 2H) 7.49 (d, J=8.79 Hz, 1H) 7.24-7.45 (m, 5H) 5.11-5.32 (m, 2H) 4.57 (d, J=16.26 Hz, 2H) 4.10-4.33 (m, 4H) 2.89 (d, J=3.95 Hz, 3H) 2.44 (t, J=7.25 Hz, 2H) 1.15-1.34 (m, 6H) 0.81-1.05 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:16][C:17]1[CH:23]=[CH:22]C(N)=[CH:19][C:18]=1[O:24][CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:16][C:17]1[CH:23]=[CH:22][C:1]([NH:2][C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: COc1cc(N)ccc1Br
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C=C(Nc1ccc(Br)c(OC)c1)c1ccccc1
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of compound 112 and 4-bromo-3-methoxyaniline (1 eq.) in DCM (0.15 M) was added PPTS (1 eq.). The mixture was heated to reflux and stirred for one day. The mixture was cooled and the solids were removed by filtration and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography (SiO2, PE:EtOAc with EtOAc from 1 to 15%) to give the title compound 113 (80%). 1H NMR (CDCl3) δ (ppm) 10.32 (br s, 1H), 7.32 (m, 5H), 7.20 (d, J 8.5, 1H), 6.19 (dd, J 8.5, 2.5, 1H), 6.11 (d, J 2.5, 1H), 5.03 (s, 1H), 4.21 (q, J 7.0, 2H), 3.50 (s, 3H), 1.32 (t, J 7.0, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:18]([F:20])[F:19])=[N:8][N:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]=1[CH:11]([F:13])[F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[C:14]([N:9]1[C:10]([CH:11]([F:12])[F:13])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:18]([F:20])[F:19])=[N:8]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1c(C(F)F)nn(C(C)(C)C)c1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1nc(C(F)F)c(C(=O)O)c1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
N-tert-Butyl-3,5-di(difluoromethyl)-4-pyrazolecarboxylic acid ethyl ester (3.40 g, 11.5 mmol) in ethanol (23 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (4.3 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (40 ml) and extracted with diethyl ether (20 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×30 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-tert-Butyl-3,5-di(difluoromethyl)-4-pyrazolecarboxylic acid (3.0 g, 11.2 mmol, 97%) was isolated as a pale reddish solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: COc1ccc(CCNc2ncnc3c(F)ccc(F)c23)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of (5,8-difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine (0.86 g, 2.6 mmol) in CH2Cl2 (10 mL) cooled to −50° C., was added 7.8 mL BBr3 (1 M in CH2Cl2, 7.8 mmol). The solution was allowed to warm to room temperature and stirred overnight, and then quenched slowly with methanol. The solvent was removed by rotary evaporation, and the residue was diluted with water and stirred for a few min. The pale yellow solid precipitate was collected by suction filtration, washed with water, and dried in vacuum at 50° C. overnight to give 0.83 g (quantitative yield) of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol. 1H NMR (d4-DMSO+d6-acetone): δ 9.5-8.5 (m, 3H), 7.97 (m, 1H), 7.61 (m, 1H), 6.99 (s, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 3.92 (m, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.11 (s, 3H). LC/MS: 316.04 (M++1). The product was used in the following reaction without further purification. M.P. 244-251° C.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:15](N(C)C)N(C)C>>[N:1]12[P:15]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCNCCN1
Reactant: CN(C)P(N(C)C)N(C)C
Product: C1CN2CCN3CCN(CCN1)P23

Procedure:
1,4,7,10Tetraaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane is prepared in the absence of a solvent by heating 5.0 g of 1,4,7,10-tetraazacyclododecane and 4.7 g of hexamethylphosphorous triamide together at about 75° C for between two and three hours and subliming the crude product at 75° C. at 0.4 mm. The yield is 5.3 g (92%) of product melting at 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28]1[CH2:33][O:32][CH:31]=[CH:30][CH2:29]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH:31]3[CH2:30][CH2:29][CH2:28][CH2:33][O:32]3)[N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)nn1C1CCCCO1
Reaction time: 8 h

Procedure:
To a mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (2.44 g, 10 mmol) and 4-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) in THF (200 mL), was added DHP (4.25 g, 50 mmol). After stirring overnight, the reaction turned clear. After concentration, the residue was dissolved in ethyl acetate and washed with Na2CO3 saturated aqueous solution. The organic layer was then washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2,5-Dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine as light yellow solid, which was used in subsequent reactions without further purification; ESMS m/z 244 (M−THP+H+); TLC Rf=0.6 (Silica; 1:1 ethyl acetate/hexanes; starting material Rf=0.2).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([O:30]C)=[O:29])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(CCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
To a mixture of methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]acetate (0.54 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at room temperature for 15 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.40 g, 78%) of 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2].[CH2:12]=O>C1N2CCN(CC2)C1.C1(C)C=CC=CC=1>[C:1]([C:3](=[CH2:12])[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: CC(C)(C)COC(=O)CC#N
Reactant: C=O
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: C=C(C#N)C(=O)OCC(C)(C)C

Procedure:
46.5 (0.3 mole) of neopentyl α-cyanoacetate, 8.1 g (0.27 mole) of paraformaldehyde, 140 g of toluene and 46.5 mg of triethylenediamine were reacted together under reflux and water was removed by azeotropic distillation. Then, 23.5 g of dioctyl phthalate, 0.465 g of hydroquinone and 0.93 g of phosphorus pentoxide were added and depolymerization allowed to take place at 150°-210° C. under a reduced pressure to afford 21.65 g of crude neopentyl α-cyanoacrylate. Redistillation thereof afforded (8.3 g of neopentyl α-cyanoacrylate (b.p. 65°-67° C./2 mmHg, m.p. 40°-41° C., yield 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Fluorophenyl)-5-methoxy-1H-indazole (137e, 1.0 mmol, 242 mg) was dissolved in dichloromethane (4 ml) and BBr3 (4 ml, 1 M in dichloromethane) was added. The reaction mixture was stirred in r.t. overnight before it was quenched with water (20 ml). The product was extracted with dichloromethane (2×20 ml) and washed with sat. NaHCO3. The organic phase was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate).
Reaction SMILES: [CH2:1]([C:10]1([C:19](Cl)=[O:20])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:24]=1[NH2:25]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:10]1([C:19]([NH:25][C:24]2[C:23]([F:22])=[CH:29][C:28]([F:30])=[CH:27][C:26]=2[F:31])=[O:20])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CCCCCCCCCC1(C(=O)Cl)Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(F)cc(F)cc2F)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 44 h
Yield: 54 %

Procedure:
The title compound was prepared according to the procedure described in Example 65, except that 398 mg (1.3 mmple) 2-n-nonylindane-2-carbonyl chloride, 220 mg (1.5 mmole) 2,4,6-trifluoroaniline, and 187 mg (1.5 mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirred at room temperature for 44 hours. There was obtained 290 mg product. 54% yield. IR(CHCl3): 1693 cm-1. 1H NMR: δ0.86 (t, 3H); 1.23 (c, 12H); 1.41 (c, 2H); 1.78 (c, 2H); 3.02 (d, 2H); 3.5 (d, 2H); 6.7 (c, 3H); 7.18 (c, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.N1C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][C@H:31]([NH:35][C:36](=[O:62])[C@H:37]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=2)[NH:38][C:39](=[O:53])[CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:32]([NH2:34])=O)[CH:25]=[CH:26][CH:27]=1)=[O:21]>CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][C@H:31]([NH:35][C:36](=[O:62])[C@H:37]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=2)[NH:38][C:39](=[O:53])[CH:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:32]#[N:34])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COC(=O)c1cccc(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CCC[C@@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.12 mL, 1.39 mmol) is added dropwise to DMF (10 mL), and the resulting solution is cooled to 0° C. After the solution is clear, pyridine (0.22 mL, 2.78 mmol) is added, followed by N-[4-(3-methoxycarbonylphenyl)-1(S)-(aminocarbonyl)butyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (0.42 g, 0.70 mmol), in one portion. The yellow reaction solution is stirred at 0° C. for 1.5 hours, after which time it is diluted with EtOAc (50 mL), and washed with saturated aqueous NaHCO3 solution (1×50 mL), saturated aqueous LiCl solution (1×50 mL), dried over MgSO4, and evaporated. The residue is chromatographed to yield N-[4-(3-methoxycarbonyl-phenyl)-1(S)-cyanobutyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide, as a yellow solid.
Reaction SMILES: [CH:1]([CH:4]1[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[CH2:9](O)CO>[Pd]>[CH2:4]([O:5][CH:6]([CH3:9])[CH2:7][OH:8])[CH:1]([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: CC(C)C1OCCO1
Agent: [Pd]
Product: CC(C)COC(C)CO
Temperature: 200 °C
Reaction time: 2 h

Procedure:
20 g of 2-isopropyl-1,3-dioxolane and 100 g of ethylene glycol were combined in a 300 mL stainless steel autoclave. 2.0 g of 5% Pd/C catalyst were added and the autoclave was sealed. The reactor was heated to 200° C. The reactor was then brought to an operating pressure of 3.45 MPa and stirring commenced at 750 rpm. Pressure was maintained through the duration of the experiment. After 2 h, the autoclave was cooled and remaining gas vented. The autoclave was opened, its contents filtered, and the filtrate analyzed by gas chromatography (GC). 83% conversion of the acetal mixture was observed. Upon analysis of the results, the mixture was found to demonstrate 95.8% selectivity to 2-isobutoxy-ethanol.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:30]1([CH2:42][C:43]([NH2:45])=[O:44])[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][CH2:33][N:32]3[CH:31]=1>>[C:30]1([C:42]2[C:43](=[O:44])[NH:45][C:3](=[O:2])[C:4]=2[C:6]2[C:14]3[C:9](=[C:10]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][CH2:33][N:32]3[CH:31]=1
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: CC(C)[Si](OCCCc1cccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-((triisopropylsilyloxy)propyl)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(OC([NH:8][C@:9]1([C:18]([OH:20])=[O:19])[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)C>[NH2:8][C@@:9]1([C:18]([OH:20])=[O:19])[CH2:11][C@@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To commercially available (1R,2S)-1-tert-butoxycarbonylamino-2-phenylcyclopropanecarboxylic acid (130 mg, 0.45 mmol) was added 4N hydrochloric acid—1,4-dioxane solution (2.0 mL, 16 v/w) and the mixture was stirred for 1 hr at room temperature. Diethyl ether (1.0 mL) was added thereto and the mixture was stirred for 5 min, after which the resulting crystals were collected by filtration. The crystals were washed with diethyl ether (1.0 mL) and dried under reduced pressure to give the title compound (81 mg, white powder, yield 84%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])=[CH:5][CH:6]=1
Reactant: Cc1ccc([C@H]2CCC[C@H]2N)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccc([C@H]2CCC[C@H]2NS(=O)(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer is charged with (+,−) cis-2-p-tolyl-cyclopentylamine (313 mg, 1.79 mmol, from preparation 9), methylene chloride (5.0 mL) and the solution cooled to 0° C. DBU (0.32 mL, 2.14 mmol) and isopropylsulfonyl chloride (0.24 mL, 2.14 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with aqueous ammonium chloride, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 250 mg (50%) of the purified title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][CH2:18][NH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27].O>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][CH2:18][N:19]3[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCCN3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCc2c1cccc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
An intermediate compound, 1-Methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline, was produced as follows: To a stirred solution of 4-(1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.30 g, 4.10 mmol) in THF-DMF (1:1, 40 mL) was added NaH (60% dispersion in oil, 0.58 g, 24.16 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, cooled to 0° C. and iodomethane (1.75 g, 12.30 mmol) was added. The mixture was stirred at room temperature overnight and diluted with ethyl acetate. Water was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified on a silica gel column using hexanes-ethyl acetate (3:1) as eluent to give 4-(1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.90 g, 66%) as a liquid. 1H NMR (400 MHz, CDCl3): δ 7.10 (t, 1H), 6.40 (m, 2H), 3.50 (br s , 4H), 3.25 (t, 2H), 2.90 (s, 3H), 2.80 (br s, 4H), 2.75 (t, 2H), 1.90 (t, 3H), 1.45 (s, 9H).