Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16]/[C:17](/[C:24]([F:27])([F:26])[F:25])=[CH:18]\[C:19](OCC)=[O:20].[H-].[Na+].C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:19](=[O:20])[CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[NH:16][C:13]2=[O:14])=[C:4]([F:15])[CH:3]=1
Reactant: O=C=Nc1c(F)cc(Cl)c2c1OCCC2
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2c1OCCC2

Procedure:
By a method analogous to that of Example 1, Step G, 2.5 grams (0.011 mole) of 5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl isocyanate was reacted with ethyl 3-amino-4,4,4-trifluorocrotonate and 0.66 gram (0.012 mole) of sodium hydride (60% in mineral oil) in 150 mL of tetrahydrofuran. The crude reaction product was subjected to column chromatography on silica gel, with 1:2 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.0 grams of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[S].[NH2:20][CH2:21][CH:22]([NH2:24])C.[C:25]1(C)C=CC=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[N:20]([CH3:25])[CH2:21][CH2:22][N:24]=4)=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1
Reactant: ClCc1ccc(-c2nsc3ccc(Cl)cc23)cc1
Reactant: Cc1ccccc1
Reactant: CC(N)CN
Agent: [S]
Product: CN1CCN=C1c1ccc(-c2nsc3ccc(Cl)cc23)cc1
Product: Cl

Procedure:
44 g of 5-chloro-3-(4'-chloromethylphenyl)-1,2-benzisothiazole, 9.6 g of sulfur and 22.5 g of 1,2-diaminopropane in 600 ml of toluene are refluxed for 24 hours. The reaction mixture is filtered hot and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in 500 ml of ether and 30 g of hydrogen chloride gas are passed into the solution, whilst cooling. The resulting crystals are filtered off and recrystallized from water. 31 g of product melting, with decomposition, at 248° C., are obtained. The yield corresponds to 57% of theory.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2].[CH2:32]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:32])[CH:15]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COc4ccccc4)C3)cc21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(COc4ccccc4)C3)cc21

Procedure:
A 200 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(phenoxymethyl)-1-piperazinyl]-3-quinolinecarboxylic acid was dissolved in a mixture of 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid, heated on a steam bath for 3 hours and then concentrated in vacuo. The residue was dissolved in 5 ml of water and 1N sodium hydroxide was added to pH 7. The resulting solid was collected, washed with water and dried, giving 188 mg of the desired product, mp 202°-204° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([Mg]Br)[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(S(/[N:18]=[CH:19]\[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)(C)(C)C>C1COCC1>[NH2:18][CH:19]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([S:3][CH2:1][CH3:2])[CH:5]=1)[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C=N\S(=O)C(C)(C)C
Reactant: CCSc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: CCSc1cccc(C(N)C2CCCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-(ethylthio)phenylmagnesium bromide in THF (10 mL 11.6 mmol) was added to a cooled (0° C.) solution of tert-butyl 2-{(Z)-[(tert-butylsulfinyl)imino]methyl}piperidine-1-carboxylate (1.5 g, 4.7 mmol) in THF (10 mL) and the mixture was stirred for 60 min The mixture was quenched with 50 mL of a 1:1 mixture of saturated aqueous ammonium chloride and 33% aqueous ammonia before extracting into ethyl acetate (100 mL). The organic phase was dried (MgSO4) and concentrated. The residue was treated with methanol (20 mL), cooled to 0° C. and then 4N hydrogen chloride in dioxane (5 mL) was added. After stirring for 30 min 4N aqueous sodium hydroxide (6 mL) was added and the mixture was extracted into DCM. The organic extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel eluting with iso-hexane on a gradient of ethyl acetate (0-60%) followed by dichloromethane on a gradient of methanol (2-10%) to give the title product as a 1.7:1 mixture of diastereoisomers (860 mg, 51%). 1H NMR (360 MHz, CDCl3): δ 7.30-7.09 (4H, m), 4.30-4.1 (2H, m), 4.05-3.88 (1H, br), 3.78-3.60 (2H, m), 2.99-2.88 (2H, m), 2.80 (1H, dt, J=2.8, 13.4 Hz), 2.11 (1H, d, J=13.6 Hz), 1.75-1.41 (5H, m), 1.34-1.30 (3H, m), 1.23 (3.5H, s), 1.20 (5.5H, s).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.I[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:15][CH2:16][OH:17])[CH:1]=[O:13]
Reactant: OCCI
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCCO
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Syringaldehyde (1.0 g,5.49 mmole), 2-iodo-1-ethanol (1.90 g,10.98 mmole) and potassium carbonate (1.90 g, 13.77 mmole) were added to 15 ml dry DMF and stirred for 24 hours at 80° C. under an argon atmosphere. The reaction mixture was added to 100 ml H2O and acidified with 10% HCl. The product was extracted into CHCl3, dried over MgSO4, and concentrated to an oil in vacuo. The remaining oil was purified by flash column chromatography using 1:1 hex/ethyl acetate as eluent (1.009 g, 81%). NMR: (CDCl3) 3.23,t,1H; 3.73,m,2H; 3.93,s,6H; 4.20,t,2H; 7.13,s,2H; 9.87,s,1H M.S. (CI): 227 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1CCC(CN)CC1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][CH:25]([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([OH:28])=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:44][CH2:45][CH2:46][CH2:47][C:42]1([NH:41][C:26](=[O:28])[CH:25]([CH2:24][CH2:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:43][NH2:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1(CN)NC(=O)C(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
1-Butoxycarbonyl-4-aminomethylpiperidine (51) (0.30 g; 1.4 mmol) is dissolved in DMF (10 mL) at ambient temperature. 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (22) (0.415 g: 1.4 mmol) is added followed sequentially by 1-hydroxybenzotriazole (0.2364 g; 1.75 mmol), triethylamine (0.2439 mL; 1.75 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2952 g; 1.54 mmol). The mixture is stirred at ambient temperature for 18 hours then poured onto ethyl acetate (300 mL) and extracted sequentially with water (100 mL), 1N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer is dried (MgSO4), filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (10%→50% ethyl acetate in hexanes) affording the desired compound (0.67 g) as a colorless oil. ESMS: MH+ 493.4
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:22]=[CH:21][C:8]2[O:9][C:10]3[CH:16]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:13][C:11]=3[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].N1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)C=CC=1>[Cu]I.O.C(Cl)Cl>[C:24]1([CH2:19][C:18]([NH:17][C:15]2[CH:14]=[CH:13][C:11]3[O:12][C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH2:2][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:22]=[CH:21][C:8]=4[O:9][C:10]=3[CH:16]=2)=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc2ncccc2c1
Reactant: Ic1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1)Oc1ccc(NC(C)=O)cc1O2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc2c(c1)Oc1ccc(NC(=O)Cc3ccccc3)cc1O2
Temperature: 170 °C
Reaction time: 48 h

Procedure:
A slurry prepared from 34.3 g (0.115 mole) of 2,7-bis(acetylamino)dibenzodioxin, 96.4 g (0.576 mole) of iodobenzene, 48.2 g (0.253 mole) of copper (I) iodide, 63.6 g (0.460 mole) of potassium carbonate, and 1500 ml of quinoline was heated with stirring at 170° C. for 48 hours. The reaction mixture was cooled to room temperature, 500 ml of methylene chloride and 500 ml of water were added, and a precipitate was separated by filtration. To the filtrate was added 500 ml of water and the organic layer was separated from the aqueous layer. The organic layer was concentrated and dried under reduced pressure to give 79.4 g of a crude product which was used without purification in the next reaction.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][NH:14][CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])(OCC1C=CC=CC=1)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][N:14]([C:42](=[O:43])[C@H:40]([CH3:41])[NH2:39])[CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cc2c(cc1OC)C(NCC(=O)OC(C)(C)C)CC2
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(O)C(=O)O
Product: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Yield: 48.5 %

Procedure:
By reacting 7 g of N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate with 4.8 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 5, there is obtained 4 g of L-alanyl-N-(5,6-dimethoxy-indan-1-yl)glycine tert-butyl ester oxalate as colorless amorphous powder.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH:9]1[CH3:20])([CH3:7])[CH3:6].[C:21](Cl)(=[O:23])[CH3:22]>[N+](C)([O-])=O>[C:21]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:19])([CH3:18])[CH:9]([CH3:20])[CH:8]2[CH:5]([CH3:7])[CH3:6])=[CH:12][C:13]=1[CH3:17])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)C2C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
At 0°-5° C. a solution of 4 g AlCl3 in 50 ml nitromethane is added to a mixture of 6 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to example I or II) and 25 g acetyl chloride. Then the reaction mixture is stirred at room temperature during 30 min. and poured out into ice and extracted three times with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure to obtain 6-acetyl-1-isopropyl-2,3,3,5-tetramethyl indan in a yield of 95%. B.p. 144°-146° C./1 mm Hg; n20D =1,5301.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1ccc(N)cc1F
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: Cc1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1F

Procedure:
A mixture of 3-Fluoro-4-methyl-phenylamine was reacted with 4-chloro-3-nitrobenzoyl chloride using the procedure of Example 10A to provide 4-Chloro-N-(3-fluoro-4-methyl-phenyl)-3-nitro-benzamide which was reacted according to the conditions described in Examples 100A, 100B, and 100C to provide the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:19]([O:26][C:27]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:26][C:27]1[C:34]([C:35]([CH3:36])([CH3:38])[CH3:37])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:3]=1)[OH:30])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C(O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-bromophenyl)pyridine (2.4 g, 10.25 mmol) in anhydrous tetrahydrofuran (25 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (4.1 mL, 10.25 mmol) was added at such a rate that temperature did not exceed −70° C. Stirring was continued on the cold bath for 30 min and a solution of 2-(benzyloxy)-3-tert-butylbenzaldehyde (2.75 g, 10.25 mmol) in tetrahydrofuran (12 mL) was added at such a rate that temperature did not exceed −65° C. Stirring was continued on the cold bath for 20 min and 2 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (250 mL) and extracted with ethyl acetate (350 mL). The organic extract was washed with water (2×100 mL) and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the crude product was used as such in the next step.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([CH3:25])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[C:18]([CH3:25])[CH:17]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(F)cc3C)CCC2)cc1
Yield: 88.2 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 500 mg (1.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 590 mg (3.8 mmol) of 4-fluoro-2-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 500 mg (95%) of 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 67°-68° C.; NMR (CDCl3) d 2.00-2.11 (m, 2H), 2.05 (s, 3H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 2.86-2.95 (m, 2H), 6.80-7.07 (m, 7H) .
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1)([CH3:32])([CH3:31])[CH3:30].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:12](=[O:13])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)=[N:38]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
(R)-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (85 mg, 0.26 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 140 μL, 0.27 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 63 mg, 0.26 mmol), 2,6-lutidine (62 μL, 0.52 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (109 mg, 77%) as a yellow oil: [α]25589=−50.0° (c=0.21, methanol); ES-HRMS m/e calcd for C27H41N3O5SSi (M+H)+ 548.2609, observed 548.2609; 1H NMR (300 MHz, CDCl3) δ −0.06 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 2.72 (s, 3H, ArCH3), 3.09 (s, 3H, SO2CH3), 3.55 (t, J=7.3 Hz, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.06 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.35 (m, 3H, Ar), 7.75 (brs, 1H, NH), 8.03 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[NH:15]2)[CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[OH:10])[CH3:2].[NH4+].[Cl-].C1COCC1.O>CO.[Fe]>[NH2:11][C:8]1[CH:7]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[NH:15]2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[OH:10]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(N)c1O
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (Compound 1) (431 mg, 1.0 mmol) and NH4Cl (268 mg, 5.0 mmol) in MeOH:THF:H2O=2:1:1 (8 mL) was added iron power (280 mg, 5.0 mmol) and the reaction mixture was heated to reflux for 1.0 h. The reaction mixture was cooled to room temperature and filtered. The filtered mass was washed with methanol (5.0 mL). The filtrate was concentrated in vacuo to afford 4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one as a white solid (386 mg, 96.3%), which was used directly for the next step.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:14][C@H:15]([C:21]([C:23]1[C:24]([C:30]#[N:31])=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[OH:19].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:1]1([C:11]([NH:14][C@H:15]([C:21]([C:23]2[C:24]([C:30]#[N:31])=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=2)=[O:22])[CH2:16][CH2:17][C:18](=[O:19])[OH:20])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Reactant: N#Cc1ncc(N)cc1C(=O)[C@@H](N)CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ncc(N)cc1C(=O)[C@H](CCC(=O)O)NC(=O)c1cccc2c1CCCC2
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
A solution of 1.91 g (0.009 mol) of 5,6,7,8-tetrahydro-1-naphthoyl chloride in anhydrous tetrahydrofuran (50 cm3) is added dropwise to a solution of 1.5 g (0.0064 mol) of alpha-L-glutamyl-5-aminopyridine-2-carbonitrile and 5.05 g (0.06 mol) of NaHCO3 in 50 cm3 of water. After stirring for 15 minutes at 20 C., the tetrahydrofuran is removed under vacuum and the remaining aqueous solution is acidified to pH 2-3 with a 6 N solution of HCl to give a precipitate of 1.4 g of N-5,6,7,8-tetrahydro-1-naphthoyl-alpha-L-glutamyl-5-aminopyridine-2-carbonitrile (yield: 55%, melting point: 141° C. in the amorphous state) after filtration and trituration in hexane. The sweetening potency of this compound, on a weight basis, is approximately 40,000 (forty thousand) times that of sucrose by comparison with a 2% solution of sucrose, 30,000 (thirty thousand) times by comparison with a 5% solution of sucrose and 20,000 (twenty thousand) times by comparison with a 10% solution of sucrose. This is tantamount to saying that an aqueous solution of 5 mg/1 of the compound has an intense sweet taste equivalent to that of a 10% solution of sucrose, corresponding to the sweetening intensities generally used in food preparations.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)c1ccnc(Br)c1
Product: Cl
Yield: 80 %

Procedure:
Into a 500-mL round bottom flask, was placed a solution of 2-bromoisonicotinic acid (10 g, 49.75 mmol, 1.00 equiv) in methanol (200 mL). This was followed by dropwise addition of thionyl chloride (24 g, 203.39 mmol, 4.09 equiv) with stirring at 0° C.-5° C. The resulting solution was stirred for 5 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum, to yield 10 g (80%) of methyl 2-bromoisonicotinate hydrochloride as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)C.[Pt]=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: c1cncc(-c2ncc[nH]2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: c1c[nH]c(C2CCCNC2)n1
Yield: 108 %

Procedure:
3-(1H-imidazol-2-yl)pyridine (4.0 g, 0.0275M) and platinum oxide (0.5 g) in ethyl alcohol (50 ml) and 1 NHCl (50 ml) was reduced at 45 psig of hydrogen for 4 hrs. The reaction mixture was filtered and the filtrate was stripped to dryness and crystallized from MeOH-EtOH to give 3-(1H-imidazol-2-yl)piperidine (4.5 g, 74% yield, mp 295° dec.).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C@H:9]([C:14]([N:16]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12].C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[NH:8]([C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[C@H:9]([C:14]([N:16]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)O

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of CBZ-L-Leu-L-Pip-OtBu (0.57 g, 1.3 mmol) in CH2Cl2 (6 mL) at 23° C. The reaction mixture was stirred at 23° C. for 1.5 h after which CCl4 (6 mL) was added. The volatiles were then removed under reduced pressure to afford crude CBZ-L-Leu-L-Pip as a colorless oil. The crude acid thus obtained was immediately utilized in the following coupling procedure.