Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)=[CH:22][C:23]=1[Cl:28])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)OC(=O)CCC)o2)cc1Cl
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2S)-1-(5-(3-chloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (example 37) (96.5 mg, 0.23 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.12 mL, 1.15 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange/brown viscous oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (116 mg, 90%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=2.0 Hz, 1H), 8.03 (dd, J=2.2, 8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.67 (dq, J=5.7, 6.5 Hz, 1H), 5.45 (dd, J=5.7, 8.6 Hz, 1H), 2.67 (t, J=7.4 Hz, 2H), 2.33-2.28 (m, 2H), 1.83-1.72 (m, 2H), 1.66-1.52 (m, 2H), 1.47 (d, J=6.5 Hz, 3H), 1.04 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][N:18]1[S:27]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)(=[O:29])=[O:28])=O)C1C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[C:23]([O:22][C@H:20]1[CH2:19][N:18]([S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[C@H:17]([CH2:15][OH:14])[CH2:21]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)O[C@@H]1C[C@@H](CO)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
LAH reduction: To a slurry of lithium aluminium hydride (0.72 g) in Et2O (120 ml) was added a solution of (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (9.0 g) in Et2O (80 ml) dropwise at −15° C. within 0.5 h. The suspension was stirred for 2 h at the same temperature, then a saturated solution of potassium-sodium tartrate (10 ml) was added dropwise. The slurry was filtered through a pad of filter aid and was washed with Et2O. The combined filtrates were washed with brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O/hexane to obtain (2S,4R)-[4-tert-butoxy-1-(naphthalene-2-sulfonyl) -pyrrolidin-2-yl]-methanol (6.1 g) as a colorless solid, mp 124–125° C.; MS 363 (M).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][C:13]([C:27](O)=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:30].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][C:13]([C:27]([N:41]1[CH2:40][CH2:39][N:38]([CH2:37][C:36]3[CH:44]=[C:45]([O:49][CH3:50])[C:46]([O:47][CH3:48])=[C:34]([O:33][CH3:32])[CH:35]=3)[CH2:43][CH2:42]1)=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=Cc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2CC1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)C3=Cc4cc(OCc5ccccc5)c(OCc5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Yield: 69.1 %

Procedure:
Using 6,7-dibenzyloxy-1,2-dihydro-3-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.69 g), triethylamine (0.52 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.75 ml), as amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(6,7-dibenzyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.6 g) as colorless crystals, m.p. 186°-190° C.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[CH:7]=1)=[O:9]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: COC(=O)c1cnn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnn(CC(C#N)(C#N)CCC(F)(F)F)c1
Yield: 34.9 %

Procedure:
0.80 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole and 0.75 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.27 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-chloroform to obtain 0.48 g of [{4-(methoxycarbonyl)-1H-pyrazole-1-yl}methyl](3,3,3-trifluoropropyl) malononitrile (referred to as the compound of the present invention (23), hereinafter) shown by below formula.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][CH3:13])[NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[CH2:12]([C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:24][CH:25]=3)[N:3]2[N:4]=1)[CH3:13]
Reactant: CCOC(=O)c1c(N)n[nH]c1CC
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(CC)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
As for Example 1, ethyl 3-amino-5-ethyl-pyrazole-4-carboxylate is reacted with 3-dimethylamino-3'-(trifluoromethyl) acrylophenone to give the product as crystals, m.p. 142°-143° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:47][C:48]1[CH:49]=[C:50](O)[CH:51]=[CH:52][CH:53]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[Br:47][C:48]1[CH:53]=[C:52]([O:1][CH2:2][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[NH:8][C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](COc1cccc(Br)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Methyl (2S)-3-hydroxy-2-(triphenylmethylamino)propanoate (5.2 g , 14.4 mmol, 1 equiv; prepared according to Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B. Tetrahedron 1993, 49, 6309) and triphenylphosphine (4.2 g, 15.8 mmol, 1.1 equiv) were dissolved in toluene (25 mL) at rt (room temperature). The reaction mixture was stirred for 30 min followed by addition of 3-bromo phenol (3.2 g, 18.7 mmol, 1.3 equiv) and DEAD (diethylazo dicarboxylate; 2.8 g, 15.8 mmol, 1.1 equiv) at rt. The reaction mixture was stirred at ambient temperature for 15 h while a white precipitate formed. The precipitate was filtered off and the solvents of the filtrate were removed in vacuuo. The remaining crude product was purified by flash chromatography (cyclohexanes/ethyl acetate 95:5) to give a white solid (5.2 g, 67.3%). 1H NMR (CDCl3, 200 MHz) δ 7.65-7.55 (m, 4 H); 7.41-7.12 (m, 9H); 6.70 (d, 2H); 4.20 (dd, 1H); 4.00 (dd, 1H); 3.75-3.60 (m, 1H); 3.73 (s, 3H); 2.87 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:21][C@H:20]([CH2:22][O:23]C(=O)CC)[C@@H:14]([O:15]C(=O)CC)[C@H:8]2[O:9]C(=O)CC)[CH:5]=[N:4][C:3]=1[C:28]#[N:29].N>>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:14]([OH:15])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:28]#[N:29]
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC
Agent: N
Product: N#Cc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N

Procedure:
A method for producing N2 -phenyl-2,6-diaminonebularine, which comprises reacting 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide with a reactive derivative of propionic acid to yield 5-amino-1-(2,3,5,-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide, dehydrating 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide to yield 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole, treating 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole with aqueous ammonia or alkali metal alkoxide to yield 5-amino-1-β-D-ribofuranosyl-4-cyanoimidazole and reacting 5-amino-1-β-D-ribofuranosyl-4-cyanoimidazole with phenylcyanamide in the presence of ammonia to yield N2 -phenyl-2,6-diaminonebularine.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[C@@H:11]([OH:26])[CH2:10]1)=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][NH:9][CH2:10][C@@H:11]2[OH:26])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1CCNC[C@@H]1O
Reaction time: 16 h
Yield: 80 %

Procedure:
Add 4 M hydrogen chloride in dioxane (90 mL) slowly to a solution of (3S,4S)-4-(4-bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.035 mol, 14.6 g) in dry dichloromethane (50 mL) at room temperature and stir for 16 h. Filter the precipitate and dry under vacuum to obtain the title compound (9.84 g, 80%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]([OH:9])[O:3]1.C([O-])([O-])O[CH2:12][CH3:13]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]([O:9][CH2:12][CH3:13])[O:3]1
Reactant: CCOC([O-])[O-]
Reactant: CC1OC(O)C=CC1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CCOC1C=CC(=O)C(C)O1
Yield: 85 %

Procedure:
A 12.8 g quantity of 2-methyl-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran and 14.8 g of ethyl orthoformate are reacted in the presence of 1 g of zinc chloride in 100 ml of benzene with refluxing for 120 minutes. After the reaction, the benzene is distilled off, the residue is poured into 50 ml of water and the mixture is extracted three times with 50 ml portions of ether. The ethereal layer is washed with an aqueous solution of sodium carbonate and then dried over magnesium sulfate. After removing the magnesium sulfate, the dried mass is distilled to remove the ether, and the residue is distilled at a reduced pressure of 30 mm Hg to give 12 g of 2-methyl-6-ethoxy-3-oxo-3,6-dihydro-2H-pyran as a yellow liquid fraction at 82° to 85° C in a yield of 85%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:16]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:19]([CH3:20])[CH3:21])[C:10]=1[N:9]=[C:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:3]=1)([CH3:17])[CH3:18]
Reactant: Brc1ccccn1
Reactant: CC(C)c1cccc(C(C)C)c1N=C(c1ccccc1)c1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1N=C(c1ccccc1)c1cccc(-c2ccccn2)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 1.26 g (3.00 mmol) of 17 in 10 mL of THF, 1.20 mL (3.00 mmol) of 2.5 M nBuLi in hexanes was added at −100° C. This reaction mixture was stirred for 1 hr at −70° C., then cooled to −100° C., and 3.20 mL (3.20 mmol) of 1.0 M ZnCl2 in THF was added. The resulting mixture was slowly warmed to room temperature, stirred for 12 hr at this temperature, and then 0.474 g (3.00 mmol) of 2-bromopyridine and 30 mg (0.06 mmol) of Pd(PtBu3)2 were added. The resulting mixture was refluxed for 3 hr, and 2 mL of water was added. This mixture was passed through short layer of silica gel 60 (40-63 um), and the silica gel layer was additionally washed with 30 mL of dichloromethane. The combined organic elute was evaporated to dryness, and the product was isolated from the residue by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether=10:1, vol.) to generate 1.10 g (88%) of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][S:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:20])=[O:19].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.Cl>C(OCC)(=O)C.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:19])=[O:20])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)O
Reactant: NS(=O)(=O)CCCCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)NS(=O)(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.0 g), DMF (10 ml), 3-(aminosulfonyl)propylacetic acid (0.95 ml), CDI(0.85 g), and DBU (0.80 g) was stirred at room temperature for 3 days. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate, and the organic layer was separated. The organic layer was washed with a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-{[({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]sulfonyl}propylacetic acid (1.2 g).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[CH:8][C:7]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1)(=O)=O.Cl.O>CO>[CH3:20][C:16]1[CH:17]=[C:18]([CH3:19])[N:14]([C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]=2[OH:5])[N:15]=1
Reactant: CCc1ccc(-n2nc(C)cc2C)c(OS(C)(=O)=O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1ccc(-n2nc(C)cc2C)c(O)c1
Yield: 36 %

Procedure:
28 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-ethylphenyl methanesulfonate was dissolved in 0.1 ml of methanol, and 0.07 ml of 5N-hydrochloric acid was added and heated at reflux for 30 minutes. To the reaction mixture added 15 ml of water, and extracted with 15 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=4:1) to yield 7.4 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].Cl.[CH3:23][O:24][NH2:25]>C(O)C>[CH3:23][O:24][N:25]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]1[CH:18]=[CH:19][CH:20]=[C:7]([NH:6][S:3]([N:2]([CH3:21])[CH3:1])(=[O:5])=[O:4])[CH:8]=1
Reactant: CN(C)S(=O)(=O)Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(c1ccccc1)c1cccc(NS(=O)(=O)N(C)C)c1
Yield: 107.7 %

Procedure:
A solution of 3-[N-(dimethylaminosulfonyl)amino]-benzophenone (500 mg) and O-methylhydroxylamine hydrochloride (830 mg) in ethanol (10 ml) is refluxed for 19 hours, and the resultant mixture is concentrated in vacuum. The residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 3% methanol-methylene chloride. The eluate is concentrated in vacuum to give 3-[N-(dimethylaminosulfonyl)amino]benzophenone O-methyloxime (590 mg) as an oil.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=3[CH3:22])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([CH3:22])=[CH:16][C:17]([NH:21][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][C:19]=3[CH3:20])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(N)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C)c1

Procedure:
210 mg of 4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylaniline (Example XV) are brought under reflux with 119 mg of ethyl bromoacetate and 117 mg of sodium acetate in 10 ml of ethanol for 24 h. After addition of water, the mixture is extracted with ether, and the organic phase is dried and concentrated in a rotary evaporator. By chromatographic purification (cyclohexane/ethyl acetate), 143 mg (53%) of ethyl N-{4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylphenyl} glycinate are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: Clc1ccc(Br)cc1
Product: COc1ccc2c(Cl)cc(-c3ccc(Cl)cc3)nc2c1

Procedure:
The title compound, m. p. 153-155° C., MS: m/e=305 (M+H+), was prepared from 4-chloro-7-methoxy-quinoline and 1-bromo-4-chlorobenzene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1)(C)(C)C.[F:31][CH:32]([F:42])[C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:19])([F:18])[F:20])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:39]([C:36]3[CH:35]=[N:34][C:33]([CH:32]([F:42])[F:31])=[CH:38][N:37]=3)=[O:40])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-difluoromethyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.90 (dd, J=13.8, 3.7 Hz, 1 H), 3.19 (dd, J=13.8, 2.7 Hz, 1 H), 3.31-3.49 (m, 1 H), 3.95 (d, J=7.6 Hz, 1 H), 4.44-5.15 (m, 4 H), 6.81 (t, J=55.8 Hz, 4 H), 7.22-7.35 (m, 1 H), 8.08 (ddd, J=11.2, 6.8, 2.7 Hz, 1 H), 8.94 (s, 1 H), 9.53 (s, 1 H), 9.67 (s, 1 H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.II.[O:13]1[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1>C1COCC1>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:16]3([OH:19])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: O=c1ccocc1
Reactant: Brc1ccc2occc2c1
Agent: II
Solvent: C1CCOC1
Product: OC1(c2ccc3occc3c2)CCOCC1
Temperature: -40 °C
Yield: 41 %

Procedure:
To a suspension of Mg (550 mg, 23.0 mmol) in dry THF (15 mL), under nitrogen atmosphere was added 5-bromobenzofuran (3.9 g, 20.0 mmol) in one portion. A crystal of iodine was added and then the contents were refluxed for 3 h. The reaction was then allowed to attain ambient temperature, and then cooled to −40° C. Pyran-4-one (3.0 g, 30.0 mmol) was added drop-wise and the resulting solution was allowed to reach room temperature. The reaction mixture was quenched by addition of 1N HCl (5 mL) and then was diluted with ether (30 mL). It was washed with water (2×15 mL) and the combined organic extract was washed with brine (15 mL), dried and concentrated under reduced pressure to give the crude carbinol as colorless oil. Purification by column chromatography using 5% EtOAc-hexanes afforded the desired product as white solid (41%). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 1H), 7.64 (d, 1H), 7.51-7.44 (m, 2H), 6.78 (d, 1H), 4.00-3.88 (m, 4H), 2.25 (t, 2H), 1.78-1.74 (m, 2H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14]1.C(OCC)C>C(Cl)Cl>[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14]1
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
To a 1 l. 138 round bottom flask was added 33.6 g (0.16 mol) of pyridinium chlorochromate, 35 g of powdered 4A molecular sieves and 200 ml of methylene chloride. After stirring the mixture at room temperature for sixty minutes, a solution of 21.3 g (0.078 mol) of ethyl cis-4-hydroxy-N-t-butoxycarbonyl-2-piperidinecarboxylate in 50 ml of methylene chloride was added. After stirring the mixture for sixty minutes at room temperature, 700 ml of diethyl ether was added. The mixture was filtered through three-fourths inch of Celite and three-fourths inch of silica gel (230-400 mesh) in a 650 ml medium porosity sintered glass funnel. The solids were washed with 1 1. of diethyl ether and the filtrate was concentrated under vacuum. To the residue was added 200 ml of diethyl ether and the mixture filtered through three-eighths inch of Celite and three-eighths inch of silica gel (230-400 mesh) in a 150 ml medium porosity sintered glass funnel. The solids were washed with 500 ml of diethyl ether and the filtrate was concentrated under vacuum. The residue was purified by high pressure liquid chromatography to provide 14.6 g of ethyl 4-oxo-N-t-butoxycarbonyl-2-piperidinecarboxylate as a colorless oil.