Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12](O)[N:7]2[N:6]=1)=[N+:2]=[N-:3].P(Cl)(Cl)([Cl:18])=O>N1C=CC=CC=1>[N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([Cl:18])[N:7]2[N:6]=1)=[N+:2]=[N-:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(CN=[N+]=[N-])nc2n1
Solvent: c1ccncc1
Product: Cc1cc(Cl)n2nc(CN=[N+]=[N-])nc2n1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
2-Azidomethyl-5-methyl[1.2.4]-triazolo[1,5-a]-pyrimidin-7-ol (3.1 g) are suspended in 20 ml of freshly distilled phosphorus oxychloride and 1.1 ml of pyridine and stirred at 50° C. for 4.5 hours. The phosphorus oxychloride is evaporated in a vacuum and the residue is taken up in 40 ml of ethyl acetate and 40 ml of water. The resulting suspension is stirred in an ice bath for 45 minutes. The product is filtered off under suction and dried in a vacuum at 40° C. There are obtained 2.1 g of 2-azidomethyl-7-chloro-5-methyl[1.2.4]triazolo[1,5-a]pyrimidine as white crystals of melting point 130°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[N:23]=2)[CH:16]=1>CN(C=O)C>[NH2:28][C:24]1[N:23]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 36.9 %

Procedure:
To a stirred solution of 2 (4.35 g, 23.38 mmol) and Cs2CO3 (15.26 g, 46.76 mmol) in dry DMF (50 mL) was added 1 (5.0 g, 15.58 mmol) at rt and the reaction was stirred at 80° C. for 16 h under nitrogen atmosphere. The reaction mixture was cooled, concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 mL). It was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 5/5) to give 3 (1.6 g, 23.3%) as brown solid.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[F:8][C:9]([F:49])([F:48])[C:10]1[CH:11]=[C:12]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:13][N:14]([CH3:40])[C:15]([N:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:28][CH2:27][N:26](C(=O)C)[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[CH3:39])=[O:16].C(Cl)[Cl:51]>>[ClH:51].[F:49][C:9]([F:8])([F:48])[C:10]1[CH:11]=[C:12]([C@H:13]([N:14]([CH3:40])[C:15]([N:17]2[CH2:22][CH2:21][C@H:20]([N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[CH2:19][C@@H:18]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:16])[CH3:2])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CC(=O)N1CCN([C@H]2CCN(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)CC1
Product: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCNCC2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added drop-wise at 0° C. to a solution of compound 2 (48 mg) in dry DCM (3 mL). The solution was stirred for 1 hour at the same temperature and for 1 hour at r.t. Then the solvent was removed in vacuo and the crude dissolved in AcOEt (5 mL). The resulting solution was washed with a saturated potassium carbonate solution and dried. After concentration in vacuo, the crude 2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (18 mg) was dissolved in dry Et2O (1 mL) and was then treated with hydrochloric acid (1M in Et2O—220 μL) at 0° C. The resulting mixture was stirred at r.t. for 30 minutes, then filtered and triturated with n-pentane to give the title compound as a whitish solid (15 mg).
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[O:2].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH2:23][CH2:24][NH:25][CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)([CH3:22])[CH3:21])=[CH:16][CH:15]=1>C(OCC)C>[ClH:3].[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH2:23][CH2:24][NH:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:1]([Cl:4])=[O:2])[CH2:29][CH2:28]2)([CH3:21])[CH3:22])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(C)(C)CCNCC2CCNCC2)cc1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(C)CCNCC2CCN(C(=O)Cl)CC2)cc1
Product: Cl
Yield: 77.4 %

Procedure:
To a solution of 2 M phosgene/toluene (2.0 ml, 4 mmole) in ethyl ether (20 ml) was added a solution of N-[2-(4-methoxyphenyl-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine (0.23 grams, 0.79 mmole) in ethyl ether (30 ml). After 30 minutes the precipitate was collected by filtration and dried in vacuo to give N-[2-(4-methoxyphenyl-1-methylethyl]-N-ethyl-(1-chlorocarbonylpiperidin-4-ylmethyl)amine hydrochloride (0.238 grams, 77%), m.p. 144-145° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:13].C(O[CH:17]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])C>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3](=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[C:11]=1[CH:17]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: Cc1cc(O)c2ccccc2c1O
Reactant: CCOC(CCCCC(=O)O)c1ccc(OC)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 44.6 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of 2-methyl-1,4-naphthohydroquinone (3.6 g, 0.02 mole) and 6-ethoxy-6-(4-methoxyphenyl)hexanoic acid (5.6 g, 0.021 mole), and the mixture was heated at 60° C. for 18 hours, with stirring. After cooling, the solvent was distilled off under reduced pressure, and then tetrahydrofuran (20 ml) was added to the residue. A 10% aqueous solution of ferric chloride was added to the solution, followed by stirring for 10 minutes, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was effected with isopropyl ether to give 6-(3-methyl-1,4-naphthoquinon -2-yl)-6-(4-methoxyphenyl)hexanoic acid (3.5 g, 45%). This product was recrystallized from isopropyl ether. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound No. 21 was prepared.
Reaction SMILES: [N:1]1([C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[NH:8][CH:9]=[N:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)NC(=O)N([C@@H:23]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@@H:24]2[OH:31])C=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>>[C@@H:23]1([N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][CH:13]=[N:14][C:6]=3[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@@H:24]1[OH:31]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: c1nc(N2CCCC2)c2[nH]cnc2n1
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Product: OC[C@H]1O[C@@H](n2cnc3c(N4CCCC4)ncnc32)[C@@H](O)[C@@H]1O
Temperature: 35 °C
Yield: 68.6 %

Procedure:
6-Pyrrolidinopurine (Sigma Chemical Co., St. Louis, Mo.) (2.6 mmoles), 0.5 g, and uracil arabinoside (5.29 mmoles, 1.29 g) were suspended in 100 ml of a 10 mM potassium phosphate 0.04% potassium azide solution with a pH of 7.4. Purified uridine phosphorylase (6000 I.U.) and purine nucleoside phosphorylase (8400 I.U.) (Krenitsky, T. A., et al. Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 35° C. Twenty days later the reaction was filtered and the filtrate chromatographed on a column containing Dowex-I-hydroxide resin (2.5×8 cm). The product was eluted from the column with 90% methanol/water (v/v). Fractions containing product were combined and the solvent removed under vacuum. The residue was dissolved in 50 ml of 30% n-propanol and water (v/v) and chromatographed on a BioRad P-2 column (5×90 cm). The product was eluted with 30% n-propanol/water (v/v). Product-containing fractions were combined and the solvent was removed under vacuum yielding 0.573 g of 9-β-D-arabinofuranosyl-6-pyrrolidino-9 H-purine. NMR and mass spectrometry were consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[NH:16]1[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[N:16]2[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]2)[C:6]1=[O:14]
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Reactant: COC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 90 °C
Yield: 8.4 %

Procedure:
4-Bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (320.0 mg, 1.180 mmol), methyl isonipecotate (1.595 mL, 11.80 mmol), DIPEA (2.056 mL, 11.80 mmol) and DMF (5 mL) were mixed and heated in sealed tube at 90° C. for 3 days. The crude mixture was purified by MDP under basic conditions to obtain the title compound (33 mg, 8.4% yield). MS (ES+): m/z 334.16 (100) [MH+]; HPLC: tR=0.80 min (UPLC, Analytical).
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:27]C(=O)C)([CH3:26])[CH2:7][CH2:8][C:9]1[N:10]([CH3:25])[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=O)C.O1CCCC1.CO.O.[OH-].[Li+]>O>[NH2:27][C@:6]([CH3:26])([CH2:7][CH2:8][C:9]1[N:10]([CH3:25])[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(CCCCCc2ccccc2)n1C)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CCCCCc2ccccc2)ccc1CC[C@@](C)(N)CO
Yield: 90.7 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[1-methyl-5-(5-phenylpentyl)pyrrol-2-yl]butane (75.0 mg, 0.18 mmol) obtained in Example (31b) in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml) were added successively water (1 ml) and lithium hydroxide monohydrate (76 mg, 1.81 mmol) with stirring, and the resulting mixture was stirred at 50° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (1:0–50:1) as the eluent to afford (2R)-2-amino-2-methyl-4-[1-methyl-5-(5-phenylpentyl)pyrrol-2-yl]butan-1-ol (53.6 mg, yield: 90%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1([C:18]([F:21])([F:20])[F:19])[C:7](=[O:8])[N:6]([C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10](O)=[O:11])[C:5](=[O:17])[NH:4]1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:44])[NH:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][C:35]=1[O:42][CH3:43].[NH2:45][C@H:46]([CH3:55])[CH2:47][C:48]([O:50]C(C)(C)C)=[O:49]>>[F:1][C:2]([F:22])([F:23])[C:3]1([C:18]([F:21])([F:20])[F:19])[C:7](=[O:8])[N:6]([C@@H:9]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:10]([NH:45][C@H:46]([CH3:55])[CH2:47][C:48]([OH:50])=[O:49])=[O:11])[C:5](=[O:17])[N:4]1[CH2:38][C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[O:44])=[C:35]([O:42][CH3:43])[CH:36]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1C(=O)NC(C(F)(F)F)(C(F)(F)F)C1=O
Reactant: COc1cc(CCl)ccc1NC(=O)Nc1ccccc1C
Reactant: C[C@@H](N)CC(=O)OC(C)(C)C
Product: COc1cc(CN2C(=O)N([C@@H](CC(C)C)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C(F)(F)F)C(F)(F)F)ccc1NC(=O)Nc1ccccc1C
Yield: 53 %

Procedure:
which had been prepared from (S)-2-(4,4-bis(trifluoromethyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid and 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl chloride as described in Example 18f, and 128 mg (0.809 mmol) of tert-butyl (R)-3-aminobutanoate. After coupling, chromatographic purification over silica gel (eluent: heptane/ethyl acetate=3/2) and cleavage of the tert-butyl ester, 299 mg (53%) of the title compound were obtained.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cc(F)ccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cc(F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 2,5-difluorophenol (6.50 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.60 mg, 29.3% yield) as a thick oil: 1H NMR δ 7.46 (s, 1H), 7.40-7.32 (m, 4H), 7.31-7.20 (m, 2H), 7.17 (s, 1H), 7.01-6.92 (m, 2H), 6.65-6.42 (m, 2H), 5.27 (m, 1H), 3.13 (m, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.28-1.80 (m, 8H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 493.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:14]=[CH2:13]
Reactant: OCCc1ccc(F)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
2-[4-Fluorophenyl]ethanol (7.0 g) was added slowly to a stirred suspension of sodium hydride (1.25 g, 60% as dispersion in oil prewashed with petroleum ether bp 60°-80°) in DMF (50 ml). The mixture was stirred for 30 min at room temperature. Allyl bromide (6.0 g) was then added slowly and the whole allowed to stir overnight. The reaction was partitioned between water and ether. The aqueous layer was further extracted with ether and the combined ethereal extracts were washed with water and dried (MgSO4). The ether was removed under reduced pressure to yield the crude subtitled compound as a colourless oil (8.7 g, 96%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][CH3:20]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](=[O:10])[N:19]([CH3:20])[CH3:18])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Product: CN(C)C(=O)c1ccc(C(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Following a similar procedure to that described in Preparation 4, but using 4-t-butyl-3-nitrobenzoic acid and dimethylamine hydrochloride instead of methanol, the title compound was obtained as an oily substance.
Reaction SMILES: CS[CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5](=[O:16])[CH2:4]1.[Cl:17]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:17][CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5](=[O:16])[CH2:4]1
Reactant: CCOC(=O)CC(=O)CN1C(=O)CC1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)CN1C(=O)CC1Cl
Reaction time: 0.05 h
Yield: 105.6 %

Procedure:
Ethyl 4-(4-methylthio-2-oxoazetidin-1-yl)-3-oxobutyrate (400 mg, 1.63 mmole) was dissolved in dry carbon tetrachloride (15 ml) and the solution was stirred and ice-cooled while chlorine (115 mg, 1.6 mmmole) in carbon tetrachloride (1.4 ml) was added in one portion. After addition of the chlorine, the cooling bath was removed and stirring was continued for 3 minutes. The solvent was removed under reduced pressure to yield ethyl 4-(4-chloro-2-oxoazetidin-1-yl)-3-oxobutyrate as a pale yellow gum (400 mg), νmax (CHCl3): 1785 (β-lactam C=O), 1750 and 1730 (keto-ester C=O) cm-1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[C:24]1([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1ccccc1C#Cc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and ethynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (60 mg, 50%); 1H NMR δ (CDCl3): 8.39 (d, J=8.55 Hz, 1H), 7.9 (br s, 1H), 7.59-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.41-7.35 (m, 3H), 7.02 (t, J=7.22 Hz, 1H), 2.21 (s, 3H); LCMS m/z: 235.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1COCC1.O>[CH3:1][NH:2][S:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of MeNH2 (10 mL of a 2N solution in THF) and 10 mL of H2O was treated with a solution of 3-nitrobenzene sulfonyl chloride (884 mg, 4 mmole) in 4 mL of THF. The reaction was stirred for 2 hours, diluted with H2O and extracted with Et2O. The extracts were washed with H2O, 0.1N HCl, aqueous NaHCO3, dried, and the solvent removed, and gave the titled product, 608 mg (70%). MS (ESI) 217 (MH+).
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1.CCOC(/[N:19]=N/C(OCC)=O)=O.N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C1COCC1.O>[NH2:19][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(C)O[PH](=O)CC1=CC(O)CC1
Agent: [N-]=[N+]=N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)O[PH](=O)CC1=CC(N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of (±)-isopropyl (3-hydroxycyclopentenyl)methylphosphinate (3) (2.5 g, 12.25 mmol), DEAD (4.0 cm3,26.95 mmol) and HN3 (12.9 cm3 of a 1.9 M solution in benzene) in anhydrous THF (100 cm3) at 0° C. was added triphenylphosphine (12.8 g, 49 mmol) in small portions over a period of 1 h. The reaction mixture was allowed to warm to room temperature and stirring continued for 12 h. The reaction mixture was then heated to 50° C. for 3 h after which time water (2 cm3) was added and heating continued for a further 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between HCl (1M, 40 cm3) and DCM (40 cm3). The organic layer was separated and further extracted with water (3×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude product was purified by ion exchange chromatography (Dowex 50 H+ form), eluting first with water until the eluate was neutral and then with aqueous ammonium hydroxide (1 M) collecting ninhydrin positive fractions. The solvent was removed in vacuo to yield the title compound as a pale yellow oil (8) (1.71 g, 68%): 1H NMR (300 MHz; CD3OD) δ 1.26 and 1.27 (3H, d, J=6.0 and 6.0 Hz, POCHCH3), 1.31 and 1.32 (3H, d, J=6.3 and 6.3 Hz, POCHCH3), 1.51 and 1.53 (3H, d, J=14.4 and 14.1 Hz, PCH3) 1.59-1.79 (1H, m, C(4)—H, 2.33-2.55 (2H, m, C(5)—H, C(5)—H′), 2.54-2.72 (1H, m, C(4)—H′) 4.05 (1H, m, C(3)—H), 4.48 (1H, m, C(2)—H), 6.52 (1H, dm, J=9.9 Hz, PCCH), 13C NMR (75.46 MHz, CD3OD) δ 13.92 and 14.10 (PCH3, d, JPC=102.1 and 101.6 Hz), 24.54 and 24.60 (POCHCH3, 2×d, 3JPOCC=46 Hz), 24.9 (POCHCH3, d, 3JPOCC=3.4 Hz), 32.86 and 32.88 (C(4), d, 3JPC=12.6 and 12.3 Hz), 35.0 and 35.13 (C(5), 2×d, 2JPC=10.0 Hz) 59.83 and 60.07 (POCHCH3, d, 2JPOC=5.7 and 5.7 Hz), 71.36 and 71.39 (C(3), d, 3JPC=6.3 and 6.3 Hz), 137.96 (C(1), d, JPC=125.7 Hz), 150.84 and 150.95 (C(2), d, 2JPC=10.9 and 11.1 Hz), 31 P NMR (121 MHz, CD3OD) δ 45.9, MS (EI) m/z 204 (38%) (MH+), 147 (30), 105 (100) (ESI) 204.1151 (MH+-C9H19NO2P requires 204.1153).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:17](=[O:19])[C@@H:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: Nc1nccs1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 44.7 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol) (Example 3, Step 1c), commercially available 2-aminothiazole (109 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-yl-amide (200 mg, 53%), as a light yellow solid. 1H NMR (DMSO-d6) δ: 12.58 (br. s., 1H), 7.50 (d, J=3.4 Hz, 1H), 7.19-7.36 (m, 3H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.05 (dd, J=10.8, 4.9 Hz, 1H), 4.40 (d, J=19.1 Hz, 1H), 4.09 (d, J=18.6 Hz, 1H), 3.76 (br. s., 2H), 1.78-1.92 (m, 1H), 1.63-1.76 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=7.1 Hz, 6H).