Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:24])[N:19]([OH:23])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.O[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:24])[N:19]([O:23][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: OCCN1CCCC1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1OCCN1CCCC1

Procedure:
To a solution of (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-hydroxy-1,3-thiazolidine-2,4-dione (Example 288; 0.044 mmol), 1-(2-hydroxyethyl)pyrrolidine (1.5 equiv.) and triphenylphosphine (1.5 equiv.) in THF (5 mL) was added DIAD (1.5 equiv.) and the resultant solution was stirred overnight at rt. The mixture was then concentrated in vacuo, and the residue was purified by reverse phase HPLC (MeCN/water/formic acid) to provide (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethoxy)-1,3-thiazolidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl.C(N(CC)CC)C>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2-Nitrobenzyl alcohol (1 g, 6.5 mmol) was dissolved in 40 ml of dry DCM and 1.36 ml of triethylamine. p-toluenesulfonyl chloride (1.24 g, 6.5 mmol) was added and the solution was stirred for 2 hours before quenching with water. The organic layer was separated and washed with 1 N HCl (1×50 ml), water (1×50 ml), 2 N NaOH (1×50 ml), water (1×50 ml) and brine (1×50 ml). The organic layer was dried over anhydrous Na2 SO4 and concentrated under reduced pressure to give a dull white solid, which was further purified by flash chromatography (silica gel, dichloromethane/ethanol=9.5:0.5) to give 2-nitrobenzyl tosylate, 22 (1.57 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.08-7.99 (dd, J=9.21 & 8.04 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.72-7.62 (m, 3H), 7.50 (d, J=8.85 Hz, 1H) 7.33 (d, J=8.43 Hz, 2H), 4.93 (s, 2H), 2.42 (s, 3H). 13C-NMR (60 MHz, CDCl3) δ 149.33, 146.12, 137.71, 135.27, 134.11, 133.09, 132.69, 132.57, 128.12, 123.89, 42.72, 20.64. MS (ESI): m/z 329.9 [(M+Na)]+.
Reaction SMILES: [CH3:1][CH:2]([CH:4](O)[CH:5]([CH3:7])[CH3:6])[CH3:3].S(=O)(=O)(O)O.[CH:14]([OH:16])=[O:15]>>[CH3:1][C:2]([CH3:3])([CH2:4][CH:5]([CH3:7])[CH3:6])[C:14]([OH:16])=[O:15]
Reactant: O=CO
Reactant: CC(C)C(O)C(C)C
Agent: O=S(=O)(O)O
Product: CC(C)CC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,4-Dimethyl-3-pentanol (29 g, 0.25 mole), dissolved in formic acid (98%, 46 g, 1 mole), was added dropwise over one hour to a rapidly-stirred, ice-cooled mixture of formic acid (98%, 3 ml) and concentrated sulfuric acid (270 ml). During the addition the reaction mixture foamed vigorously and was stirred for a further one hour at 10°-20° C. The mixture was poured on to ice (1 kg) and the resulting solution extracted with hexanes (3×200 ml). The combined organic phases were extracted with 2N potassium hydroxide (2×200 ml) plus ice (50 g) and the aqueous extracts washed with hexanes (100 ml). The aqueous phase was then acidified (pH 2) and the product extracted into hexanes (3×200 ml). After washing with saturated sodium chloride and drying (MgSO4), the solution was evaporated under reduced pressure and the residue distilled to give 2,2,4-trimethylpentanoic acid (36 g).
Reaction SMILES: N1C=CN=C1.[F:6][C:7]([F:28])([F:27])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]C(=O)C)=[CH:10][CH:9]=1>CO>[F:6][C:7]([F:27])([F:28])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:12][CH:13]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
Imidazole (960 mg, 14 mmol) was added to N-(4-trifluoromethylphenyl)-2-acetoxy-benzamide (13 g, 40 mmol) in methanol (300 ml) and the solution stirred at room temperature for two hours. The white precipitate was filtered and dried giving 7.3 g (65%) of pure N-(4-trifluoromethylphenyl)-2-hydroxy-benzamide as a white solid.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.[CH2:35]([NH:39][C:40](=[O:53])[CH:41]([CH2:51][CH3:52])[CH2:42][C@H:43]([OH:50])[C@@H:44](N)[CH2:45][CH:46]([CH3:48])[CH3:47])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([NH:39][C:40](=[O:53])[C:41]([NH2:1])([CH2:51][CH3:52])[CH2:42][CH:43]([OH:50])[CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH:36]([CH3:38])[CH3:37]
Reactant: CCCC[C@H](N)C(=O)O
Reactant: CCC(C[C@H](O)[C@@H](N)CC(C)C)C(=O)NCC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(N)(CC(O)CCC(C)C)C(=O)NCC(C)C
Temperature: -15 °C

Procedure:
20.7 mg of L-N-[(2R or S)-5-ethylthio-2-(1-naphthylmethyl)pentanoyl]norleucine was dissolved in 0.5 ml of dry DMF. Then, 17.4 μl of triethylamine, 12.9 μl of DPPA and 20 mg of (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid isobutylamide monohydrochloride was added thereto under stirring at -15° C. The mixture was stirred at the same temperature for one hour and then at 5° C. overnight. The reaction solution was diluted with 20 ml of ethyl acetate, washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain 16.9 mg of (2RS,4S,5S)-5-{L-N-[(2R or S)-5-ethylthio-2-(1-naphthylmethyl)pentanoyl]norleucyl}-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid isobutylamide as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([Cl:11])=[N:8]2)=[C:4]([Cl:12])[N:3]=1.Br[CH2:14][CH2:15][CH:16]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Cl:11])[N:8]2[CH2:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]c(Cl)nc2n1
Reactant: CC1(C)OCC(CCBr)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2c(Cl)nc3c(Cl)nc(N)nc32)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A mixture of 2-amino-6,8-dichloropurine (0.82 g), 5-bromoethyl-2,2-dimethyl-1,3-dioxan (0.9 g) and anhydrous potassium carbonate (0.83 g) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 18 hours under dry nitrogen. The mixture was then filtered and the filtrate evaporated. The residue was purified by column chromatography on silica (100 g) [eluent 2% methanol-dichloromethane] to give 2-amino-6,8-dichloro-9-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)purine (t.l.c. r.f. 0.50, 5% methanol-dichloromethane) as a pale solid (0.62 g, 45%). Recrystallisation from diethyl ether gave an off-white solid m.p. 149°-150° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([NH:21]C=O)(C(OCC)=O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.[OH-].[Na+].O>C(O)(=O)C>[NH2:21][C@H:5]([C:4]([OH:24])=[O:3])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CCOC(=O)C(Cc1c[nH]c2ccccc12)(NC=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 8 h
Yield: 100.8 %

Procedure:
A mixture of 40 g (0.12 mol) of the compound of Example 6 and 24.0 g (0.60 mol) of sodium hydroxide in 240 ml. of water was heated at reflux for 18 hours. 48 ml of glacial acetic acid was added to the solution and heating was continued for an additional 8 hours. The suspension was allowed to stand at 0° overnight and the white precipitate was collected, washed with icecold water and dried to yield 24.7 g (100%) of crude product. Recrystallization from 80% aqueous acetic acid afforded, after drying at 100°/0.05 mmHg, 21.2 g (86%) of white crystals, m.p. 292° (dec.) (lit. m.p. 293°) which was identical with an authentic sample.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]>O>[OH:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C=O)ccc1O
Solvent: O
Product: COc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of concentrated nitric acid (900 ml) and water (900 ml) was added 4-hydroxy-3-methoxybenzaldehyde (300 g) at a temperature under 10° C. After stirring 1 hour at 0° C. the precipitate was filtered and washed with water.
Reaction SMILES: O[C@@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:3]1=2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:39]([C@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:3]1=2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Yield: 84.2 %

Procedure:
Heat a mixture of (R)-tert-butyl 5-hydroxy-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (1.60 g, 4.65 mmol), diphenylphosphoryl azide (DPPA, 1.4 mL, 6.50 mmol) and DBU (1.0 mL, 6.50 mmol) in toluene (20 mL) at 65° C. under nitrogen for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (1.45 g, 85%). APCI MS m/z 356 (M−N2)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5]2.[Br:19][C:20]1[CH:21]=[C:22]([C:32](O)=O)[N:23]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:24]=1>>[Br:19][C:20]1[CH:21]=[C:22]([C:32]2[O:13][C:12](=[O:14])[C:11]3[C:2](=[CH:3][C:4]4[C:9]([CH:10]=3)=[N:8][C:7]([C:15]([F:18])([F:16])[F:17])=[CH:6][CH:5]=4)[N:1]=2)[N:23]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:24]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Nc1cc2ccc(C(F)(F)F)nc2cc1C(=O)O
Product: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2cc3ccc(C(F)(F)F)nc3cc12

Procedure:
Prepared from 6-Amino-2-trifluoromethyl-quinoline-7-carboxylic acid and 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid analogously to the procedure described in step h) of example H-18. This gives the title compound as orange crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Si](C)(C)C)=[CH:18][C:17]=1[F:26])=[O:5])[CH3:2].[I:27]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:27])=[CH:18][C:17]=1[F:26])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a cooled (−10° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (140 mg, 0.343 mmol) in DCM (5 mL) was added iodine monochloride (1M in DCM, 0.90 mL) dropwise over 10 minutes. On complete addition the mixture was allowed to stir at ambient temperature for 20 minutes then quenched by the addition of saturated sodium thiosulphate solution (3 mL). The solution was partitioned between DCM (50 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give a yellow solid. The solid was triturated with diethyl ether, filtered and left to air dry to provide the title compound as a yellow solid (148 mg, 85%). LCMS (method B): RT=2.37 min, M+H+=426.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=O)C.Cl>C(O)C.[Pd]>[OH:4][C:5]1[C:6]([CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1
Reactant: CC(=O)Oc1cc2c(cc1C=Cc1cccs1)OCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Oc1cc2c(cc1CCc1cccs1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
A mixture of 1-(5-acetoxy-2,3-dihydrobenzofuran-6-yl)-2-(2-thienyl)ethene (0.55 g, 0.0019 mol), in ethanol (20 ml) and 12N HCl (0.5 ml) was hydrogenated at 40 psi using 10% Pd/C (0.55 g) as catalyst. After filtration and concentration the crude 5-acetoxy-6-(2-(2-thienyl)ethyl)-2,3-dihydrobenzofuran was dissolved in methylene chloride (20 ml) and washed with saturated sodium bicarbonate (2×10 ml) saturated sodium chloride (10 ml) and concentrated. The resulting yellow oil was dissolved in ethanol (10 ml) and 50% NaOH (0.2 ml). The mixture was allowed to stir for 1/2 hour at room temperature and was concentrated. The crude product was dissolved in methylene chloride (20 ml) and washed with 10% acetic acid (10 ml), saturated sodium carbonate (10 ml), saturated sodium chloride (10 ml). The combined organic layers were dried (MgSO4), and concentrated to a dark oil. Purification by chromatography over silica gel (hexane/ethyl acetate, 90/10, as eluent) afforded 5-hydroxy-6-(2-(2-thienyl)ethyl)-2,3-dihydrobenzofuran (66 mg, 13%). m.p. 79°-85° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38](=[O:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:38]([C:34]1[S:35][CH:36]=[CH:37][C:33]=1[NH:32][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]1)=[O:29])(=[O:40])[CH3:39]
Reactant: CC(=O)c1sccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1sccc1NC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1-(3-aminothiophen-2-yl)ethanone (140 mg, 0.98 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetyl-thiophen-3-yl)-amide as a off white powder (40 mg, 15.8%). HRMS (ES+) m/z Calcd for C29H27Cl2F2N3O2S+H [(M+H)+]: 590.1242. found: 590.1244.
Reaction SMILES: [CH2:1]([N:4]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:5]1[C:10](=[O:11])[N:9]2[C@H:12]([C:19](O)=[O:20])[CH2:13][C@:14]([N:16]=[N+:17]=[N-:18])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:32]([O:39][C:40](=[O:52])[NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH2:51])=[CH:46][CH:45]=1)=[NH:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10](=[O:11])[N:9]2[C@H:12]([C:19](=[O:20])[NH:51][CH2:50][C:47]3[CH:48]=[CH:49][C:44]([C:42]([NH:41][C:40]([O:39][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:52])=[NH:43])=[CH:45][CH:46]=3)[CH2:13][C@:14]([N:16]=[N+:17]=[N-:18])([CH3:15])[C:8]2=[N:7][CH:6]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)C[C@@]2(C)N=[N+]=[N-]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.6 %

Procedure:
To a solution of 18f (270 mg, 0.636 mmol) and [(4-Aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester (272 mg, 0.763 mmol) in 6 mL CH2Cl2/DMF (5:1) at 0° C., were added HOAT (95 mg, 0.700 mmol), NaHCO3 (187 mg, 2.23 mmol), and EDCI (171 mg, 0.890 mmol). The mixture was allowed to warm to rt and stir for 15 h. The mixture was diluted with EtOAc, washed with H2O, 1 N HCl, H2O, sat. NaHCO3, and brine. The mixture was dried (Na2SO4) and concentrated to afford 393 mg (90%) of intermediate 18 g.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[Se:10][C:9]=1[C:17]([O:19]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: [NH4+]
Reactant: CCOC(=O)c1[se]c(C(C)(C)C)cc1N=NN(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc(C(C)(C)C)[se]c1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (200 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]-5-(tert-butyl)selenophene-2-carboxylate (1.2 g) in THF (30 mL) for 5 min and a catalytic amount of PEG-400 was added and stirred at rt for 48 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product as a pale brown color solid, which was recrystallized from chloroform-hexane (300 mg, 28%), mp 218-220° C. IR (Neat) νmax 3337, 3156, 2958, 1631, 1602, 1326, 1250, 1219, 1177, 1113, 1006 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.20 (1H, s, —CONH2), 7.41 (1H, s, H-4), 6.01 (1H, br s, —CONH2), 3.56 (3H, s, —NCH3), 3.16 (3H, s, —NCH3), 1.37 (9H, s, t-butyl); 13C NMR (100 MHz, DMSO-d6): δ 168.0, 166.1, 151.1, 129.0, 116.9, 36.8, 32.4; LC-MS (positive ion mode): m/z 323, 325 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:14].S(Cl)(Cl)=O.[C:28]([OH:36])(=[O:35])/[C:29](=[C:31](\[CH:33]=O)/[Cl:32])/[Cl:30].N1C=CC=CC=1>C(Cl)CCl>[Cl:30][C:29]1[C:28](=[O:35])[O:36][CH:33]([O:14][C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:18]2)[C:31]=1[Cl:32]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCN(CC)c1ccc(C2(OC3OC(=O)C(Cl)=C3Cl)OC(=O)c3ccccc32)c(C)c1
Yield: 84.2 %

Procedure:
In a manner similar to that described in Example 1 above, 2.0 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid, 0.77 g of thionyl chloride and 1.1 g of mucochloric acid were interacted in 20.0 ml of ethylene dichloride in the presence of 0.8 ml of pyridine to obtain 2.5 g of 3-[3,4-dichloro-2(5H)-furanon-5-yl]oxy-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula II: R0 =R=R1 =R2 =H; R4 =R4' =R5 =CH3 ; X=O; Y=3,4-dichloro-2-(5H)-furanon-5-yl), an orange-colored oil. A significant infrared maximum appeared at 1758 cm-1 (C=O;s). A toluene solution of the product spotted on an acidic clay-coated paper developed a yellow-colored image.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:16])[C:13]([O-:15])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[K+].[Br-]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:13]([NH:22][C@@H:21]([CH3:23])[C:20]([O:19][CH3:18])=[O:24])=[O:15])=[O:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)c1ccccc1NC(=O)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)C(=O)Nc1ccccc1C(C)(C)C

Procedure:
A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with the following solids: 2-(2-tert-Butylphenylamino)-2-oxoacetate (70.008 g, 316.402 mmol), alanine methyl ester hydrochloride (44.368 g, 317.862 mmol), hydroxybenzotriazole hydrate (HOBT) (47.324 g, 350.210 mmol), and 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC.HCl) (121.668 g, 635.4 mmol). N,N′-dimethylformamide (DMF) (1250 mL) was added via graduated cylinder, and the reaction mixture stirred to partially dissolve and suspend the solid reagents. N-methylmorpholine (108 mL, 99.36 g, 982 mmol) was then added in one portion via graduated cylinder. After stirring at room temperature for 18 hours, the reaction mixture was partitioned between EtOAc (ca. 600 mL) and 1N HCl (ca. 500 mL). The aqueous phase was washed two times with EtOAc (ca. 300 mL), and the combined organic layers were washed successively with 1N HCl (ca. 300 mL), H2O (ca 300 mL), saturated NaHCO3 (ca. 300 mL), and brine (ca. 300 mL). The resulting pale yellow organic solution was dried over MgSO4, then concentrated to yield a pale yellow crystalline mass (95 g, 97%). TLC: (silica, 1:1 hexanes/EtOAc) Rf: 0.54. MP: 60.1–62.1° C.; IR (KBr) 3284, 1747, 1662, 1503, 1216, 755 cm−1; 1H NMR: (CDCl3, TMS) δ 9.55 (br, 1H), 8.01 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.42 (dd, J=7.8 Hz, J′=2.6 Hz, 1H), 7.15–7.31 (m, 2H), 4.64 (p, J=7.5 Hz, 1H), 3.80 (s, 3H), 1.54 (d, J=7.5 Hz, 3H), 1.46 (s, 9H) ppm.