Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1.[N:24]1[NH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:27][CH:28]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:32]2[CH:31]=[CH:30][C:29]([C:26]3[NH:25][N:24]=[CH:28][CH:27]=3)=[CH:34][CH:33]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(I)c(Cl)cc21
Reactant: OB(O)c1ccc(-c2ccn[nH]2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)c(Cl)cc21
Temperature: 130 °C

Procedure:
A 5 mL Biotage™ microwave vial was charged with 6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (Intermediate 5, 73.2 mg, 0.150 mmol), 4-(2H-pyrazol-3-yl)-phenylboronic acid (33.9 mg, 0.180 mmol) and Pd(PPh3)4 (8.7 mg, 5 mol %) followed by dioxane (1.5 mL) and 1M aqueous K2CO3 (180 uL). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 130° C. for 10 min. The suspension was then diluted with EtOAc (5 mL) and washed with 1M aqueous K2CO3 (twice, 1 mL) and water (twice, 1 mL). The organic layer was evaporated to dryness in vacuo to give yellow oil. The oil was dissolved in ACN and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The solvent was evaporated to dryness in vacuo to give the crude product as pale yellow solid. LR-MS (API-ES): calculated for C23H27ClN4O3SSi 502.1, observed m/e 503.0 (M+H)+ (Rt 3.30 min).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:19]=[CH:20]/[CH:21]=C/C(O)=O)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]>[Cl-]>[CH3:18][O:17][C:13]1[CH:12]=[C:11](/[CH:19]=[CH:20]/[CH:21]=[CH:1]/[C:2]([Cl:4])=[O:3])[CH:10]=[C:9]([O:8][CH3:7])[C:14]=1[O:15][CH3:16]
Reactant: COc1cc(/C=C/C=C/C(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Product: COc1cc(/C=C/C=C/C(=O)Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After oxalyl chloride (0.055 ml; 0.63 mmol) was added to a solution of (E,E)-5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoic acid (116 mg; 0.44 mmol) in dimethylformamidemethylene chloride (0.1ml-5 ml) under ice cooling. The ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of (E,E)-5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([C@@H:16]3[CH2:18][C@H:17]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([C@@H:16]2[CH2:18][C@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN([C@@H]2C[C@H]2c2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Yield: 45.3 %

Procedure:
The mixture of 0.08 g (0.22 mmole) of 2-chloro-7,7-difluoro-5-methyl-9-(trans-2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-287), 0.069 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-65:35) gave 0.059 g of give 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-288) as a white solid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])(C)C)=[O:11])(OCC)=O)C.[CH3:17][C:18](O)(C)C.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][CH:26]=1)=O>C1COCC1>[I:31][C:28]1[CH:29]=[CH:30][C:25](/[C:23](/[CH3:22])=[CH:9]/[C:10]([O:12][CH2:13][CH2:16][CH2:17][CH3:18])=[O:11])=[CH:26][CH:27]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)O
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Solvent: C1CCOC1
Product: CCCCOC(=O)/C=C(\C)c1ccc(I)cc1
Reaction time: 1 h

Procedure:
A solution of tert-butyl diethylphosphonoacetate (10.0 g, 39.6 mmol) in 30 mL of dry THF was added slowly to a freshly prepared solution of 19 mL of 2.5 M (hexanes) lithium tert-butoxide and tBuOH (30 mL) and stirred for 1 h. A solution of 4-iodoacetophenone (1b) (9.0 g, 36.6 mmol) in 20 mL of dry THF was added to the reaction mixture and stirring was continued overnight. The solvents were removed under vacuum. The residue was dissolved in 400 mL of Et2O and was washed with water (2×30 mL) followed by brine (30 mL) and dried over MgSO4. After filtration and evaporation of the solvent, the crude product was then purified by silica gel column chromatography, eluting with 1% EtOAc in hexane. The product 2b was obtained as an oil (10.0 g, 79% yield). 1HNMR (CDCl3, 300 MHz) δ 1.515 (s, 9H), 2.48 (s, 3H), 6.03 (s, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.68 (d, 2H, J=8.4 Hz). 13C NMR (CDCl3, 75.0 MHz) δ 17.5, 28.3, 80.2, 94.6, 119.5, 128.0, 137.6, 141.9, 152.6, 166.1. Anal. Calcd. for C14H17IO2: C, 48.85; H, 4.98; I, 36.87; 0, 9.3 : Found C, 49.40; H, 5.00, I, 35.97. HRMS (M+H) calc, 345.0351; found, 345.0319.
Reaction SMILES: [BH4-].[K+].[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([CH2:24][C:25](=[O:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:32])=[N:12]2)=[CH:7][CH:6]=1.ClCCl>O.C(O)C>[OH:31][CH:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:24][CH:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:32])[N:15]1[C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[N:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[N:12]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(O)CCC(C)C)nc2n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
Potassium borohydride (0.41 g) dissolved in distilled water (12 cc) is added at a temperature in the region of 20° C. to a suspension of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (3.0 g) in ethanol (50 cc), and the suspension is stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of distilled water (300 cc) and dichloromethane (150 cc) which has been cooled to a temperature in the region of 0° C. The aqueous phase is separated after settling has occurred, and re-extracted with dichloromethane (2×150 cc). The organic phases are combined, washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The product obtained is recrystallized twice in diisopropyl ether. 3-(2-Hydroxy-5-methylhexyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (2.0 g), m.p. 110° C., is thereby obtained.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[Mg+].[Br-].[CH3:30][C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]=[O:37]>C(Cl)Cl>[CH3:30][C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:37]
Reactant: Cc1sccc1C=O
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1sccc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (11.8 g, 27 mmol) in dry CH2Cl2 (75 mL) was added EtMgBr (10.0 mL, 3.0M in Et2O) and the solution was stirred for 3 hrs. Then a solution of 2-methylthiophene-3-carboxaldehyde (3.3 g, 27 mmol) in CH2Cl2 (20 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl (aq) and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with a second portion of CH2Cl2. The extracts were combined and washed with a small portion of water, dried (Na2SO4), and filtered. The solvent was evaporated in vacuo to give a thick syrup which was triturated with Et2O to give a solid which was recrystallized with charcoal treatment from EtOAc to give (2-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, B1. 1H NMR (CDCl3) supported the assigned structure. ##STR36##
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[CH3:20].C([O-])(C)(C)C.[K+]>CS(C)=O>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cc(N)ccc1Br
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2c(C)cccc2[N+](=O)[O-])ccc1Br

Procedure:
The product (3.90 g) is obtained according to the method of stage 1 of Example 4, by using 2.78 g of 2-fluoro-3-methyl-nitrobenzene and 5 g of 4-bromo-3-methyl-aniline in the presence of 3.22 g of potassium tert-butanolate in 70 mL of DMSO.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:31]([OH:32])=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:38]([NH2:40])[CH3:39]>>[CH2:38]([NH:40][C:25](=[O:26])[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]3[C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[C:31]([OH:32])[C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Reactant: CCN
Agent: Cl
Product: CCNC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1

Procedure:
According to a method similar to Example (49), from (4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetic acid (187 mg, 0.374 mmol) obtained in Example (7) and ethylamine hydrochloride (61 mg, 0.75 mmol), the title compound was obtained as a colorless powder (129 mg, yield: 65%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:37])[CH:24]([NH:25][C:26](=[O:36])/[C:27](/[C:30]4[N:31]=[C:32]([NH2:35])[S:33][CH:34]=4)=[N:28]\[OH:29])[C@H:21]3[S:20][CH2:19][C:18]=2/[CH:38]=[CH:39]\[C:40]2[N:41]=[N:42][S:43][CH:44]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].C1(OC)C=CC=CC=1>C(OC(C)C)(C)C>[F:45][C:46]([F:51])([F:50])[C:47]([O-:49])=[O:48].[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][CH:24]2[C:23](=[O:37])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18](/[CH:38]=[CH:39]\[C:40]4[N:41]=[N:42][S:43][CH:44]=4)[CH2:19][S:20][C@H:21]23)=[O:36])[N:31]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C\c4csnn4)CS[C@H]23)cs1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)O)=C(/C=C\c4csnn4)CS[C@H]23)cs1
Product: O=C([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Diphenylmethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (1.6 g, 2.6 mmol) was added to a mixed solution of trifluoroacetic acid-anisole (3 ml--3 m l) cooled to 0° C. The reaction solution was stirred at 5° C. for 1.5 hours. The reaction solution was added in diisopropyl ether (100 ml) and stirred. Precipitates were collected by filtration, cleansed with diisopropyl ether and dried thereby trifluoroacetate of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylic acid (1.13 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[C:11](OC)([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)N>>[N:13]1([CH:11]=[N:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[OH:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccncc1O
Reactant: COC(N)(OC)N1CCCCC1
Product: Oc1cnccc1N=CN1CCCCC1
Temperature: 100 °C

Procedure:
4-Amino-3-pyridinol (3.3 g) was added to 1-piperidinylformamide dimethyl acetal (50 ml) and the mixture was stirred at 100° C. until it became homogeneous (approximately one minute). The reaction mixture was cooled, and placed in an ice bath for a half hour. The crystallized product was filtered, washed well with diethyl ether, and air dried to yield 4.64 g of product. This was recrystallized from ethyl acetate and dried under high vacuum and refluxing ethanol overnight to yield 3.39 g of fluffy needles, m.p. 171°-172.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]2[N:13]([CH2:22][OH:23])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CCOC(C)=O.CCCCCC>[CH2:1]([O:8][C:9]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]2[N:13]([CH2:22][O:23][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Yield: 92.1 %

Procedure:
Following the general procedure detailed for 84, 91 (0.029 g, 0.074 mmol, 1 equiv) was treated with Et3N (0.052 mL, 0.371 mmol, 5 equiv) and CH3SO2Cl (0.017 mL, 0.148 mmol, 2 equiv). Radial chromatography (SiO2, 1 mm plate, 50% EtOAc-hexane) furnished 93 (0.032 g, 0.035 g theoretical, 91%) as a white solid: mp 130-132° C.; 1H NMR (500 MHz, CDCl3) major rotamer δ 8.40 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.61-7.35 (m, 7H), 6.63 (s, 1H), 5.27-5.17 (m, 2H), 4.51-4.33 (m, 4H), 3.60 (s, 3H), 2.86-2.81 (m, 1H), 2.54 (s, 3H), 2.32-2.23 (m, 1H), 2.07-2.04 (m, 1H), 1.76-1.70 (m, 2H); 13C NMR (125 MHz, CDCl3) major rotamer δ 155.3, 153.7, 139.5, 136.6, 133.1, 128.6 (2C), 128.0 (2C), 127.7, 127.6, 127.3, 125.4, 124.3, 123.4, 122.8, 106.9, 71.1, 70.1, 53.0, 48.3, 36.8, 36.2, 26.7, 24.5; IR (film) νmax 3063, 3022, 2938, 2858, 1701, 1593 cm−1; FABHRMS (NBA) m/z 470.1648 (M+H+, C25H27NO6S requires 470.1637).
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.O1CN1>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH2:7][CH2:6][C:5]([OH:36])([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1CC=C(F)CC1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C1NO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(O)CC=C(F)CC1
Temperature: -78 °C

Procedure:
A mixture of benzyl 4-fluorocyclohex-3-ene-1-carboxylate (1.77 g, 7.56 mmol) and 38 mL of THF was stirred vigorously and cooled to −78° C. To the reaction mixture was added dropwise over 15 minutes a solution of 0.5 M potassium bis(trimethylsilyl)amide in toluene (2.56 g, 12.8 mmol. The reaction mixture was allowed to stir vigorously for 1 hour. In a separate flask, 3-phenyl-2-(phenyl-sulfonyl)oxaziridine (2.17 g, 8.31 mmol) was dissolved in 2 mL of THF. The oxaziridine solution was then added to the reaction mixture dropwise. The reaction mixture was allowed to stir for 2 hours more and quenched with a saturated aqueous ammonium chloride solution. The biphasic reaction was separated and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel, eluting with 0-15% EtOAc in hexanes, to give benzyl 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylate as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([I:10])=[CH:7][C:8]=1[I:9])#[N:2].[OH-:17].[Na+].Cl>O>[C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([I:10])=[CH:7][C:8]=1[I:9])(=[O:17])[NH2:2]
Reactant: N#Cc1c(I)cc(I)c(CCC(=O)O)c1I
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(I)cc(I)c(CCC(=O)O)c1I
Temperature: 60 °C

Procedure:
30 g of 3-(3-cyano-2,4,6-triiodophenyl)propionic acid is introduced into a solution of 8 g of caustic soda in 100 ml of water. The solution is then maintained for 3 hours at 60° C., decolorized by repeated treatment with active carbon, and brought to pH 1 by adding concentrated hydrochloric acid. After several hours of agitation in an ice bath, the precipitate is vacuum-filtered, washed with water, and dried at 50° C. Yield: 29 g (94% of theory) of 3-(3-carbamoyl-2,4,6-triiodophenyl)propionic acid as a white powder, mp>280° C.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21](OCC)=[O:22])[N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14]2=[O:30])([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])[N:15]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:14]2=[O:30])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CC1c2ccc(C(C)(C)C)cc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(C(C)(C)C)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
N-[(5-tert-Butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.19 g of sodium, 0.80 g of guanidinium chloride and 1.81 g of ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 10 cm3 of water and 30 cm3 of diethyl ether and then stirred at a temperature in the region of 0° C. for 1 hour. The precipitate obtained is filtered off, washed with twice 10 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 1.1 g of N-[(5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of a white powder melting at 262-263° C. Ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is described in Example 10. (Analysis: C19 H28 N4 O2; % calculated C, 66.25; H, 8.19; N, 16.27; O, 9.29%. found C, 66.13; H, 8.50; N, 16.12).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16](=[O:29])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1>C1COCC1>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:29])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CCC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Product: COc1ccc(CCC(O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.2 %

Procedure:
A solution of 1-(3-(tert-Butoxycarbonylmethoxy)phenyl)-3-(3,4-dimethoxyphenyl)propan-1-one (10) (3.0 g, 7.49 mmol) in THF (5 mL) at −20° C. was treated with a solution of (+)-B-chlorodiisopinocamphenylborane (2.9 g, 8.99 mmol) in THF (10 mL) at −20° C. The resulting mixture was allowed to stand in a −20° C. freezer for 48 h after which time the mixture was evaporated and treated with diethyl ether (25 mL) followed by diethanolamine (8 mL). The viscous mixture was allowed to stir at room temperature for 3 h, after which time, was filtered through a pad of Celite with the aid of diethyl ether. The cloudy filtrate was evaporated and flash chromatographed (silica gel, 30% 40% EtOAc/hexanes) to afford 2.72 g (90%) of a clear colorless oil. (95% ee by Chiracel HPLC, 25% i-PrOH/hexanes, retention time 44.4 min for the R-enantiomer and 35.7 min for the S-enantiomer): IR (neat) 3525, 2935, 1750, 1515, 1150 cm−1; 1H NMR (CDCl3, 300 MHz) 7.30-7.25 (m, 2H), 6.99-6.73 (m, 5H), 4.68 (m, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.72-2.63 (m, 2H), 2.12-1.97 (m, 2H), 1.50 (s, 9H); 13C NMR (CDCl3, 75 MHz) 168.4, 158.5, 149.3, 147.6, 146.9, 134.8, 130.0, 120.6, 119.5, 114.0, 112.6, 112.2, 111.7, 82.7, 74.1, 66.1, 56.3, 56.2, 41.0, 32.0, 28.4.