Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=C(C)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)c1ccc(O)cc1
Yield: 63.2 %

Procedure:
Ethyl 3-(4-benzyloxyphenyl)but-2-enoate (3.4 g) in ethyl acetate (100 ml) was hydrogenated over a 10% palladium-on-carbon catalyst (250 mg) at atmospheric pressure/ambient temperature. The catalyst was removed by filtration and the filtrate evaporated to give an oil. The oil was purified by chromatography on silica gel using a 4/1 (v/v) mixture of hexane and ethyl acetate as eluent to give ethyl 3-(4-hydroxyphenyl)butanoate (1.51 g) as a pale yellow oil; NMR(CDCl3): 1.20(3H,t), 1.27(3H,d), 2.52(2H,q), 3.22(1H,m), 4.08(2H,q), 4.84(1H,s), 6.71(2H,m) and 7.08(2H,m); m/z 208(M). Ethyl 3-(4-allyloxyphenyl)butanoate was prepared using the procedue used to prepare ethyl 3-(4-allyloxyphenyl)propionate (see Example 1) but using ethyl 3-(4-hydroxyphenyl)butanoate in place of ethyl 3-(4-hydroxyphenyl)propionate; NMR(CDCl3) 1.17(3H,t), 1.25(3H,d), 2.51(2H,m), 3.22(1H,m), 4.05(2H,q), 4.50(2H,m), 5.33(2H,m), 6.06(1H,m), 6.82(2H,m) and 7.11(2H,m); m/z 249 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:27][C:28](=O)[CH3:29].CCO>O>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:27]=[C:28]([CH3:29])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: CC(=O)CCl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 90.1 %

Procedure:
A 1 L round-bottomed flask was charged with 1-(3-(benzyloxy)pyridin-2-yl)thiourea (31.7 g, 122 mmol), triethylamine (29.0 mL, 207 mmol), 1-chloropropan-2-one (13.6 mL, 171 mmol), and EtOH (400 mL). The reaction mixture was heated to reflux overnight, then poured into water and extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (32.7 g, 89.9% yield) as a yellow solid. 1H NMR (CDCl3) δ 8.58 (s, 1H), 7.93 (m, 1H), 7.39 (m, 5H), 7.08 (d, 1H), 6.80 (dd, 1H), 6.37 (s, 1H), 5.08 (s, 2H), 2.32 (s, 3H). LCMS (25 to 95) Rt=2.94 min (apci) m/z=298 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of methyl 6-chloro-5-hydroxynicotinate (10.5 g) in DMF (80 mL) was added 60% sodium hydride (2.80 g) at 0° C., and the mixture was stirred at 0° C. for 0.5 hr. Benzyl bromide (10.5 g) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was poured into water, and the precipitate was collected by filtration. The crude crystals were purified by silica gel column chromatography (petroleum ether/THF) to give the title compound (6.00 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CCCCCC.CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 100.8 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply 97.05 g of 2,3,4,5-tetrafluorobenzoic acid (2, 500 mmol) were suspended under argon and with stirring in 100 ml of n-hexane and 0.5 ml of N,N-dimethyl formamide. To this suspension 44 ml of thionyl chloride (d=1.64, 600 mmol) were added at room temperature, and the mixture was heated to reflux for 15 hours. The light yellowish solution was evaporated in a rotary evaporator at 50° C. reducing the pressure first to 200 torr until distillation ceased, then to 30 torr holding this pressure for 3 minutes to yield 107.1 g of the crude acid chloride 2a as a pale yellow liquid, which was kept under argon and directly used for step 3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Mg]Br)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([F:28])[C:17](S(C2C=CC=CC=2)=O)=[N:18][CH:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([F:28])[C:17]([C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=2[F:12])=[N:18][CH:19]=1
Reactant: O=S(c1ccccc1)c1ncc(Cl)cc1F
Reactant: COc1cc([Mg]Br)c(F)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(Cl)cc2F)c(F)cc1Cl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A Grignard solution of 12.9 g (0.049 mol) of 4-chloro-2-fluoro-5-methoxyphenylmagnesium bromide in 60 ml of THF was added with stirring at 23-30° C. to a solution of 10 g (0.0392 mol) of 5-chloro-3-fluoro-2-phenylsulfinylpyridine in 150 ml of THF over a period of 10 min, and the mixture was stirred at 23° C. for another 4 h. The reaction mixture was concentrated under reduced pressure, taken up in methylene chloride and extracted in succession with 1 N hydrochloric acid, 1 N of aqueous sodium hydroxide solution and with water, and dried. The solution was filtered with suction through silica gel, concentrated, stirred with pentane, filtered off with suction and dried, affording 5.7 g (50.1% of theory) of the title compound of mp. 120-122° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:21][O:22][C@@H:23]1[CH2:28][CH2:27][NH2+:26][CH2:25][C:24]1([CH3:30])[CH3:29]>CC(O)C>[CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15]([N:26]3[CH2:27][CH2:28][C@@H:23]([O:22][CH3:21])[C:24]([CH3:30])([CH3:29])[CH2:25]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: CO[C@@H]1CC[NH2+]CC1(C)C
Agent: [Cl-]
Solvent: CC(C)O
Product: CO[C@@H]1CCN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
Temperature: 50 °C

Procedure:
To a solution of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.55 g, 18.8 mmol) in iPrOH (170 mL) was added (R)-4-methoxy-3,3-dimethylpiperidin-1-ium chloride, Example 7-D (3.08 g, 17.1 mmol) and TEA (7.2 mL, 51.4 mmol). The reaction mixture was then heated overnight at 50° C. At that point the solvent was removed in vacuo and the residue was purified via FCC (0-50% EtOAc/heptane) to give the title compound. MS (ESI+) m/z 401.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>>[Si:16]([O:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1Br
Solvent: Cc1ccccc1
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 4-bromo-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-isochromen-1-one (intermediate A8, 2 g, 5.22 mmol) in toluene (30 ml) PdCl2(PPh3)2 (0.183 g, 0.261 mmol) was added followed by 2-(tributylstannyl)pyridine (4.55 ml, 10.44 mmol) and the resulting mixture was heated to reflux overnight. The mixture was allowed to cool to RT and then and filtered through a celite pad. The solvent was removed in vacuo, the crude was dissolved in AcOEt and an aqueous sat. sol of KF was added and the mixture was stirred for 2 hrs. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel Biotage cartridge (cyclohexane to cyclohexane:EtOAc=20:80) to afford 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(pyridin-2-yl)-1H-isochromen-1-one as a pale yellow oil (Intermediate B58.1, 0.508 g, 1.33 mmol).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[C:6]([Cl:20])[C:5]=1[F:21])=O.F[C:23](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:1]([S:2][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[C:6]([Cl:20])[C:5]=1[F:21])[CH3:23]
Reactant: CS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Temperature: 25 °C

Procedure:
A suspension of (R)-N-[4-methylsulphinyl-3-fluoro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 2) (5.41 g) in trifluoroacetic anhydride (65 ml) was heated under reflux for 30 minutes. The reaction mixture was evaporated and the residue was redissolved in MeOH (32 ml) and triethylamine (32 ml) and ethyl iodide (2.2 ml) was added. The reaction mixture was heated under reflux for 3 hours, allowed to cool to room temperature and volatile material was removed by evaporation. The residue was partitioned between EtOAc (150 ml) and brine (100 ml); the organic phase was separated, dried and volatile material was removed by evaporation. The residue was purified by flash column chromatography eluting with 10-20% EtOAc/isohexane to give the title compound (2.16 g) as a yellow solid. NMR (CDCl3) 1.27 (s, 3H), 1.76 (s, 3H), 2.88-2.95 (q, 2H), 3.55 (s, 1H), 7.32 (t, 1H), 8.15 (d, 1H), 8.92 (s, 1H); m/z: 344.
Reaction SMILES: [N:1]1([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N:1]1([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[Cl:27])=[CH:16][CH:15]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(Cn1cnc2ccccc21)Nc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(-c2ccccc2Cl)cc1
Temperature: 110 °C
Yield: 31.3 %

Procedure:
2-Benzimidazol-1-yl-N-(4-bromophenyl)-acetamide (100 mg, 0.30 mmol) (Example 6A), PdCl2(PPh3)2 (22 mg, 0.03 mmol), K2CO3 (120 mg, 0.8 mmol) and 2-chlorophenylboronic acid (71 mg, 0.45 mmol) were combined and dissolved in DME (0.5 mL), EtOH (0.5 mL) and H2O (0.2 mL). This mixture was heated in a microwave at 110° C. for 10 minutes. SCX purification of the reaction mixture, followed by further purification using prep LCMS yielded the desired product (34 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.21 (2H, s), 7.2-7.3 (2H, m), 7.36-7.45 (5H, m), 7.55 (2H, d, J=8 Hz), 7.67-7.72 (3H, m), 8.25 (1H, s), 10.59 (1H, s). MS (ES) m/z: 362.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]=2[C:17]([OH:19])=[O:18].N1C=CC=CC=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[C:28]=1O>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]=2[C:17]([O:19][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:18]
Reactant: COc1ccc2c(C(=O)O)c3ccccc3nc2c1
Reactant: Oc1c(F)cccc1F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Oc3ccccc3)c3ccccc3nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-acridine-9-carboxylic acid (0.50 g) was suspended in 10 mL thionyl chloride (3-10 mL) and reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure to obtain a yellow solid which was dissolved in CH2Cl2 and pyridine (0.44 g) under argon. A solution of 2,6-difluorophenol (0.32 g) in CH2Cl2 was added dropwise. The solution was stirred overnight at room temperature then diluted with more CH2Cl2 (100 mL) and washed with water (3×50 mL) . The organic layer was dried over Na2SO4 and concentrated to obtain the product which was further purified by chromatography on silica gel (30% ethyl acetate/hexane) to yield the pure product as a creamy solid. 1H NMR (acetone-d6) δ 4.08 (s, 3H), 7.39-8.29 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.Cl>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[CH2:8][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL), heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was filtered and concentrated. The residue was dissolved in THF (50 mL). Morpholine (1.9 g, 22 mmol) was added to the THF solution. The mixture was stirred at ambient temperature for 1 hour and then filtered. The solvent of the filtrate was evaporated. The bright orange residue obtained was then mixed with 5% HCl solution (30 mL) and extracted with ethyl acetate (2×25 mL). The aqueous layer was basified with NaOH solution to pH 8 and then extracted with methylene chloride. Both ethyl acetate solution and methylene chloride solution were dried over anhydrous Na2SO4 separately. Evaporation of ethyl acetate solution afforded an orange oil which was recrystallized from hexane:ether solution to yield 450 mg of a yellow solid, 4-(3-methyl-4-nitrophenyl)morpholine (18%), the by-product. Evaporation of methylene chloride solution afforded 660 mg of the desired compound, 4-(5-fluoro-2-nitrobenzyl)morpholine (27.5%).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:10][C:11](=[O:32])[C@H:12]([NH:24]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O)[CH3:9].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C@H:12]1[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:24]1)=[O:32])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCC(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (30 mL) was dropwise added to an ethyl acetate solution (30 mL) of (R)-2-tert-butoxycarbonylamino-5-(4-chlorophenyl)-5-oxopentanoic acid ethyl ester (5.6 g) at room temperature. The resulting reaction solution was stirred at room temperature for 2 hr and concentrated under reduced pressure to give 5.0 g of a yellow oily substance. To an ethyl acetate solution (100 mL) of this crude product, a saturated sodium hydrogencarbonate aqueous solution (100 mL) was dropwise added. The resulting reaction solution was stirred at room temperature for 20 min and then extracted with ethyl acetate. The extract solution was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3.5 g of the title compound as a light yellow oily substance. The physical property values of this compound were as follows:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:29]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3Cc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
A mixture of the product of Example 22B (0.72 g, 1.5 mmol), benzyl bromide (0.26 g, 1.5 mmol) and potassium carbonate (3.0 g in 3 mL of H2O) in tetrahydrofuran (6 mL) was stirred at room temperature for 72 hrs, diluted with ethyl acetate, washed with water and partitioned. The isolated organic layer was concentrated and the residue was chromatographed on silica gel, eluting with 60%-100% ethyl acetate/hexanes to afford the title compound (0.58 g, 72%) as an amorphous solid. 1H NMR (300 MHz, d6-DMSO) 9.00 (s, 1H), 8.42 (s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.48 (m, 1H), 7.28 (m, 5H), 6.95 (d, J=7.5 Hz, 1H), 6.83 (m, 1H), 6.58 (m, J=6.0 Hz, 1H), 6.50 (m, 1H), 6.36 (d, J=7.5 Hz, 1H), 4.64 (m, 2H), 4.01 (s, 3H), 3.57 (m, 1H), 3.41-3.20 (m, 2H), 2.90 (m, 1H), 2.67 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H); MS (DCI/NH3) m/e 470 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[NH:10].[CH2:22]([O:29][C:30](=[O:45])[C@H:31]([CH2:40][CH2:41][C:42](O)=[O:43])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C:33]([NH:32][CH:31]([CH2:40][CH2:41][C:42]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[NH:10])=[O:43])[C:30]([O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:45])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCO)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCOC(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 119.8 %

Procedure:
2.48 g (7.9 mmol, 1 eq.) of N—(N-(6-hydroxyhexyl)carbamimidoyl)-4-methylbenzenesulfonamide and 2.67 g (7.9 mmol, 1 eq.) of Boc-L-glutamic acid 1-benzyl ester were dissolved under nitrogen in dry dichloromethane. 198.9 mg (1.58 mmol, 0.2 eq.) of DMAP and 1.810 g (8.7 mmol, 1.1 eq.) of DCC were added at room temperature. The reaction was stirred overnight and a white precipitate appeared. The precipitate was removed by filtration and the solvent evaporated to afford 5.99 g of a mixed yellow oil/solid compound. This compound was purified by flash chromatography over silica (eluant pure AcOEt; Rf=0.71) to afford 4.83 g of a slightly yellow oil (yield=97%).
Reaction SMILES: [CH3:1][CH:2]1[CH:26]=[C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C:23](=[O:27])[NH:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][CH2:5]1>CC(O)=O>[CH3:1][CH:2]1[CH2:26][CH:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C:23](=[O:27])[NH:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:6][CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)C=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)CC4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following the analogous general procedure of Example 8, compound 29 was catalytically hydrogenated in HOAc to yield the title compound 30.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4](P(OCC)(OCC)=O)[CH3:5].[H-].[Na+].[C:17]([O:21][C:22]([C:24]1[S:25][C:26]([CH:29]=O)=[CH:27][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([C:24]1[S:25][C:26](/[CH:29]=[C:4](/[C:3]([O:2][CH3:1])=[O:14])\[CH3:5])=[CH:27][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/c1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
2-(Diethylphosphono)propanoic acid methyl ester (23.0 g, 0.103 mol) was dissolved in tetrahydrofuran (150 mL), 60% sodium hydride (2.4 g, 0.06 mol) was added at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example 1, step 2 (11.0 g, 0.052 mol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N-hydrochloric acid solution, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (13.1 g, 0.047 mol, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[C:4](I)=[CH:3]1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3]1
Reactant: CC1(C)C=C(I)C(=O)C1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC1(C)C=C(c2ccccc2)C(=O)C1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A 250 mL round bottom flask was charged with 4,4-dimethyl-2-iodo-2-cyclopenten-1-one from Step 1 (1.59 g, 6.7 mmol), bis(benzontrile)-palladium(II) chloride (235 mg, 0.61 mmol), phenylboronic acid (983 mg, 8.1 mmol), triphenylarsine (308 mg, 1.0 mmol), 2.0 M Na2CO3 (8.4 mL, 16.8 mmol) and benzene (70 mL). The reaction flask was well purged with nitrogen and the reaction was stirred at 80° C. for 2.5 h. The reaction was allowed to cool to r.t., diluted with NH4OAc buffer 25% w/v (100 mL) and extracted with EtOAc. The organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% EtOAc in hexane to give the title compound as a light yellow syrup.