Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.[NH2:28][CH2:29][CH2:30][CH2:31][S:32][C:33]1[C:43]2[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38][C:37]=2[CH:36]=[CH:35][C:34]=1[Cl:51].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>CN(C=O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[Cl:51][C:34]1[CH:35]=[CH:36][C:37]2[CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:43]=2[C:33]=1[S:32][CH2:31][CH2:30][CH2:29][NH:28][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN)c2CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCCSc1c(Cl)ccc2c1CCNCC2)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
To a stirred solution of 4-trifluoromethylbenzoic acid (60.0 mg, 0.316 mmol) in anhydrous DMF (1.2 mL) at ambient temperature under nitrogen, add EDC (63.6 mg, 0.332 mmol), 1-hydroxybenzotriazole (44.8 mg, 0.332 mmol), 4-dimethylaminopyridine (40.5 mg, 0.332 mmol) and a solution of 6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (123 mg, 0.332 mmol) in DCM (2 mL). Stir for 18 h at ambient temperature. Add water, extract twice with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Treat the residue with trifluoroacetic acid (0.272 mL, 0.640 mmol) in DCM (0.451 mL) at ambient temperature for 18 h. Concentrate in vacuo and purify by preparative reverse phase HPLC [Column: YMC ODS-AQ 120 Å 20×250 mm [S10-20 μm]; eluent: 95:5 to 5:95 A/B; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow rate 20 mL/min] to give the title compound as a white solid (31.0 mg, 18%). MS (APCI+) m/z 443 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].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>O1CCCC1>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C@@H:32]([N:30]2[CH2:31][C@H:27]([C@H:25]([O:23][C:15]3[N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[CH3:26])[CH2:28][C:29]2=[O:42])[CH3:33])=[CH:35][CH:36]=1
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: COc1cc(-c2cc3ncccc3c(O)n2)cc(OC)c1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4cc(OC)c(OC)c(OC)c4)cc4ncccc34)CC2=O)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
114.6 g of powdered 7-(3,4,5-trimethoxy-phenyl)-[1.6]naphthyridine-5-ol is suspended in 900 mL tetrahydrofurane. A solution of 115.9 g of (R)-4-[(S)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one and 136 g triphenylphosphine in 1000 mL tetrahydrofurane is added. The suspension is cooled to 0° C. During 40 minutes a solution of 105 mL diisopropylazodicarboxylate [DIAD] in 400 mL tetrahydrofurane is added at 0° C. to 2° C. The suspension is stirred for 3.5 hours at this temperature and then warmed up to 20° C. The solvent is evaporated under reduced pressure. The residue is suspended in 680 mL of tert-butylmethylether. Seeding crystalls of triphenylphosphinoxid are added and the mixture is stirred 16 hours at 20° C. The precipitate is filtered and washed with tert.-butylmethylether. The filtrate is evaporated under reduced pressure. The crude product is dissolved in a mixture of 220 mL of 2-propanol and 1100 mL of isopropyl acetate at 40° C. 48 mL of trimethylchlorosilane are added during 15 minutes. The suspension is stirred for 2 hours at 20° C. The precipitate is filtered and washed with isopropyl acetate and dried at 60° C.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C)C=O.O>[OH:9]/[N:8]=[C:1](\[Cl:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O/N=C/c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O/N=C(\Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a colorless, homogeneous solution of (E)-benzaldehyde oxime (24.4 g, 201 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added N-chlorosuccinimide (26.9 g, 201 mmol) portion-wise over 30 min. During each addition, the reaction mixture became yellow and then gradually returned to near colorlessness. Additionally, an exotherm was noted with each portion added. (It is extremely important to make sure the reaction initiates after the addition of the first ˜1/5 of the NCS; an ice-bath was readily available.). After the addition was complete, the homogeneous reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 250 mL of water and extracted with ether (3×100 mL). The organic layers were combined, washed with water (2×100 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), and washed with brine (100 mL). The aqueous layers were back extracted with ether (100 mL), and the combined organic layers (400 mL) were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)—N-hydroxybenzimidoyl chloride (30.84 g, 198 mmol, 98% yield) as a fluffy, pale yellow solid. The product had an HPLC ret. time=1.57 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=155.8. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.30-7.64 (m, 3H), 7.73-7.87 (m, 2H), and 12.42 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][CH2:15][CH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[C:19]1[CH3:29])(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([O:14][CH2:15][CH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH2:24][CH2:25][CH2:26][CH:27]=[O:28])=[C:19]1[CH3:29])(=[O:13])[CH3:12]
Reactant: CC(=O)OCCC[C@H]1CCCC(CCCCO)=C1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCCC[C@H]1CCCC(CCCC=O)=C1C
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a solution of 2.9 ml (30.6 mmole) of oxalyl chloride in 80 ml of CH2Cl2 at -50° C. was added a solution of 4.74 ml (61.2 mmole) of DMSO in 14.0 ml of CH2Cl2. This mixture was then stirred at -50° C. for another 5 minutes and added slowly with 4.1 g (15.3 mmole) of (R)-3-[3-(acetyloxy)propyl]-2-methyl-1-cyclohexene-1-butanol in 16.3 ml of CH2Cl2. The mixture was then stirred at -50° C. for another 35 minutes and added with 20.0 ml (143 mmole) of triethylamine to give a white suspension. After stirring at -50° C. for 5 minutes, the mixture was stirred at room temperature for 10 minutes, added with 20 ml of water and extracted with 2×300 ml of CH2Cl2. The combined extracts were then washed with 2×50 ml of water, brine, dried over Na2SO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (6:1, hexane/EtOAc) to give 3.6 g (87.8%) of the unstable (R)-3-[3-(acetyloxy)propyl]-2-methyl-1-cyclohexene-1-butanal as an oil. [α]D25 =-17.11° (CHCl3, c=1.04). IR (CHCl3): 1725, 2725 cm-1. 1H NMR (200 MHz): δ1.25 (m, 1H), 1.61 (s, 3H), 1.56-1.75 (m, 10H), 1.91 (n, 2H), 2.05 (s, 3H), 1.95-2.10 (m, 2H), 2.40 (dt, J=1.8, 7.3 Hz, 2H), 4.06 (m, 2H), 9.77 (t, J=1.8 Hz, 1H). Mass spectrum: M+ (266). Anal. for C16H26O3 : Calc. for C, 72.14; H, 9.80. Found: C, 70.12; H, 9.72.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Ca+2].[Cl-].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)[S:28][C:27]=2[CH:45]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[C:30]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=3)=[O:7])=[C:29]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:35][CH:36]=3)[S:28][C:27]=2[CH:45]=1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(F)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-4-fluorobenzoic acid (0.66 g; 3.0 mmol) and 1.57 mL (18.0 mmol) of oxalyl chloride in 10 mL of dichloromethane in a flask protected from moisture by a calcium chloride filled drying tube was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure to a white solid acid chloride. The crude acid chloride was dissolved in 50 mL of dichloroethane in an argon atmosphere, to this was added at 0° C. 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) (0.72 g; 2.0 mmol) and 1.6 g (12.0 mmol) of aluminum chloride. The mixture was stirred in the cold for 4 h, then poured into 200 mL of saturated aqueous sodium bicarbonate, and stirred for 1 h. Extraction was carried out with EtOAc (4×50 mL) and the combined organics were washed with brine and dried by passage through sodium sulfate. The mixture was subjected to flash chromatography on silica gel, eluting with a gradient of EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%) to afford 3-bromo-4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone contaminated with starting benzothiophene. This mixture was used without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].P.Cl[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CO.COCCOC>[C:1]1([NH:7][C:8]([NH:10][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with phenylurea (100 mg, 0.734 mmol, 1 equivalent), potassium phosphate (234 mg, 1.10 mmol, 1.5 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (6.7 mg, 0.00734 mmol, 0.01 equivalents) and phosphine ligand (0.029 mmol, 0.04 equivalents). Then 1,2-dimethoxyethane (1.34 mL) was syringed into the vial. After stirring the mixture for 1 hour at room temperature, 4-chlorotoluene (96 μL, 0.808 mmol, 1.1 equivalents) was added. The vial was sealed with a crimp top and placed in a heating block at 85° C. After 15 hours, the reaction vial was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with dimethylformamide (0.6 mL) and stirred for 15 minutes. The slurry was then filtered through a pad of diatomaceous earth. The vial was rinsed with dimethylformamide (0.6 mL) before passing through the filter. The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil. A 1:1 mixture of methanol:water (3.5 mL) was added dropwise to the crude concentrate, leading to the precipitation of product. The solids were collected by filtration and washed with 1:1 methanol:water (3 mL). The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg. (literature reference: Kotecki B J, et al. Org. Lett. 2009; 11: 947-950). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (t, J=22.7 Hz, 2H), 7.42 (dd, J=8.5, 1.0 Hz, 2H), 7.31 (t, J=5.4 Hz, 2H), 7.26 (dd, J=10.7, 5.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 6.95 (dd, J=10.5, 4.2 Hz, 1H), 2.24 (s, 3H).
Reaction SMILES: C(=O)([O-])O.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:6][C:16]1[CH:17]=[C:10]([O:9][CH3:8])[C:11]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:26]([CH3:28])[CH3:27])=[CH:12][C:13]=1[CH:14]=[O:15]
Reactant: COc1ccc(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Br)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 10.9 g of sodium hydrogen carbonate and 2.32 ml of bromine to a solution of 10 g of 4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 200 ml of chloroform at 0° C., the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium sulfite was then added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (11.7 g) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][C:15](N)=[O:16].C(=O)(O)[O-]>>[NH2:5][C:4]1[C:3]2[C:2](=[C:9]([Br:10])[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[N:1]=[C:15]([OH:16])[N:14]=1
Reactant: N#Cc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: NC(N)=O
Agent: O=C([O-])O
Product: Nc1nc(O)nc2c(Br)cc([N+](=O)[O-])cc12
Yield: 89.4 %

Procedure:
2-Amino-3-bromo-5-nitro-benzonitrile (1.9003 g, 7.85 mmol) was heated with urea (1.8862 g, 31.4 mmol) at 180–185° C. for 3 hrs. The cooled mixture was powered and treated with bicarbonate solution, filtered and washed with water. The solid was the collected and washed with ethanol, ether, and used for the next step reaction without further purification. 2.0 g product was obtained. Yield 89%; 1H NMR (500 MHz, DMSO-d6): δ 8.44455–8.45011(d, J=2.78 Hz, 1H), 8.87071–8.87544(d, J=2.365 Hz, 1H), 9.39866–9.40333(d, J=2.335 Hz, 1H), 9.50740–9.51282(d, J=2.71 Hz, 1H); ESI-MS: 285, 287 (M++1)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.[I:11]I.[OH-].[K+]>CN(C=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[I:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: Cc1cc2cn[nH]c2cn1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(I)n[nH]c2cn1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 5-methyl-1H-pyrazolo[3,4-c]pyridine [76006-06-9](1.00 g, 7.51 mmol) in DMF (15 mL) were added iodine (2.86 g, 11.3 mmol) and potassium hydroxide (1.05 g, 18.8 mmol). The reaction mixture was stirred at RT for 60 h. The mixture was diluted with 10% sodium thiosulfate and water, the resulting suspension was filtered. The solid was washed with water and dried under vacuum. MS (LC/MS): 260.0 [M+H]+; tR (HPLC conditions d): 0.28 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[C:33]([CH2:32][C:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:34]
Reactant: N#CCBr
Reactant: CCOC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (0.28 g, 1.00 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (1.00 mL, 1.00 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (0.69 mL, 1.00 mmol) was added as a solution in tetrahydrofuran (30 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The combined organic extracts were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes) to obtain the title compound. MS (DCI+) m/z 333 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cccc(N)c2)CC1
Yield: 79.8 %

Procedure:
A solution of 3-aminobenzoic acid (1.51 g, 11 mmol), 1-methylpiperazine (1.1 mL, 10 mmol), EDCI.HCl (2.87 g, 15 mmol) and Et3N (2.8 mL, 20 mmol) in CH2Cl2 (10 mL) is stirred at room temperature for 20 hours. Then saturated NaHCO3 aqueous solution is added. The aqueous layer was extracted with CH2Cl2, and the organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 1.75 g of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([NH:17][CH2:18][CH2:19][NH2:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:20][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
5.5 g (39.7 mmol) of 6-chloronicotinonitrile were dissolved in 70 ml of DMSO, and 10.2 g (63.5 mmol) of N-Boc-ethylenediamine and 11 g (79.4 mmol) of potassium carbonate were added. The mixture was stirred at 90° C. for 12 h. The residue was taken up in a mixture of water and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was chromatographed on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 10:1 to 2:1). This gave 7.9 g (77% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].C(CN)O>O.C(O)(=O)C.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(I)c1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 6 hours and 30 minutes, add 1-iodo-3-methoxy-benzene (2.4 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 ml) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 7N ammonia in methanol to give the title compound: mp 73–75° C.; mass spectrum (ion spray): m/z=401.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]Cl)[CH:3]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:3]=1)[O:10][C@@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13][N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CC[C@@H](Oc2cc(Cl)ccc2C#N)c2ccccc2)CC1
Yield: 78.3 %

Procedure:
4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile (0.3 g) and 1,1-dimethylethyl piperazinecarboxylate (0.4 g) were subjected to the procedure described for Example 11 to give the product as a clear gum (0.35 g).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(Cl)[Cl:42].O>C(OCCOCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClOCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCCOC(C)=O
Solvent: O
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 95 %

Procedure:
A 200 mg quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 5 ml of ethoxyethyl acetate. The solution was cooled in an ice bath with stirring. Thereto was added dropwise over 10 minutes 1.21 ml of a 0.285M solution of Cl2O in carbon tetrachloride. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 202 mg of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 95% yield.