Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](=[O:22])=[O:21]>C1COCC1>[Cl:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=C=O
Reactant: Clc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
4-Chloropyridine hydrochloride (25 g) is neutralized with aq. Na2CO3 (10%) and extracted with DCM. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-chloropyridine (19 g). To a solution of diisopropylamine (31 mL, 217.6 mmol) in dry THF is added n-butyllithium (115 mL, 184.1 mmol) dropwise at −78° C. under nitrogen. After 30 min, a solution of 4-chloropyridine (19 g, 167.4 mmol) in dry THF is slowly added under nitrogen. The reaction mixture is further stirred for 1 h at −78° C. before addition of solid CO2, let warmed to RT and stirred at RT for 12 h under nitrogen. After this time, reaction mixture is concentrated under reduced pressure and acidified with aq. HC1 solution (1.5 N) under ice-cooled condition. Precipitate is filtered under reduced pressure and dried overnight under vacuum to afford 15 g (57%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 6 13.83 (bs, 1H), 8.92 (s, 1H), 8.64-8.63 (d, J=5.4 Hz, 1H), 7.66-7.65 (d, J=5.4 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BrH:11].N([O-])=O.[Na+].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>CC(C)=O.[Cu-]=O.O>[Br:11][CH:17]([CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1)[C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Br
Reactant: CC(=O)c1cccc(N)c1
Reactant: C=CC(=O)OCC
Agent: O=[Cu-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Br)Cc1cccc(C(C)=O)c1

Procedure:
solution of 5 g of m-aminoacetophenone in 100 ml of acetone was combined with 25 ml of water and 15 ml of 47% hydrobromic acid and the resultant mixture was stirred for 30 minutes with 10 ml of an aqueous solution containing 3.32 g of sodium nitrite added dropwise in advance thereto at 5 C. The produced reaction solution and 28 ml of ethyl acrylate added dropwise thereto and 0.53 g of copper (I) oxide added piecemeal thereto at 40° C. were stirred for 2 hours. The resultant mixture was combined with water, extracted with ethyl acetate An organic layer was washed with water and a saturated aqueous saline solution, dried with anhydrous magnesium sulfate, and distilled under a vacuum to expel the solvent to obtain ethyl 2-bromo-3-(3-acetylphenyl)propionate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C:13]([F:16])([F:15])[CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:16][C:13]1([F:15])[CH2:12][NH:11][C@@H:10]([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([F:9])[CH:6]=2)[C:1]#[N:2])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1c1cc(F)cc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(F)cc([C@H]2CC(F)(F)CN2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidine-1-carboxylate (I-23) (0.45 g, 1.4 mmol) in DCM (3 mL) was added TFA (3 mL) and stirred at room temperature for 1 hour. All the solvents were removed under reduced pressure. The crude was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to yield (R)-3-(4,4-difluoropyrrolidin-2-yl)-5-fluorobenzonitrile (I-24) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1 H), 7.42 (d, J=9.2 Hz, 1 H), 7.29-7.26 (m, 1 H), 4.46 (t, J=8.8 Hz, 1 H), 3.52-3.30 (m, 2 H), 2.74-2.60 (m, 1 H), 2.20-2.04 (m, 1 H), 1.90 (bs, 1 H). MS m/z 227.1 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([O:28][CH2:29][CH3:30])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH2:29]([O:28][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:35]4[C:31](=[O:37])[CH2:32][CH2:33][C:34]4=[O:36])[CH2:6][CH2:7]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][CH3:27])[CH3:30]
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OCC
Reactant: O=C1CCC(=O)N1
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-diethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A2) and succinimide as starting compounds.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:4])=[O:3].CN(C=O)C.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40].Cl>O=S(Cl)Cl>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[CH:17]=[C:13]([C:14]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=[O:4])=[O:3]
Reactant: NCCCO
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
5-(Bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoic acid [A method of preparing this compound is disclosed in co-pending NZ Application No. 521851] (9) was heated under reflux in excess SOCl2 (60 mL) and catalytic DMF for1 h. Evaporation under reduced pressure, followed by azeotroping in benzene, gave the crude acid chloride. This was dissolved in dry Me2CO and treated at 0° C. with 3-amino-1-propanol at 0° C. for 5 min. The mixture was acidified to pH 2-3 with 0.2 N HCl, concentrated to half volume, and then solid NaBr was added, followed by extraction with EtOAc (2×). Evaporation, and chromatography of the residue on silica gel, eluting with EtOAc/MeOH (9:1), gave give 2-(5-{[(3-hydroxypropyl)amino]carbonyl } {2-[(methylsulfonyl)oxy]ethyl}-2,4-dinitroanilino)ethyl methanesulfonate (8) (68%) as a yellow gum; 1H NMR [(CD3)2SO] δ 8.54 (t, J=5.7 Hz, 1 H), 8.53 (s, 1 H), 7.45 (s, 1 H), 4.43 (t, J=5.1 Hz, 1 H), 4.33 (t, J=5.2 Hz, 4 H), 3.69 (t, J=5.2 Hz, 4 H), 3.57 (q, J=5.9 Hz, 2 H), 3.26 (after D2O exchange, t, J=7.0 Hz, 2 H), 3.12 (s, 6 H), 1.66 (pent, J=6.7 Hz, 2 H). HRMS (FAB) calcd. for C16H25N4O12S (MH+) m/z 529.0910; found 529.0904.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C=O.[C:35](O)(=O)C.[BH3-]C#N.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:35])[CH2:9][CH2:8]1)=[O:5]
Reactant: CC(=O)O
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0° C. and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).
Reaction SMILES: [CH:1]([N-:4][CH:5]([CH3:7])C)([CH3:3])C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][N:11]=1.[O:18]1CCCC1>C1CCCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:7]2[CH2:3][CH2:1][NH:4][C:5]2=[O:18])=[CH:12][N:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Reactant: ClCc1ccc(Cl)nc1
Agent: [Li+]
Solvent: C1CCCCC1
Product: O=C1NCCC1Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere at a temperature of from −78° C. to −60° C., 180 ml of a 1.5 molar solution of lithium diisopropylamide (LDA) in cyclohexane are added dropwise to 31.4 g of N-trimethylsilylpylrolid-2-one in 150 ml of tetrahydrofuran CIF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.5 g of 2-chloro-5-chloromethylpyridine in 40 ml of THF are added, and the mixture is stirred for a further 16 hours at that temperature and then for a further three hours at room temperature. The reaction mixture is poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off. The ethyl acetate phase is dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetatelhexane (7:1) as eluant The title compound having a melting point of 117-118° C. (compound 1.3) is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1nc(SC)ncc1C=O
Reaction time: 2 h
Yield: 30.2 %

Procedure:
4-Methylamino-2-methylsulfanyl-5-pyrimidinemethanol (2.40 g, 13.0 mmol) in 7 mL of acetic acid was added to a solution of sodium dichromate-dihydrate (1.30 g, 4.4 mmol) in 6 mL of acetic acid. After 2 hours at room temperature, additional sodium dichromate-dihydrate (0.3 g, 1.0 mmol) in 1 mL of acetic acid was added. After a total reaction time of 3.5 hours, the bright yellow solid was removed by filtration. Water (30 mL) was added to the filtrate, followed by aqueous ammonium hydroxide until basic (pH 9.0). The mixture was cooled in the refrigerator for 30 minutes. The precipitate was collected and dissolved in ethyl acetate, and the solution was dried over MgSO4. Filtration and concentration in vacuo gave 0.72 g (30%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxaldehyde; mp 99-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=1.O1CCOCC1.Cl.N>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][C:24]1[NH:25][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.9 %

Procedure:
A mixture of 628 mg of dimethyl aminoterephthalate, 546 mg of 3-chlorophenylacetonitrile and 15 mL of 4N hydrogen chloride dioxane solution was stirred at room temperature for 7 hours. Further continuing the stirring at 30° C. for 63 hours and at 70° C. for 25 hours, ice was added to the reaction mixture, followed by addition of 7 mL of 25% aqueous ammonia. Whereupon precipitated crystals were recovered by filtration, and washed with water, ether and chloroform by the order stated. Subjecting the crystals to through-flow drying under heating, 670 mg of the title compound was obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:15]>N1CCCCC1.C(O)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:15]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)c1
Yield: 96.1 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 127 mg 6-(3-ethoxyphenyl)-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 200 mg (96%) of the title compound as a brown solid.
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]1)([OH:38])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: COCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2-c2ccccc2Cl)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1-c1ccccc1Cl)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A 250 mL three-necked flask was charged with magnesium turning (2.88 g, 0.12 mol) and a small crystal of iodine. The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (60 ml) was added dropwise to the above mixture. After heating under reflux for 2 h most of magnesium had been consumed and the Grignard solution was cooled to rt. A 250 mL three-necked flask was charged with (3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 11 mmol) and THF (50 mL), evacuated and refilled with N2. The mixture was cooled in a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. The mixture was quenched with satd aq NH4Cl (100 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude product which was purified by flash column chromatography to afford pure (3R)-tert-butyl 3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (2.5 g, 47%).
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[N+:14]([O-:27])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH:21]([CH2:25][OH:26])[CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:29].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[N+:14]([O-:27])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH:21]([CH2:25][OH:26])[CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CC(CO)C3
Agent: N
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CC(CO)C3
Temperature: 20 °C
Reaction time: 17 h
Yield: 60.9 %

Procedure:
H2O2 (70%, 0.46 mL, 7.7 mmol) was added drop-wise (over 5 min) to a stirred solution of 1-oxide 140 (292 mg, 0.77 mmol), TFA (0.32 mL, 3.9 mmol), and TFAA (1.24 mL, 7.7 mmol) in DCM (25 mL) at 20° C. and the mixture stirred at 20° C. for 17 h. Another aliquot of H2O2 (70%, 0.46 mL, 7.7 mmol) and TFAA (1.24 mL, 7.7 mmol) were added and the mixture was stirred for 1 h. Aqueous NH3 solution (2 M, 30 mL) was added at 0° C. and the mixture stirred at 0° C. for 10 min, then stirred at 20° C. for 20 min. The mixture was extracted with DCM (5×80 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 141 (169 mg, 61%) as a dull orange solid: mp (MeOH/DCM) 112-114° C.; 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.73 (d, J=6.4 Hz, 2H, CH2O), 3.45 (br s, 4H, 2×CH2O), 3.21-3.37 (m, 4H, H-8, CH2), 3.00-3.09 (m, 2H, CH2), 2.83-2.92 (m, 1H, H-7), 2.50 (t, J=6.4 Hz, 2H, CH2N), 2.39 (br s, 4H, 2×CH2N), 2.07-2.15 (m, 2H, CH2), OH not observed; 13C NMR [(CD3)2SO] δ 154.1, 153.7, 149.3, 138.7, 133.5, 115.3, 113.3, 66.0 (2), 63.4, 57.2, 53.0 (2), 41.5, 35.6, 35.1, 28.0, 21.0. HRMS (FAB+) calcd for C18H25N4O4 (MH+) m/z 361.1876, found 361.1878.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1.[NH2:21][C@H:22]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:46][CH:45]=1)[C:23]([NH:25][C@H:26]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][C:41]([I:43])=[CH:42][C:36]=2[N:35]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:54]([O:53][CH2:52][CH2:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([C@H:22]2[NH:21][C:2](=[O:1])[N:25]([C@H:26]([C:34]3[NH:38][C:37]4[CH:39]=[CH:40][C:41]([I:43])=[CH:42][C:36]=4[N:35]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23]2=[O:24])=[CH:49][CH:48]=1)([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](N)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OCCOc1ccc([C@H]2NC(=O)N([C@@H](Cc3ccccc3)c3nc4cc(I)ccc4[nH]3)C2=O)cc1
Temperature: -20 °C
Yield: 91.4 %

Procedure:
To a solution of diphosgene (29 μL, 0.24 mmol) in 1:1 v/v toluene/tetrahydrofuran (20 mL) at −78° C. under an atmosphere of nitrogen was added a solution of (R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-acetamide (210 mg, 0.34 mmol) and N,N-diisopropylethylamine (239 μL, 1.37 mmol) in tetrahydrofuran (6 mL) dropwise with stirring. The reaction was allowed to warm to −20° C. then quenched with ice water (10 mL) and stirred for 10 minutes. The mixture was poured into ethyl acetate (30 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 20 to 60% v/v ethyl acetate/hexanes to give (R)-5-[4-(2-tert-butoxy-ethoxy)-phenyl]-3-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-imidazolidine-2,4-dione (140 mg, 64%).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]1([CH3:29])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH2:11]([N+:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC[n+]1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
In a 100 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 9.3 g of pyridine and 5.0 g of octadecyl p-toluenesulfonate, and the mixture was refluxed for 6 hours. After cooling the reaction mixture to room temperature, precipitated crystals were collected by filtration under reduced pressure. The resulting crystals were washed with acetone to obtain 5.9 g of the title compound. Melting point: 133*.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([OH:25])=[CH:22]2)=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:22]2[C:23]3[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:24]=3)[CH:19]=[CH:20][C:21]=2[OH:25])=[N:3][N:4]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2ccc(O)c(-c3nnc(Cl)c4ccccc34)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
In a 1 L flask under nitrogen were mixed 1,4-dichlorophthalazine (11.4 g, 57.3 mmol) with 7-methoxy-naphthalen-2-ol (10.0 g, 57.5 mmol). To this was added 1,2-dichloroethane (450 ml). After stirring for 10 min, aluminum chloride (7.64 g, 57.4 mmol) was added. The resulting suspension was stirred for 20 hrs at 80° C. After cooling to room temperature, the black suspension was poured on ice-water (500 ml) and stirred for 1 hr. The two layers were separated. The aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude solid was triturated with dichloromethane (35 ml) for 1 hr and collected by filtration to give 15.2 g of the title compound as a grey solid. (Yield: 80%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.CN(C)C=O.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: NCCOc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Temperature: 55 °C

Procedure:
2,4-Dichloro-5,6-dimethyl-3-nitropyridine (1.00 g), anhydrous N,N-dimethylformamide (5 ml), triethylamine (0.63 ml), and 2-phenoxyethylamine (0.59 ml) were combined and the resulting mixture was heated to 55° C. for 24 hours. Thin layer chromatography (TLC) monitoring of the reaction indicated that it was complete. The solvent was removed under reduced pressure and the remaining oil was dissolved in dichloromethane (DCM) and washed once with water. Following 2 additional extractions with DCM, the organic layers were combined, dried with magnesium sulfate, and the solvent was removed under reduced pressure. The product was passed through a column using 20/80 ethyl acetate/hexane as the eluant. NMR analysis of the resulting yellow solid indicated sufficient purity for use in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3](OC)=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C([O:36][CH3:37])=C(C(CBr)=CC=1)C(OC)=O.[F:38]C1C=CC(S)=CC=1>>[Br:1][C:2]1([O:36][CH3:37])[CH:12]=[CH:11][C:10]([CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([F:38])=[CH:19][CH:20]=2)=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: Fc1ccc(S)cc1
Product: COC(=O)C1=C(CSc2ccc(F)cc2)C=CC(Br)(OC)C1

Procedure:
Prepared by proceeding in a manner similar to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 4-fluorothiophenol.