Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([NH:16][C@H:17]([C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[C:33]([O:35]CC)=[O:34])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([NH:16][C@H:17]([C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3CCCCC3C(=O)O)ccc2c1
Reaction time: 10 h
Yield: 75.4 %

Procedure:
A solution of 2.8 g of ethyl 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2N--NaOH solution was warmed to 60° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200 - 300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10:9:1). The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid as an amorphous solid.
Reaction SMILES: C[O:2][C:3]1[CH2:12][C:11]2[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[N:33]=[C:32]5[C:27]([CH:28]=[CH:29][C:30](=[O:34])[NH:31]5)=[CH:26][CH:25]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH:4]=1.Cl>C(O)C.O1CCCC1>[O:2]=[C:3]1[CH2:12][C:11]2[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[N:33]=[C:32]5[C:27]([CH:28]=[CH:29][C:30](=[O:34])[NH:31]5)=[CH:26][CH:25]=4)[CH2:17][CH2:18]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: COC1=CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2C1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one (360 mg, 0.78 mmol) was dissolved in a mixture of ethanol (6 mL) and tetrahydrofuran (2 mL). To this was added 10% hydrochloric acid (1.5 mL) and the mixture was stirred at room temperature for 15 minutes, then quenched with saturated sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (20 mL) and the organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The crude solid was purified by column chromatography (6:94 triethylamine/ethyl acetate) to yield the title compound (263 mg, 75%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 7.76 (d, 1H), 7.60 (d, 1H), 7.20 (t, 1H), 7.00–6.95 (m, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.60 (s, 2H), 3.04 (t, 2H), 2.90–2.80 (m, 4H), 2.80–2.40 (m, 8H), 1.90–1.60 (m, 4H), MS ES+ 447.05 (M+H)+ (Exact mass: 446.23).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-Hydroxy-2-nitrobenzoic acid (10.5 g) was dissolved in 60 ml of N,N-dimethylformamide, then 15 ml of benzyl bromide and 19.0 g of potassium carbonate were added at 0° C. and the mixture was stirred for one night at room temperature. The reaction solution was filtered through Celite and concentrated in vacuo. Water was added to the resulting residue and the mixture was extracted with ether, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give 20.7 g of benzyl 3-benzyloxy-2-nitrobenzoate.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:7](=[N:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[OH2:12]>O1CCOCC1.Cl([O-])(=O)(=O)=O.[Ag+]>[OH:12][CH2:2][C:3]1[C:11]2[C:7](=[N:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: BrCc1cccc2nsnc12
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: OCc1cccc2nsnc12
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of silver perchlorate (4.75 g, 23 mmol) in water (10 mL) was added to a solution of 4-bromomethyl-2,1,3-benzothiadiazole (4.38 g, 19 mmol) in 1,4-dioxane. The mixture was refluxed for 4 hours to afford a light-yellow suspension. After cooling to room temperature, the precipitate was filtered off through a pad of celite and washed with CH2Cl2. The filtrate was washed with water and brine, dried over Na2SO4. Concentration using a rotary evaporator and subsequent column chromatography on silica gel using hexane/ethyl acetate (5:1) as the eluent afforded 4-hydroxymethyl-2,1,3-benzothiadiazole (2.0 g, 63%) as a light-yellow solid. Rf=0.23 (hexane/ethyl acetate=5:1); 1H NMR (200 MHz, CDCl3) δ2.73 (t,J=6.4 Hz, 1H), 5.18 (d,J=6.4 Hz, 2H), 7.58 (m, 2H), 7.94 (m, 1H); HRMS:Calcd. for C7H6N2OS 166.0201, found 166.0219.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([Cl:10])[CH:4]=1.[CH2:11]([O:13][C:14](=[O:20])[C:15](OCC)=[O:16])[CH3:12].[NH4+].[Cl-]>C(OCC)C.C(Br)C>[CH2:11]([O:13][C:14](=[O:20])[C:15]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[Cl:10])=[O:16])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1ccc(I)c(Cl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Yield: 80.1 %

Procedure:
A suspension of magnesium (6.7 g; 0.275 moles) in ethyl ether (125 ml) under stirring and nitrogen flow was added with ethyl bromide (180 mg). A solution of 1,3-dichloro-4-iodobenzene (50 g; 0.183 moles) and ethyl bromide (180 mg) in ethyl ether (100 ml) was dropped in about 1 hour keeping the temperature at 15-20° C. The suspension was stirred for further 2 hours. After decanting the magnesium in excess, the solution was dropped in about 1 hour in a solution of diethyloxalate (29.32 g; 0.2 moles) in ethyl ether (125 ml) cooled to −70° C. At the end of the addition it was stirred at −70° C. for 1 hour, then the temperature was left to rise to 10° C. and the stirring was kept on for another hour. The suspension was added with a saturated solution of NH4Cl (125 ml), the phases were separated and the aqueous one extracted with ethyl acetate (50 ml). The organic phases were washed with a solution of sodium bisulfite and treated with discolouring charcoal. After filtration, the organic solution was distilled under vacuum to give a crude which was purified by chromatography (SiO2; hexane/ethyl ether 9/1) to give 36.2 g of (2,4-dichloro-phenyl)-oxo-acetic acid ethyl ester (yield 80%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:15][C@H:16]1[CH2:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([NH:15][CH:16]2[CH2:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH2:17]2)=[O:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: N[C@H]1CCCNC(=O)C1
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)NC1CCCNC(=O)C1

Procedure:
Following General Procedure A above using N-(3,4-dichlorophenyl)-D,L-alanine (Example Q) and 3-(S)-amino-ε-caprolactam (Sigma), the title compound was prepared as a solid having a melting point of 199° C. The reaction was monitored by tlc on silica gel (Rf=0.4 in 50% ethyl acetate/hexanes) and purification was by preparative thin layer chromatography using 50% ethyl acetate/hexanes as the eluant.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2>>[N:26]1[C:27]2[C:22](=[C:21]([NH:20][C:15]([C:12]3[CH:13]=[C:14]4[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]4[CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[O:16])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Reactant: Nc1cccc2ncccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccc4ncccc34)ccc12
Yield: 30 %

Procedure:
This compound was prepared according to the method of Example 15, using 91 mg (0.329 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 52 mg (0.362 mmol, 1.1 equiv) 5-amino-quinoline as starting materials, to give 38 mg (30%) of pale yellow powder: mp 176-178° C.; Anal. calcd for C24H24N4O: C, 74.96; H, 6.29; N, 14.57. Found: C, 74.33; H, 6.53; N, 14.31.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:11]
Reactant: CCI
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1F
Reaction time: 24 h
Yield: 92 %

Procedure:
A mixture of 2-fluorophenol (8.6 g, 77 mmol), iodoethane (9.2 mL, 120 mmol) and potassium carbonate (21 g, 150 mmol) (finely powdered) was stirred in acetone (100 mL) at 50° C. overnight, then at room temperature for 24 h. The mixture was filtered over a pad of silica gel, and was rinsing with ether. The solution was carefully concentrated (due to volatility of product), then microfiltered to give 1-ethoxy-2-fluoro-benzene (92%) as a yellow oil. 1H NMR (CDCl3, 500 MHz), δ 7.12-6.94 (m, 2H), 6.91-6.86 (m, 1H), 6.83-6.77 (m, 1H), 4.01 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].I[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29].O>CS(C)=O>[CH2:3]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Sodium hydride (60%, 326 mg, 8.14 mmol) was added to dimethyl sulfoxide (5 ml) under argon atmosphere and cooled to 0° C. To this mixture, diethyl 2-(7-octeny)malonate (2 g, 7.40 mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added, followed by stirring for 1 hour. After cooling to 0° C., 1-iodo-5,5,6,6,6-pentafluorohexane (2.68 g, 8.88 mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added to the reaction mixture, followed by stirring for 2 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20) to give diethyl 2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.3 g, Yield 70%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][C:8]=1[CH2:31][CH2:32][CH3:33])C.[OH-].[Na+]>C1COCC1.CO>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][CH2:17][O:16][C:10]1[CH:9]=[C:8]([CH2:31][CH2:32][CH3:33])[C:7]([O:6][CH2:5][C:4]([OH:34])=[O:3])=[C:12]([CH2:13][CH2:14][CH3:15])[CH:11]=1
Reactant: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)cc(CCC)c1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)cc(CCC)c1OCC(=O)O
Temperature: 55 °C

Procedure:
A solution of {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}-acetic acid ethyl ester (244 mg, 0.524 mmol) in THF (3 mL) and MeOH (6 mL) was treated with 2.5N aqueous NaOH (2 mL). The solution was heated at 55° C. for 2.5 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (1 mL) and acidified with 5N aqueous HCl (2 mL). The mixture with CH2Cl2 (3 mL) was transferred to a ChemElute cartridge (5 g) and eluted with CH2Cl2 (40 mL). The eluent was concentrated to a white foam (228 mg, 100%): 1H NMR (400 MHz, CDCl3) δ 0.94 (t, 6H, J=7.3 Hz), 1.60 (sextet, 4H, J=7.6 Hz), 2.37 (s, 3H), 2.50-2.54 (m, 4H), 2.98 (brt, 2H), 4.19 (brt, 2H), 4.37 (s, 2H), 6.56 (s, 2H), 7.42-7.43 (m, 3H), 7.98-7.99 (m, 2H); MS (ES) m/e 438.2 [M+1].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[NH2:17][CH2:18][CH:19]([OH:22])[CH2:20][NH2:21]>>[OH:22][CH:19]([CH2:20][NH:21][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:3])=[O:5])[CH2:18][NH:17][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Reactant: NCC(O)CN
Product: O=C(COc1cccc(C(=O)O)c1)NCC(O)CNC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R15 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with 1,3-diaminopropan-2-ol. A white powder is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:28])[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([O:28][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
Suspend (R)-4-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.78 g, 11.2 mmol) in dry tetrahydrofuran (115 ml) under a nitrogen atmosphere and add sodium hydride NaH (60% weight dispersion in mineral oil, 1.17 g, 29.3 mmol). Stir the resulting mixture for 30 minutes and then add sequentially sodium iodide (600 mg, 4.0 mmol) and benzyl bromide (2.7 mL, 22.7 mmol). Stir the resulting mixture for 2.5 hours and then quench by the addition of a 1:1 mixture of saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Dilute the resulting mixture with ethyl acetate and discard the aqueous phase. Wash the organic phase with saturated aqueous sodium chloride, dry over magnesium sulfate, filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 40:60 ethyl acetate:hexanes) to give the desired compound as a white foam (4.96 g, 85%).
Reaction SMILES: NSOO[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)=[CH:7][CH:6]=1.[NH2:32][S:33](NC1C=C(NN)C=CC=1)(=[O:35])=[O:34]>>[NH2:32][S:33]([C:10]1[CH:9]=[C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)(=[O:35])=[O:34]
Reactant: NNc1cccc(NS(N)(=O)=O)c1
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Product: CCOC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1CCc1ccc([N+](=O)[O-])cc1-2

Procedure:
This compound was prepared using the same procedures for Ethyl 1-{4-[(aminothio)peroxy]phenyl}-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate of Example 2, where 3-(aminosulfonamido)-phenylhydrazine was used in place of 4-(aminosulfonamido)-phenylhydrazine. Its structure was confirmed by 1H NMR and MS (443, M+1). C20H18N4O6S, Calc.: C: 54.29; H: 4.10; N: 12.66; Found, C: 54.27; H: 4.09; N: 12.55.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]([CH3:25])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (132 mg, 0.36 mmol), N-methylaniline (0.1 mL, 99 mg, 0.92 mmol) and DMAP (120 mg, 0.98 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (4:1) on silica gel to give 59 mg (38% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.42-1.60 (m, 4 H), 1.63 (s, 9 H), 2.24-2.43 (m, 1 H), 3.19 (s, 3 H), 3.28-3.41 (m, 2 H), 3.92 (m, 2 H), 4.48 (d, J=7.42 Hz, 2 H), 7.03-7.12 (m, 2 H), 7.20-7.35 (m, 3 H), 7.60 (dd, J=8.79, 1.76 Hz, 1 H), 7.82 (d, J=1.17 Hz, 1 H), 7.94 (d, J=8.79 Hz, 1 H); MS (ESI) (M+H)+=442.0; Anal. Calcd for C24H31N3O3S+1.00 TFA+0.20 EtOAc+0.10H2O (575.04): C, 55.98; H, 5.92; N, 7.31. Found: C, 55.89; H, 5.87; N, 7.30.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>CO.C(O)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][NH:6][C:4]1[CH:5]=[N:1][NH:2][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: Nc1cn[nH]c1
Solvent: CO
Solvent: CC(=O)O
Product: c1csc(CNc2cn[nH]c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. stirring mixture of 1H-pyrazol-4-amine (250 mg, 3.008 mmol) and thiophene-2-carbaldehyde (281 uL, 3.008 mmol) in methanol and acetic acid (5.0 ml, 10:1 ratio) was added 5-ethyl-2-methylpyridine borane complex (444 uL, 3.008 mmol). The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo. With the aid of a 0° C. chilling bath, a 10 M solution of NaOH in water was carefully added. The ice bath was removed and stirring was continued for nearly 1 hour. The aqueous layer was extracted with DCM (3×), washed with brine, and dried over MgSO4 and concentrated. The obtained crude product was left under vacuum to remove the volatiles. The obtained viscous oil was diluted with DCM and evaporated under a gentle stream of nitrogen overnight. Solid crystals of the amine separated out and were washed with three aliquots of Hex:EtOAc=9:1. In this way, 391 mg (2.181 mmol; 72%) of the desired product were obtained in more than 97% purity by 1H-NMR analysis. 1H NMR (400 MHz, DMSO-d6) δ 4.21 (d, J=5.6 Hz, 1H), 4.92 (t, J=6.0 Hz, 1H), 6.94 (dd, J=5.1, 3.4 Hz, 1H), 7.10-6.99 (m, 3H), 7.36 (dd, J=5.1, 1.2 Hz, 1H), 12.05 (br s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[CH2:25]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:24]=[CH2:25])[CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: C=Cc1cccc(-c2nc(-n3cnc4cc(OC)c(OC)cc43)sc2C(=O)O)c1
Yield: 63.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-vinylphenylboronic acid (22 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-vinyl-phenyl)-thiazole-5-carboxylic acid (26 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H); 8.04 (t, 1 H); 7.85 (s, 1 H); 7.83 (dt, 1 H); 7.59 (dt, 1 H); 7.48 (t, 1 H); 7.40 (s, 1 H); 6.83 (dd, 1 H); 5.92 (dd, 1 H); 5.33 (dd, 1H); 3.86 (s, 3 H); 3.85 (s, 3 H). MS 408 m/z (M+1).
Reaction SMILES: [CH:1]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(OCC)(O[CH2:23][CH3:24])(=O)=O>O1CCCC1>[CH2:23]([O:15][CH2:14][CH:13]([CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16])[CH3:24]
Reactant: CC(CO)C1CCCCCCCCCCC1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(C)C1CCCCCCCCCCC1
Yield: 95.9 %

Procedure:
15 g of 2-cyclododecylpropan-l-ol were stirred with 4 g of sodium hydride in 150 ml of tetrahydrofuran for two hours at the boiling temperature excluding air. 6 g of diethyl sulfate were then added dropwise, and the mixture was refluxed for a further two hours. The cooled reaction mixture was poured onto ice and extracted by stirring with 20 ml of 10% strength NaOH and 50 ml of tert.-butyl methyl ether. The aqueous layer was again extracted by shaking with tert.-butyl methyl ether, and the combined organic layers were again extracted by shaking with 10% strength NaOH and distilled. After removal of the solvents, 9.5 g of 2-cyclododecylpropyl ethyl ether were obtained at 92-95° C. and 0.2 mbar.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[CH3:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1)[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:51][C@@H:52]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[CH3:17]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: CCn1ncc(C)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To a solution of 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (130 mg, 0.48 mmol) [from Example 245(b)] in DCM (5 mL) at 25° C. was added PyBrOP (250 mg, 0.54 mmol) in one portion, followed by addition of DIPEA (0.7 mL, 4.01 mmol). After 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (150 mg, 0.50 mmol) was added to above solution. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (210 mg, 79%) as a white solid: LC-MS m/z (ES) 551 (M+H)+.