Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:51]([NH:53][CH3:54])=[O:52])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH:31]3[C:39]4[C:34](=[CH:35][C:36](CCCO[Si](C(C)(C)C)(C)C)=[CH:37][CH:38]=4)[CH2:33][CH2:32]3)S(C3C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=3)(=O)=O)[CH:9]=2)=[CH:6][N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C(N)(C)C.[CH2:80]1C[O:83][CH2:82][CH2:81]1>>[NH2:1][C:2]1[C:3]([C:51]([NH:53][CH3:54])=[O:52])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH2:80][CH2:81][CH2:82][OH:83])[CH:38]=4)[CH2:33][CH2:32]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(CN(C3CCc4cc(CCCO[Si](C)(C)C(C)(C)C)ccc43)S(=O)(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)cnc1N
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CC(C)N
Product: CNC(=O)c1nc(-c2cccc(CNC3CCc4ccc(CCCO)cc43)c2)cnc1N
Reaction time: 0.5 h
Yield: 33 %

Procedure:
3-Amino-6-[3-({[5-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2,3-dihydro-1H-inden-1-yl][(3,5-dinitrophenyl)sulfonyl]amino}methyl)phenyl]-N-methyl pyrazine-2-carboxamide (600 mg, 0.77 mmol) was dissolved in THF and refluxed for an hour in the presence of tetrabutylammonium fluoride in THBF. The reaction mixture was partitioned with water and extracted with ethyl acetate (10 mL×3) and dried over MgSO4. Filteration and concentration under vacuum gave tan oil, which was subjected to the solution of dichloromethane and isopropylamine. After being stirred for 30 min, the solvent was removed in vacuo and purified by flash column chromatography to give the 3-amino-6-[3-({[6-(3-hydroxypropyl)-2,3-dihydro-1H-inden-1-yl]amino}methyl)phenyl]N-methylpyrazine-2-carboxamide (110 mg, 33% yield): 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 1H), 8.06 (bs, 1H), 7.91 (s, 1H), 7.52 (m, 1H), 7.40 (m, 2H), 7.11 (d, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 4.32 (d, 1H), 3.66 (t, 2H), 3.02 (d, 3H), 2.99 (m, 1H), 2.81 (m, 1H), 2.69 (t, 2H), 2.44 (m, 1H), 1.90 (m, 4H), 1.32 (m, 3H), 0.82 (m, 2H); MS (EI) for C25H29N5O2: 432.23 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]#[N:12])=[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:4]2[N:3]=1.[OH-:13].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:10]([C:11]([NH2:12])=[O:13])=[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:4]2[N:3]=1
Reactant: [OH-]
Reactant: Cc1nn2c(c1C#N)NCCC2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nn2c(c1C(N)=O)NCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1.0 g portion of 4,5,6,7-tetrahydro-2-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile was dissolved with stirring in 5.0 ml of concentrated sulfuric acid. The mixture was stirred for 6 hours at room temperature then poured onto ice. This mixture was made basic with concentrated ammonium hydroxide and then was filtered to give the product of the example as a colorless solid, mp 234°-236° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(CCOc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Reaction time: 1.25 h
Yield: 15.1 %

Procedure:
To a solution of Intermediate 13b (1.15 g, 5.0 mmol), 2-(4-methyl-piperazin-1-yl)-ethanol (864 mg, 6.0 mmol), and triphenylphosphine (2.62 g, 10.0 mmol) in THF (10 mL), was added diisopropyl azodicarboxylate (2.0 g, 10.0 mmol) dropwise and stirred for 75 min. The mixture was diluted with diethyl ether (50 mL) and extracted with 10% aqueous citric acid soln (2×). The combined aqueous layers were basified with solid potassium carbonate until pH=9. The aqueous layer was then extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried (NaSO4) and evaporated in vacuo. Purification by FCC using 0-12% [9:1 MeOH/880 ammonia] in DCM. The resulting product was crystallised (diethyl ether) to give the title compound (270 mg, 0.756 mmol, 15%). LCMS (Method 1): Rt 2.31, 1.72 min, m/z 358/359 [MH+].
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])C(C)=O.[CH:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])OCC.[C:19]([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:17]([O:16][C:9]([O:13][CH2:14][CH3:15])([CH3:19])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: CCOC(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(OCC)OCC
Temperature: 45 °C
Reaction time: 8 h
Yield: 845 %

Procedure:
A mixture of ethyl pyruvate (13.92 g, 0.120 moles), triethyl orthoformate (19.44 g, 0.131 moles), ethyl alcohol (9.0 g), and p-toluenesulfonic acid monohydrate (0.0432 g, 0.00227 moles) was stirred at 45° C. overnight under nitrogen atmosphere. Next, after cooling to room temperature, Na2CO3 (1.20 g) was added and the mixture was stirred for 15 minutes. The reaction mixture was then filtered and ethyl alcohol and residual triethyl orthoformate were distilled off under reduced pressure. The residue was subjected to fractional vacuum distillation giving 18.2 g of pure ethyl pyruvate diethyl ketal. NMR (d6-DMSO): 1.27 ppm (t, —CH3, ethyl (ketal), 6H) 1.34 ppm (t, —CH3, ethyl (ester), 3H), 1.40 ppm (s, —CH3—C—COO—, 3H), 3.45 ppm (q, —OCH2CH3, (ketal), 4H), 4.29 ppm (q, —OCH2CH3, (ester), 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47].[CH:48](=O)[CH2:49][CH3:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:66]CCCl>>[ClH:66].[ClH:66].[OH:46][C@@H:4]1[C@H:3]([OH:47])[C@@H:2]([NH:1][CH2:48][CH2:49][CH3:50])[CH2:6][C@H:5]1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[O:38])[CH2:32]1)=[N:11][C:12]=2[NH:16][CH2:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCC=O
Reactant: ClCCCl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{(R)-1-[9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea (Example 26 step 2) (17 mg, 26 mmol) in DCE (1 ml) is treated with propanaldehyde (1.5 mg, 26 mmol) and placed under an atmosphere of argon. Sodium triacetoxyborohydride (10 mg, 51 μmol) is added and the reaction mixture is stirred at room temperature overnight. The mixture is quenched with 2M NaOH (5 drops) and the solvent is removed in vacuo. The residue is purified by C-18 reverse phase column chromatography eluting with acetonitrile:water:HCl (0.1%) (gradient of 20 to 100% acetonitrile) to yield the title compound. (MH+ 677.14)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(O)(=O)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1.[Zn].[O-2].[O-2].[Mn+4]>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[N:8]=[CH:9][C:4]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cc2)nc1
Reactant: CS(=O)(=O)Cl
Agent: [Mn+4]
Agent: [O-2]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)nc1

Procedure:
{4-[(5-nitropyridin-2-yl)oxy]phenyl}methanol was subjected to reduction of nitro group by using zinc and acetic acid, the obtained compound reacted with methanesulfonyl chloride in pyridine, and the obtained compound was subjected to oxidation by using manganese dioxide to give the title compound having the following physical data.
Reaction SMILES: [NH3:1].[CH2:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>>[CH2:2]([N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCO
Reactant: N
Product: CCCCCCCCN(CCCCCCCC)CCCCCCCC

Procedure:
Reacting n-octanol with ammonia in a molar ratio of 7:1 under the same reaction conditions gave tri-n-octylamine in a yield of over 95 mol%. The 2.5% by weight of di-n-octylamine formed at the same time were separated quantitatively from the reaction product, added to fresh feed and alkylated with octanol. The resulting reaction mixture likewise contained the secondary amine in amount of about 2% by weight, so that in the steady state where the secondary amine formed is being returned again and again the reaction to the tertiary amine was virtually quantitative.
Reaction SMILES: C(NC([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[N:18]=1)(C(OCC)=O)C(OCC)=O)(=O)C.[Br:25]C1C(F)=CC=C(C)N=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]([F:23])=[CH:21][CH:22]=[C:17]([CH2:16][Br:25])[N:18]=1
Reactant: CCOC(=O)C(Cc1ccc(F)c(Br)n1)(NC(C)=O)C(=O)OCC
Reactant: Cc1ccc(F)c(Br)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)nc1Br

Procedure:
Diethyl 2-acetamido-2-((6-bromo-5-fluoropyridin-2-yl)methyl)malonate: 2-Bromo-3-fluoro-6-methylpyridine (2.24 g, 11.79 mmol), NBS(2.34 g, 13.15 mmol), CCl4 (40 mL), and AIBN (0.10 g, 0.609 mmol) were added together and heated to reflux under argon for 4.5 h. The CCl4 was removed. The residue was dissolved in EtOAc and washed with water and brine. It was dried over Na2SO4, and concentrated to give 2-bromo-6-(bromomethyl)-3-fluoropyridine which was used in the next step without purification. MS (ESI) m/z: 269.9 (M+H)+. NaH (0.707 g of 60% dispersion, 17.69 mmol) was placed in a three-neck flask with 15 mL of DMF. It was cooled in an ice-bath. A solution of diethyl 2-acetamidomalonate (3.59 g, 11.79 mmol) in 15 mL of DMF was added dropwise via an additional funnel White foam formed and the mixture was stirred in the ice-bath for 20 minutes after the addition. A solution of 2-bromo-6-(bromomethyl)-3-fluoropyridine in 10 mL of DMF was added through an additional funnel dropwise. The ice-bath was removed and it was stirred at rt under argon for 2 h. It was quenched with water and extracted with EtOAc. The EtOAc solution was washed with water and brine, dried over Na2SO4, and concentrated. It was purified by normal phase chromatography to give 106A as an off-white solid (2.39 g, 50%). MS (ESI) m/z: 405.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.[Br-].[O:16]([CH2:23][CH2:24][CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:16]([CH2:23][CH2:24][CH2:25][CH:26]=[CH:1][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)COc1ccc(C=O)cc1
Agent: [Br-]
Product: COC(=O)COc1ccc(C=CCCCOc2ccccc2)cc1

Procedure:
Preparation takes place in analogy to Example XLIII from methyl (4-formylphenoxy)acetate and (4-phenoxybutyl)(triphenyl)phosphonium bromide. The product is obtained as an E/Z mixture.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[O:14]1.N1C=CC=CC=1.Cl>C(Cl)Cl.O>[OH:10][C:9](=[C:16]1[C:17](=[O:19])[O:18][C:13]([CH3:21])([CH3:12])[O:14][C:15]1=[O:20])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(=O)C(=C(O)COc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
93.8 g (0.55 mol) of phenoxyacetyl chloride are added dropwise to a solution, cooled to 8° C., of 72.1 g (0.5 mol) of 2,2-dimethyl-1,3-dioxane-4,6-dione and 79.1 g (1.0 mol) of pyridine in 250 ml of methylene chloride so that the temperature does not rise above 10° C. The mixture is subsequently stirred at room temperature for 2.5 hours, a mixture of 250 g of ice, 250 ml of water and 30 ml of concentrated hydrochloric acid is added and the mixture is extracted by shaking. The organic phase is washed twice with 100 ml of water each time and dried over magnesium sulfate. The solvent is distilled off, a solid remaining, which is recrystallized from t-butyl methyl ether. 72 g (52% of theory) of white crystals of the compound (6), which melt at 85°-87° C., with decomposition, are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[OH-].[Li+].Cl>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a 25 mL volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-39) (1.95 g), toluene (4.85 ml), and methanol (1.05 ml) were added under a nitrogen atmosphere, then added lithium hydroxide monohydrate (169 mg) at 0° C. After the mixture was stirred at 0° C. for 4 hours, 10 w/w % of hydrochloric acid was added to adjust to pH to less than 1, and extracted with toluene 3 times. The organic layers were combined and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=3:1) to give 1.077 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].O1CCCC1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:32]=[C:33]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])[CH:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (31.4 mg, 0.20 mmol) was dissolved into 1.7 mL of anhydrous tetrahydrofuran and treated with sodium hydride (8.0 mg, 60% dispersion in mineral oil, 0.20 mmol). This was stirred under nitrogen for 1 hour at ambient temperature, then the reaction was treated with 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-2a) (50 mg, 0.17 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7:13 ethyl acetate:hexanes) to afford 64.3 mg of the title product (I-2b).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH2:3]([NH+:27]([CH2:26][CH3:31])[CH2:28][CH3:29])[CH3:4].[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([O-:2])=[O:23]
Reactant: ClCc1ccccn1
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Product: CC[NH+](CC)CC
Product: NC(Cc1cc(Br)c(OCc2ccccn2)c(Br)c1)C(=O)[O-]
Yield: 21 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 2-chloromethylpyridine and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 21% yield of 2-amino-3-[3,5-dibromo-4-(pyridin-2-ylmethoxy)phenyl]propionate triethylammonium. LC/MS (electrospray): m/z 429 (M−1).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[ClH:15].NO.C(=O)([O-])O.[Na+].C[N:24]([CH:26]=O)C>C(OCC)(=O)C.O>[Cl:15][C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:7][C:26]#[N:24]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccncc1
Reactant: Cl
Agent: NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC=C(Cl)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To ice-cooled DMF (32.1 mL, 0.400 mol) was added POCl3 (18.6 mL, 0.200 mol) dropwise with stirring over 1 h. After 30 min, the mixture was allowed to warm to room temperature. Then, 4-acetylpyridine (11.1 mL, 0.100 mol) was added dropwise over 2 h. DMF (50 mL) was added additionally and the mixture was maintained at room temperature with a water bath. Hydroxylamine hydrochloride (13.9 g, 200 mmol) was added portion wise over 2 h being careful to keep the reaction temperature under 80° C. DMF (50 mL) was added again and hydroxylamine hydrochloride (13.9 g, 200 mmol) was added portion wise over 30 min. Then, the mixture was heated at 80° C. After 1.5 h, the mixture was allowed to cool to room temperature and stirring was continued overnight. The mixture was cooled to 0° C., water (500 mL) was added, and the mixture was neutralized with sodium hydrogen carbonate. Water (500 mL) was added again to dissolve all, and the mixture was extracted with ethyl acetate (500 mL, 3×200 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, filtered and concentrated at reduced pressure. The black residue obtained was dissolved with ethyl acetate (300 mL) and the solution was filtered through a pad of silica gel (100 g). The silica gel was washed with ethyl acetate (1 L). The filtrate was concentrated at reduced pressure to give a gray solid. 1H NMR analysis indicated the purity was about 60%. This solid was triturated with dichloromethane (100 mL) and filtered. The filtrate was purified by column chromatography (120 g×2, silica, Combiflash, dichloromethane to 50:50 dichloromethane/ethyl acetate) to afford the title compound (5.97 g, 36%) as a white solid:
Reaction SMILES: [C:1]([C:6]1[N:7](S(C2C=CC=CC=2)(=O)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)([O:3]CC)=[O:2].C[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.[OH-].[Na+].CO.[CH2:40]1COCC1>>[Cl:15][C:11]1[C:12]([NH:35][S:32]([C:28]2[CH:27]=[CH:26][CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:1]([OH:3])=[O:2])=[C:14]2[CH3:40]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)[nH]c2ccc(Cl)c(NS(=O)(=O)c3ccccc3)c12

Procedure:
In the manner outlined in Example 69, Step B, 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3-methyl(phenyl)sulfonamide (0.39 g, 0.75 mmol) was hydrolysed in 2:1:1 10% sodium hydroxide solution/methanol/THF (20 ml, 14 h at RT (room temperature) followed by 5 min at reflux), to give the title compound (from ethyl acetate);
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=O)(C)(C)C.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[CH3:14][C:9]1([CH3:15])[NH:8][CH2:13][CH2:12][N:11]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN(S(C)(=O)=O)CCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.60 mmol) and NEt3 (1.3 mL, 9.34 mmol) in DCM (11 mL) was cooled to 0° C. before the drop wise addition of a solution of methanesulfonyl chloride (580 mg, 5.00 mmol) in DCM (2 mL). The resulting mixture was warmed to r.t. and allowed to stir for 30 min before H2O was added. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was dissolved in DCM (10 mL) and TFA (2 mL) was added. The resulting mixture was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was partitioned between DCM and sat. aq. NaHCO3 and the aqueous phase was loaded onto an Isolute® SCX-2 cartridge which was washed with H2O and MeOH. The product was eluted with 2M NH3/MeOH affording the title compound (800 mg, 90%). LCMS (method A): RT 0.29 min [M+H]+ 193.3
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:5][CH:4]=1.CSC1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: CSc1ccc(NN=C(C#N)C#N)cc1
Reactant: NN
Agent: CSc1ccc(N)cc1
Solvent: N#CCC#N
Solvent: O
Product: CSc1ccc(NN=C2C(N)=NN=C2N)cc1
Yield: 77 %

Procedure:
This compound was prepared using 108 mg (0.5 mmol) of 2-[(4-methylsulfanylphenyl)-hydrazono]malononitrile, which was derived from 4-methylthioaniline (117 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 95 mg (77%) of the title compound as an orange solid.