Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>CN(C)C=O>[CH2:17]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCn1cc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A solution of methyl pyrazole-4-carboxylate (10 g) in N,N-dimethylformamide (100 ml) was treated with potassium carbonate (10.95 g) and 1-bromodecane (19.31 g) and the mixture was stirred for 16 hours at room temperature. Ethyl acetate was added and the solution was washed with water (6x), dried over magnesium sulfate and the evaporated residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give methyl 1-decylpyrazole-4-carboxylate (19.4 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:37]([NH:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[C:12]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25]I>CN(C=O)C.O>[CH3:25][N:11]1[C:12]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[CH:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10]1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(-c2ccccc2)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (830 mg, 0.02 mol) was added portionwise to a mixture of 2-(3-phenyl-1H-pyrazol-5-yl)isoindoline-1,3-dione (5 g, 0.0173 mol) and methyl iodide (1.5 mL, 0.024 mol) in DMF (80 mL) at 10° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and the aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 1:19 to 2:8) yielding a mixture of the title compound and the regioisomer 2-(2-methyl-5-phenyl-pyrazol-3-yl)isoindoline-1,3-dione (850 mg, 5:1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[P:12](=O)(O)([OH:14])[OH:13]>O>[P:12]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:14])=[O:13]
Reactant: O=P(O)(O)O
Reactant: COc1cc(C=O)ccc1O
Solvent: O
Product: COc1cc(C=O)ccc1OP(=O)=O

Procedure:
A phospho-vanillin reagent was prepared by dissolving 6 grams vanillin in water in a 1 liter flask and diluting to volume with water. 350 ml. of this vanillin reagent was admixed with 50 ml. of water in a 2 liter flask. Thereafter, 600 ml. of concentrated phosphoric acid, specific gravity 1.7, was added to the vanillin reagent with constant stirring. The mole ratio of vanillin to phosphoric acid in the reagent is 1.56 × 10-3.
Reaction SMILES: [F:1][C:2]([F:25])([CH3:24])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][C:6]=1[CH3:23].CCCCCCCCCCCCN>>[F:25][C:2]([F:1])([CH3:24])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[CH3:23]
Reactant: Cc1cc(CN2C(=O)c3ccccc3C2=O)cnc1OCC(C)(F)F
Agent: CCCCCCCCCCCCN
Product: Cc1cc(CN)cnc1OCC(C)(F)F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (699 mg, colorless oil) from 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (1.18 g, 3.41 mmol) in a similar manner to Step-5 of Amine-12.
Reaction SMILES: [CH2:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[NH:4][C:3](=[O:15])[CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[NH:4][C:3](=[O:15])[CH2:2]1
Reactant: O=C1CCC2=C(CCc3ccccc32)N1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC[C@H]2c3ccccc3CC[C@@H]2N1
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A mixture of 1,4,5,6-tetrahydro-2H-benzo[f]quinolin-3-one (10 g, 50.2 mmol) and triethylsilane (17.5 g, 150 mmol) in dichloromethane (100 ml) was stirred for 10 minutes. Trifluoroacetic acid (69 g, 605 mmol) was added dropwise with stirring and the mixture was stirred for 8 hours at room temperature. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate, and dried to afford (4aRS,10bSR)-trans-1,4,4a,5,6,10b-hexahydro-2H-benzo[f]quinolin-3-one (7.94 g, 39.5 mmol, 79%) as white crystals.
Reaction SMILES: [N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[Pd]>[N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: C1=CC2(CCN(CCCCN3CCC4(C=Cc5ccccc54)CC3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2c(c1)CCC21CCN(CCCCN2CCC3(CCc4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,4-Bis-spiro[ind-2-en-1,4'-piperidin-1'-yl]butane (compound 4a) (3 g) in ethanol (90 ml) were added acetic acid (5 ml) and 5% palladium on carbon (0.9 g). The mixture was hydrogenated in a Parr apparatus for 2 hours ar 3 atm. The catalyst was filtered off and the solvent evaporated. The remaining oil was solved in diluted aqueous NH4OH (200 ml, pH>9). The title compound 5a was extracted with ethyl acetate and worked-up as above and finally crystallized from ethyl acetate. Yield 1.6 g. Mp 113°-115° C. 1H NMR (CDCl3) δ1.55-1.65 (m,8 H), 1.95-2.10 (m,8 H), 2.15 (t,4 H), 2.45 (broad s,4 H). 2.95 (t,8 H), 7.10-7.30 (m,8 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C=O.[CH3:31]CN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (150 mg, 0.36 mmol) in THF (3 mL) was added aqueous formaldehyde 37 Wt % (58 μL, 0.72 mmol) and Et3N (149 μL, 1.07 mmol). The reaction mixture was then stirred at room temperature (20° C.) for 1 h. After this time sodium triacetoxyborohydride (152 mg, 0.72 mmol) was added and stirring at room temperature (20° C.) continued for 18 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by prep HPLC (low pH) to give as a light brown solid (48 mg, 33%).
Reaction SMILES: [CH:1]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]([N:34]=[C:35]=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:27]([NH:34][C:35]([NH:20][CH2:19][CH:16]1[CH2:17][CH2:18][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15]1)=[O:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)C1)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of C-(1-benzhydryl-pyrrolidin-3-yl)-methylamine (0.26 g, 0.97 mmol) in dry CH2Cl2 (5 ml) was added diphenylmethyl isocyanate (0.18 ml, 0.97 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using CH2Cl2: CH3OH (20:1) gives the desired product in 80% yield.
Reaction SMILES: P(Cl)(Cl)Cl.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:44](=[O:45])[N:16]2[C:17]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH:19]([CH3:22])[S:20](=O)[C@H:15]12)=[O:12]>CN(C=O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:44](=[O:45])[N:16]2[C:17]([C:28]([O:30][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:29])=[C:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:19]([CH3:22])[S:20][C@H:15]12)=[O:12]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1C
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@H]1C
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
A 41.5 ml portion of PCl3 was added to a solution of 32 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-3-em-4-carboxylate 1-oxide in 200 ml of DMF at -50° C., and the mixture was stirred at -30° C. for 5 minutes and poured in ice water to extract with AcOEt. The AcOEt layer was washed with 5% aqueous NaHCO3 and saturated aqueous sodium chloride solutions, and dried over Na2SO4, followed by distilling off the AcOET under reduced pressure, thus yielding crude crystals. Recrystalization from AcOEt-Et2O (1:3) afforded 17 g (55%) of diphenylmethyl 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH:20]4[CH2:22][CH2:21]4)[CH2:25][CH2:26]3)=[N:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)nc1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(N2CCN(CC3CC3)CC2)nc1

Procedure:
In analogy to example 1.a 6-chloro-N-[2-(4-chloro-phenyl)-ethyl]-nicotinamide was reacted with 1-(cyclopropylmethyl)piperazine. Off-white solid. MS (ISP): 399.3 ([M+H]+)
Reaction SMILES: N=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[NH:11])[NH:3]1.[Br-:12].[CH3:13][C:14]1[S:15][C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=2[N+:18]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]>O>[Br-:12].[NH:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH:13]=[C:14]2[NH+:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:17]3[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=3[S:15]2)=[N:3]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: Cc1sc2ccccc2[n+]1CCC(=O)O
Agent: [Br-]
Solvent: O
Product: N=C1N=C(C=C2Sc3ccccc3[NH+]2CCC(=O)O)c2ccccc21

Procedure:
Three grams (0.02 mole) of 1,3-diiminoisoindoline was dissolved in 25 ml of warm water. Three grams (0.01 mole) of 2-methyl-3-carboxyethyl benzothiazolium bromide was added to the solution. A molar excess of 1,3-diiminoisoindoline was employed to avoid bis substitution. The solution was stirred and heated on a steam bath for 10 minutes. An orange solid separated from the solution. The solution was then cooled and the solid collected by filtration. The dye was redissolved in hot water with the aid of sodium hydroxide. The solution was filtered, and the filtrate was acidified with excess acetic acid to reprecipitate the dye. The dye was washed with water and methanol and vacuum dried at 70° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]2[C@:12]34[CH2:17][CH2:18][N:19]([CH:20]=[O:21])[C@@H:6]([C@@H:7]3[CH2:8][CH2:9][C:10](=[O:22])[CH2:11]4)[CH2:5][C:4]=2[CH:3]=1.Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].N#N>CN(C=O)C.[OH-].[Na+]>[OH:16][C:14]1[C:13]2[C@:12]34[CH2:17][CH2:18][N:19]([CH:20]=[O:21])[C@@H:6]([C@@H:7]3[CH2:8][CH2:9][C:10](=[O:22])[CH2:11]4)[CH2:5][C:4]=2[CH:3]=[C:2]([O:1][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[N:26][N:25]=2)[CH:15]=1
Reactant: O=CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cc(O)cc(O)c13
Reactant: Clc1nnnn1-c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cc(Oc2nnnn2-c2ccccc2)cc(O)c13
Yield: 117.9 %

Procedure:
A mixture of 2,4-dihydroxy-N-formylmorphinan-6-one (3.6 g, 12 mmol), 5-chloro-1-phenyltetrazole (2.3 g, 12.7 mmol) and anhydrous K2CO3 (8.4 g, 60.8 mmol) in 150 ml DMF was stirred at 80+ 5° C. for 16 hrs uner N2. The K2CO3 was filtered off and washed with 10 ml DMF. The combined filtrates were evaporated under vacuum to afford a dark brown residue which was taken up in 200 ml 2 N NaOH and the aqueous solution washed with ether (2×100 ml). The basic solution was the acidified with conc. HCl and extracted with CHCl3 :i-PrOH=3:2. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 6.3 g of a gum. The crude product was chromatographed over silica gel and eluted with CHCl3 /MeOH=40:1 to give 1.3 g of pure ketone which after crystallization from DMF-EtOAc had a m.p. of 254°-256°.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:7].[OH-].[Li+]>CO.O>[CH:20]1([CH2:19][C@H:4]([CH2:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:7])[C:3]([OH:26])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)[C@@H](CC(=O)NCCNc1ccc(F)cc1)CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C[C@@H](CC1CCCCC1)C(=O)O)NCCNc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
(R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid methyl ester (220 mg, 0.60 mmol, 1.0 eq.) was dissolved in a mixture of MeOH (4.5 mL) and H2O (3 mL) and placed in a 0° C. ice bath. Lithium hydroxide (30 mg, 1.25 mmol, 2.1 eq.) was added in one portion and allowed to stir for 8 hours, slowly warming to 23° C. After the reaction was judged complete by LC/MS, methanol was removed by evaporation. Ethyl acetate (75 mL) was added to the resulting solution and was extracted with 1 M HCl (50 mL). The aqueous phase was extracted 2×75 mL of ethyl acetate and the combined organic phases were washed with saturated sodium bicarbonate (50 mL), saturated sodium chloride (50 mL) dried over magnesium sulfate, filtered and evaporated to provide 183 mg of (R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid an yellow oil (0.52 mmol, 86%) and was used directly in the following reaction.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][NH2:24])(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:25]([O-:27])=[O:26]>C(O)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][N:24]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-chloro-3-nitrobenzenesulfonohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 78 mg of the title compound (77%) as a yellow solid in 73% purity by HPLC (Rt: 3.65, 5.39, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 503.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26](Cl)=[N:27]OS(C)(=O)=O)=[CH:24][CH:23]=1.CN(C)CCN(C)C.O>O1CCCC1>[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]2[NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:6][C:7]=3[N:27]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: CS(=O)(=O)ON=C(Cl)c1ccc(F)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc3[nH]c(-c4ccc(F)cc4)nc3c2)C1
Yield: 38.6 %

Procedure:
A solution of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (140 mg, 0.5 mol), 4-fluoro-N-(methylsulfonyloxy)benzimidoyl chloride (152 mg, 0.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (123 mg, 1.06 mmol) in tetrahydrofurane (0.8 ml) was shaken in a closed vial at 60° C. overnight. Water was added, and the mixture was extracted twice with ethyl acetate. The cobined organic layers were dried (MgSO4) and evaporated. Flash chromatography (10 g silica gel, 10 to 30% ethyl acetate in heptane) yielded a white solid (92 mg, 46%), MS (ISP): 398.2 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24][N:23]1[CH2:40][C:41](O)=[O:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:41](=[O:42])[CH2:40][N:23]2[CH2:24][CH2:25][CH2:26][C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:21])[CH2:11][CH2:10]1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenyl(piperidin-4-yl)methanol (0.13 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.42-7.48 (m, 4H), 7.16-7.35 (m, 16H), 4.63-4.71 (m, 1H), 4.20 (d, J=1.5 Hz, 2H), 3.77-3.84 (m, 1H), 3.42-3.54 (m, 2H), 2.97-3.06 (m, 1H), 2.57-2.68 (m, 4H), 1.74-1.87 (m, 2H), 1.46-1.64 (m, 3H), 1.29-1.42 (m, 2H); MS (ESI+) m/z 559 (M+H)+.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CCN=C=NCCCN(C)C.[NH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].S(C1C=CC(C)=CC=1)([O-])(=O)=O.CN1CCOCC1>C(Cl)(Cl)Cl.C(#N)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
Boc-Gly-OH (17.52 g, 0.1 mole) in a mixture of CHCl3 (50 ml) and acetonitrile (50 ml) was cooled to -15° C. and EDCI (19.17 g, 0.1 mole) was added and stirred for 20 minutes. To this, a pre-cooled solution of H-Gly-OBzl.tosylate (37.1 g, 0.11 mole), NMM (12.09 ml, 0.11 mole) in CHCl3 (100 ml) was added and stirred overnight at room temperature. After removing the solvent, the residue was taken in CHCl3 and extracted with acid and base. Chloroform was removed under reduced pressure, triturated with pet. ether, filtered, washed with pet. ether and dried to obtain 30.2 g of I (yield: 93.7%), m.p. 82°-83° C. Rf2, 0.52; Rf4, 0.82. Anal. Calcd. for C16H22N2O5 : C, 59.61; H, 6.88; N, 8.69%. Found C, 59.43; H, 6.88; N, 8.35%