Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>ClCCl>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
200 ml of dichloromethane then 10 ml, i.e. 7.26 g (71.7 mmol) of triethylamine were added to 5 g (29.5 mmol) of 2-aminoindan hydrochloride. The mixture was stirred for 30 min, then 3.4 ml, i.e. 3.84 g (35.4 mmol) of ethyl chloroformate were added dropwise. The mixture was stirred for 30 min, then ice-water and an excess of 1N hydrochloric acid were added. The precipitate was filtered, washed, dried and purified by chromatography on a silica gel column, eluted with an 80:20 mixture of dichloromethane/ethyl acetate. 4.25 g of amorphous solid were isolated.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>>[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([Cl:5])=[C:7]([S:14]([N:17]2[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:8]=1[OH:13])=[O:34]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Yield: 28.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (62 mg, 0.18 mmol) and 2-bromophenylisocyanate (44 mg, 0.22 mmol) were coupled to form the desired urea (28 mg, 29%). LC-MS (m/z) 539.8 (M+).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][O:15][C:16]1[C:36]([O:37][CH3:38])=[CH:35][C:19]([CH2:20][O:21][C:22]([N:24]([CH3:34])[C@@H:25]([CH2:29][S:30][S:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[O:23])=[C:18]([N+:39]([O-:41])=[O:40])[CH:17]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:14][O:15][C:16]1[C:36]([O:37][CH3:38])=[CH:35][C:19]([CH2:20][O:21][C:22]([N:24]([CH3:34])[C@@H:25]([CH2:29][S:30][S:31][CH2:32][CH3:33])[C:26]([O:28][CH2:2][C:3]#[N:4])=[O:27])=[O:23])=[C:18]([N+:39]([O-:41])=[O:40])[CH:17]=1
Reactant: CCSSC[C@@H](C(=O)O)N(C)C(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCSSC[C@@H](C(=O)OCC#N)N(C)C(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
2-Bromoacetonitrile (0.115 ml, 1.65 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.105 ml, 0.604 mmol) were added to a solution of (R)-2-((((4,5-dimethoxy-2-nitrobenzyl)oxy)carbonyl)(methyl)amino)-3-(ethyldisulfanyl)propanoic acid (Compound 2k-F) (238 mg, 0.549 mmol) in DMF (2.5 ml), and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford (R)-cyanomethyl 2-((((4,5-dimethoxy-2-nitrobenzyl)oxy) carbonyl)(methyl)amino)-3-(ethyldisulfanyl)propanoate (Compound 21-F) (221 mg, 85%).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O>CC(C)=O.C(OCC)(=O)C>[Cl:8][CH2:9][C:10]1[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: CC(=O)NC(N)=S
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C

Procedure:
A mixture of acetylthiourea (591 mg, 5 mmol) and 1,3-dichloroacetone (667 mg, 5.25 mmol) in acetone (15 mL) was heated at reflux for 7 hours, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography to give the title compound. MS (DCI) m/e 191 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 12.21 (s, 1H), 7.22 (s, 1H), 4.70 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:23]=[CH:24][C:18]=3[N:17]=2)=[C:11]([Cl:37])[CH:10]=1)(C)(C)C.Cl>C1(OC)C=CC=CC=1.O1CCOCC1>[Cl:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])[CH:10]=[C:11]([Cl:37])[C:12]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]3[O:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[N:28][N:29]=3)[CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 100 ml rbf was added 0.090 g (0.157 mmol) of 3-(3,5-Dichloro-4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-phenyl)-propionic acid tert-butyl ester, a few drops of anisole, and 3 mL 4M HCl in 1,4-dioxane. The purple solution was allowed to stir at r.t. for 72 h. The reaction mixture was concentrated and the residue purified by basic HPLC (ACN/0.005 mM H2O—NH4OH, 2.5:7.5 to 8:2) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (t, J=7.45 Hz, 2 H) 3.07 (t, J=7.33 Hz, 2 H) 7.75 (s, 2 H) 7.84-7.89 (m, 2 H) 7.99 (d, J=7.45 Hz, 1 H) 8.20 (dd, J=8.46, 1.39 Hz, 1 H) 8.32-8.37 (m, 2 H) 8.56 (br. s., 1 H). MS (m/z) 515.0 M (+1) tR=1.19, Meth 10
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][S:9]([CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:2]=1.CO/[CH:20]=[CH:21]/[C:22]([O:24][Si](C)(C)C)=[CH2:23]>C1(C)C=CC=CC=1>[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][S:9]([N:8]1[CH:20]=[CH:21][C:22](=[O:24])[CH2:23][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:11])=[O:10]
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: C[Si](C)(C)CCS(=O)(=O)N=Cc1cccnc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)N1C=CC(=O)CC1c1cccnc1
Yield: 39.6 %

Procedure:
To a solution of 2-trimethylsilyl-ethanesulfonic acid pyridin-3-ylmethyleneamide (665 mg) in toluene (4.5 mL) was added Danishefsky's diene (0.46 mL, 2.4 mmol) under Ar atmosphere. The mixture was heated at reflux for 90 minutes. The toluene was removed in vacuo and the residue was dissolved in dichloromethane (ca. 10 mL) and treated with 2N HCl (ca. 10 mL) for 5 minutes. 10% Aqueous sodium bicarbonate was added carefully to adjust to pH 8. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure. Purification of the residue by flash chromatography (gradient hexane/ethyl acetate) gave 1-(2-trimethylsilyl-ethanesulfonyl)-2,3-dihydro-1H-[2,3′]bipyridinyl-4-one (322 mg, 40% overall).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH2:13])[CH3:9]>CO>[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:13][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[CH3:9]
Reactant: CCN(CC)CCN
Reactant: O=C1NC(=S)CS1
Solvent: CO
Product: CCN(CC)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (5.32 g) in methanol (200 mL) was added N,N-diethylethane-1,2-diamine (6.17 mL). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.44 g).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>[OH-].[Na+].O1CCOCC1.C(OCC)(=O)C>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[C:18]([OH:20])=[O:19])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81024.5 %

Procedure:
Nε -Carbobenzyloxy-L-lysine (30.0 g, 0.107 mmol) was dissolved in a solution of 2N NaOH (60 mL) and dioxane (150 mL) under nitrogen. After about 15 minutes at room temperature, the mixture was cooled to about 0° C. and subsequently treated with additional 2N NaOH (60 mL) and p-toluenesulfonyl chloride (20.4 g, 0.107 mmol) in 5 g portions over about 15 minutes. The mixture was stirred at about 0° C. for about 1 hour and at room temperature for about 18 hours before it was neutralized to pH 6 with 1N HCl. The mixture was then diluted with ethyl acetate and the organic phase was separated and washed with brine. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases were treated further as mentioned above. Following drying and solvent evaporation of the combined organic phases, the residue was first pre-columned on silica gel (elution with 10% methanol in dichloromethane) and subsequently recrystallized from ethyl acetate/hexanes (2:1) to give 37.67 g (81%) of the title compound as a white solid, m.p. 120°-121° C.; 1H NMR (CDCl3) δ 8.37 (v br s, 0.5H), 7.71 (d, J=8.0 Hz, 2H), 7.32 (s, 5H), 7.23 (d, J=7.6 Hz, 2H), 6.49 and 4.89 (2m, 1H), 5.73 (d, J=8.4 Hz, 1H), 5.10 and 5.04 (2s, 2H), 3.91 (m, 1H), 3.17-3.02 (m, 2H), 2.35 (s, 3H), 1.73-1.66 (m, 2H), 1.40-1.24 (m, 4H); 13C NMR (CDCl3) ppm 199.88, 175.06, 174.57, 158.37, 156.89, 143.66, 136.86, 136.32, 129.66, 128.54, 128.10, 127.19, 67.47, 66.89, 55.28, 40.95, 40.44, 32.25, 29.10, 28.75, 21.77, 21.46; IR (KBr, cm-1) 3382, 3264, 2950, 1738, 1656 1550, 1334, 1286, 1160, 1092, 818, 678, 568; MS m/z (MH+) 435.1590, obsd 435.1595.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21](C)(C)[O:22][SiH2]C(C)(C)C)[CH:15]=1)[CH:10]1[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][OH:22])[CH:15]=1)[CH:10]1[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)C1CC1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
Aq. 1M NaOH (16 mL) was added to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (700 mg, 1.64 mmol) in MeOH (32 mL). The mixture was heated to reflux for 2 h, and was allowed to cool to rt. The solvents were partially removed under reduced pressure, and the resulting aq. layer was diluted with water (100 mL). The mixture was extracted with Et2O (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 40:60) yielded the title compound (550 mg, quantitative yield). LC-MS: tR=0.98 min; ES+: 312.04.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CS(C)=O.Br[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[Br:25]>C1(C)C=CC=CC=1>[Br:25][C:24]([F:27])([F:26])[C:23]([F:29])([F:28])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[Br:25])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(=Cc1ccc(OC(F)(F)C(F)(F)Br)cc1)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Temperature: 24 °C
Yield: 42 %

Procedure:
4,4'-bis(hydroxy)-α-methylstilbene (100.0 g, 0.442 mole) is added to a 3 liter, 4 necked round bottomed flask along with DMSO (dimethylsulfoxide) (1150 ml) and toluene (350 ml). The resulting mixture is deoxygenated with nitrogen for 15 minutes, then KOH (58.4 g, 0.884 mole as 85 percent pellets, the remaining 15 percent being water) is added all at once. The mixture is stirred and heated to reflux, and water is removed azeotropically by distillation of the water/toluene azeotrope for a total of 10 hours. A Soxhlet extractor containing a drying bed of anhydrous Na2SO4 is placed on the reactor, and the toluene is refluxed through this drying bed to remove residual water. Toluene (260 ml) is removed by simple distillation, then the remaining mixture is cooled to 24° C. 1,2-Dibromotetrafluoroethane (276 g, 1.06 mole) is added slowly over 30 minutes, and the reaction mixture is stirred at 24° C. for 8 hours. After filtration and evaporation, the residue is flushed through a column of alumina using hexane as the eluent. Hexane is removed by evaporation, and the resulting residue weighs 109.4 g (0.19 mole) for an isolated yield of 42 percent.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11](OC(OCC)CBr)[CH3:12]>>[Br:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]2[N:9]([CH:11]=[CH:12][N:1]=2)[CH:8]=1
Reactant: CCOC(CBr)OCC
Reactant: N#Cc1cc(Br)cnc1N
Product: N#Cc1cc(Br)cn2ccnc12
Yield: 32 %

Procedure:
Prepared from 2-amino-5-bromo-nicotinonitrile (example C.23 step 1) (26 g, 131 mmol) and bromoacetaldehyde diethyl acetal (90%, 45 mL, 263 mmol) as described in example C.20 step 1. Obtained the title compound as a light brown solid (9.3 g, 32%). MS (ISP) 222.1 [(M+H)+], 224 [(M+2+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.C1(C2C3C([N:27]4[CH2:32][CH2:31][CH2:30][C@H:29]([C:33](=[O:43])[CH2:34][P:35]([O:40]CC)([O:37]CC)=[O:36])[C@@H:28]4[C:44]([O:46]C(C)(C)C)=[O:45])=CC=CC=3C3C2=CC=CC=3)C=CC=CC=1.C(=O)([O-])O.[Na+].C[Si](Cl)(C)C>C(#N)C.O.CO.C(O)(C)C>[P:35]([CH2:34][C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][NH:27][C@H:28]1[C:44]([OH:46])=[O:45])=[O:43])([OH:37])([OH:40])=[O:36]
Reactant: CCOP(=O)(CC(=O)[C@H]1CCCN(c2cccc3c2C(c2ccccc2)c2ccccc2-3)[C@H]1C(=O)OC(C)(C)C)OCC
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CC(C)O
Product: O=C(CP(=O)(O)O)[C@H]1CCCN[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Mix trifluoroacetic acid (30 mL) with acetonitrile (10 mL) and add, by dropwise addition, to an ice-cold solution of N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, tert-butyl ester (3.5 g, 5.8 mmol) in acetonitrile (40 mL) and water (4 mL). Stir for 15 minutes, warm to room temperature and stir for an additional hour. Pour into saturated aqueous sodium hydrogen carbonate (500 mL) and extract into ethyl acetate (3×200 mL). Evaporate to a residue and take up the residue in acetonitrile (20 mL) and methylene chloride (20 mL). Place under a nitrogen atmosphere and add trimethylsilyl chloride (5 mL, 35 mmol). Stir overnight then add water. Stir for 15 minutes then blow to a residue with a stream of dry nitrogen. Take up the residue in water (100 mL) and wash with toluene (5×100 mL). Freeze dry to give a residue. Take up the residue in methanol (10 mL) and isopropanol (5 mL). Add propylene oxide (5 mL) and filter to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH:5]([C:10]1[CH:11]=[C:12]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[C:33]([C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[CH3:32])[CH:26]=1)[CH2:22][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:47])=[O:3])[CH:11]=[C:12]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][CH:38]=3)[CH:13]=2)[CH2:17]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2)c1
Temperature: 78 °C

Procedure:
To compound 52a, 2-{5-[1-(3,5-Di-tert-butyl-benzyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester (85.3 mg, 0.13mmol) in EtOH (6.6 ml) was added 2M KOH (0.66 ml, 1.3 mmol). The reaction was heated to 78° C. for 1 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (50.0 mg, 58%). 1H NMR (300 MHz, MeOD) δ ppm 0.95 (d, J=6.41 Hz, 6 H) 1.34 (s, 18 H) 1.40-1.56 (m, 1H) 1.61-1.71 (m, 1 H) 1.89-2.14 (m, 5 H) 3.01-3.25 (, 3 H) 3.50-3.61 (m, 2 H) 3.73-3.78 (m, 1H) 4.29-4.40 (m, 2 H) 7.30-7.39 (m, 2 H) 7.48 (s, 1 H) 7.57 (d, J=1.88 Hz, 2 H) 7.73-7.82 (m, 4 H) Calcd for C39H50F3NO2 (M+H) 621.82, Found 622.5.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(NCO)c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCl)c1ccccc1C(F)(F)F
Yield: 100.6 %

Procedure:
To 15.50 g of N-hydroxymethyl-2-(trifluoromethyl)benzamide in 200 ml of dichloromethane, 16.83 g of thionyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the precipitated solid was washed with 50 ml of hexane to obtain 16.90 g of the desired product as white crystals.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][O:57][P:58]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)(=[O:60])[O-:59]>CN(C=O)C.C(N(CC)CC)C>[OH:60][P:58]([C:61]1[CH:62]=[C:63]([NH:67][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:64]=[CH:65][CH:66]=1)([O:57][CH3:56])=[O:59]
Reactant: COP(=O)([O-])c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COP(=O)(O)c1cccc(NC(=O)CC[C@H](N)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OtBu (303 mg, HOAt (136 mg, 1 mmol) and HATU (380 mg, 1 mmol) were dissolved in 1 mL of DMF, and triethylamine (0.278 ml) was added thereto. 10 minutes later, the mixture of monomethyl(3-aminophenyl)phosphonate and dimethyl ester was added thereto and stirred at room temperature overnight. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[Cl:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].C(N(CC)CC)C>O1CCCC1>[Cl:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: Cc1c(Cl)cccc1CN
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2cccc(Cl)c2C)c(=O)c1=O
Yield: 89.8 %

Procedure:
Tetrahydrofuran (10 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol, Example 3), 3-chloro-2-methylbenzylamine hydrochloride (0.96 g, 5.0 mmol, Example 96, Step 1), and triethylamine (0.51 g, 5.0 mmol) were stirred together at room temperature for 65 hours. Processing the reaction mixture as in Example 96, Step 2 provided 1.44 g of a white solid. Two recrystallizations of the crude product from methanol gave 1.12 g of the title compound as a fluffy, white solid: mp 236°-237° C. (softens 233° C.). MS (m/z) 321/323 ([M+H]+). HPLC indicates a major component (99.6%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[C:27]([O:33]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:41]CC2C=CC=CC=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[C:27]([OH:33])=[CH:26][C:25]=2[OH:41])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCNC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Yield: 68 %

Procedure:
Pd(OH)2/C (0.01 mmol) was added to the intermediate obtained in Step F (0.1 mmol) dissolved in EtOH (5 ml) and the resulting mixture was subjected to hydrogenation under one atmosphere of hydrogen for 1 hour. The catalyst was filtered off through a Celite® pad and the ethanol was removed under reduced pressure. The reaction mixture was purified by column chromatography (DCM/MeOH:90/10) to obtain the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F-].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(#N)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:10][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=2)=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=Cc1ccc(O)cc1O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1O
Temperature: 90 °C

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (6.62 g, 48 mmol, Fluka), potassium fluoride (5.57 g, 96 mmol, Aldrich) and 4-chlorobenzyl chloride (13.50 g, 84 mmol, Aldrich) in acetonitrile (50 mL) was heated at 90° C. for 24 hours. After cooling, the mixture was partitioned between ether (2×100 mL) and water (2×100 mL). Organic layers were washed with brine (100 mL), combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 75S, hexanes, then hexanes-dichloromethane 1:1 as solvent) to give partial separation. Pure fractions of product were combined and concentrated and the residue crystallized from hexanes with traces of dichloromethane to give 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde as white crystals. (Yield 4.74 g). Mother liquor and impure fractions were combined and further purified by flash chromatography (Biotage 40L, same solvent as before) and pure fractions were combined and concentrated. The residue was re-crystallized to give second crop of 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde. (Yield 3.03 g).