Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[CH:54][N:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]2[CH:61]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=2)=[CH:54][N:53]=1
Reactant: COc1ncc(-c2cccc(N)c2)c(OC)n1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c(OC)n1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,4-dimethoxy-pyrimidin-5-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.019 g of product in 69% yield: LCMS (ESI) m/z 434 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[F:10][CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][F:10])=[CH:4][C:3]=1[CH3:9]
Reactant: OCCF
Reactant: Cc1cc(O)ccc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCCF)ccc1Br
Reaction time: 8 h

Procedure:
A solution of 4-bromo-3-methyl-phenol (3.74 g, 20 mmol), 2-fluoro-ethanol (2.29 mL, 22 mmol), and triphenylphosphine (5.77 g, 22 mmol) in dry THF (15 mL) was cooled to 0° C. under stirring. Diethyl azodicarboxylate (40% in toluene, 10 mL, 22 mmol) was added and the reaction mixture was allowed to come to RT overnight. After 18 h at RT the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography eluting with DCM/petroleum ether 1:6 to afford the title compound as colourless oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])C(O)=O)[CH3:2].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:26][C:27]1[C:28]([OH:38])=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[C:30]([Cl:33])=[CH:31][CH:32]=1.C[N:40]([CH:42]=[O:43])C>>[Cl:33][C:30]1[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])=[C:28]([OH:38])[C:27]([NH:26][C:42]([NH:40][CH:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[O:43])=[CH:32][CH:31]=1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CCC(CC)C(=O)O
Reactant: CN(C)C=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CCC(CC)NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a solution of 2-ethylbutyric acid (0.125 mL, 1.0 mmol) in DMF (0.5 mL) was added DPPA (0.25 mL, 1.2 mmol) and TEA (0.25 mL, 1.8 mmol) and the reaction heated at 70° C. After 18 hrs, 3-Amino-6-chloro-2-hydroxy-benzenesulfonamide (1.0 mmol) was added and the reaction heated at 70° C. After 18 hrs, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and concentraed under reduced pressure. The crude residue was purified via HPLC to give 51 mg (15%) of 6-Chloro-3-[3-(1-ethyl-propyl)-ureido]-2-hydroxy-benzenesulfonamide. LC-MS (m/z) 336 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CC(C)(C)CN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2c(NCC(C)(C)C)nc(Cl)nc12
Reaction time: 3 h
Yield: 94 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 179 mg (2.1 mmol) of neopentylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 355 mg (yield: 96.1%) of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[H][H]>C1COCC1.[Pd]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a hydrogenation reactor, (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate (3B; 25 g, 56 mmol) was dissolved in THF (200 mL), and 15 mL of 4N HCl was added to the reaction mixture. Then, 10% Pd/C (2.5 g) was added to the reaction mixture. Hydrogen was introduced into the reactor until pressure reached 4 MPa. The reaction was stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with THF. The pH of the solution was adjusted to about 7 by adding saturated NaHCO3 (aq) while the solution was on an ice bath. The organic layer was separated, and the aqueous layer was washed with CH2Cl2 (2×15 mL). The combined organic fractions were dried with anhydrous Na2SO4 to give a solution of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-aminophenyl)propanoate 3C. The solution was used directly in step 3.
Reaction SMILES: N#N.[C:3]([CH2:22][CH2:23][S:24][CH2:25][CH2:26][NH2:27])([C:6]([C:9]([C:12]([C:15]([C:18]([F:21])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4].CN(C)C.Cl[C:33](OCC)=[O:34].C[Si](Cl)(Cl)Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:3]([CH2:22][CH2:23][S:24][CH2:25][CH2:26][N:27]=[C:33]=[O:34])([C:6]([C:9]([C:12]([C:15]([C:18]([F:19])([F:20])[F:21])([F:16])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]
Reactant: CCOC(=O)Cl
Reactant: NCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)C
Agent: C[Si](Cl)(Cl)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C=NCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 95 %

Procedure:
In a 500 mL three neck flask (with mechanical stirrer, temperature probe, dropping funnel —N2), containing dry toluene (350 mL), one equivalent of each of the C6F13C2H4SCH2CH2NH2 (0.1 mol) and trimethyl amine (0.1 mol) were added. The mixture was cooled to 0° C. Ethyl chloroformate (0.11 mol) was added dropwise within 20 min. The mixture was allowed to warm to room temperature while stirring was continued. A second equivalent of triethyl amine was added followed by the dropwise addition of methyl trichlorosilane (0.12 mol) at 30-40° C. (addition time about 20-30 min). The dropping funnel was replaced with a reflux condenser. The mixture was heated to 100° C. for 1 h (less than the reflux temperature of toluene). After the mixture was cooled to ambient temperature the precipitated ammonium salts were filtered into a flask using a glass frit. Under steady N2 flow, both toluene and generated ethoxy methyl dichlorosilane were distilled off at 200 mm Hg (266.6×102 Pa). The collected organic by-product was treated with dilute aqueous bicarbonate solution to quench the silane. The residue was dried at 2 mm Hg (2.67×102 Pa) using a dry-ice cooled trap to furnish C6F13C2H4SCH2CH2NCO in 95% yield as a light red-brown liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]2)[C:7]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:6]=2[N:5]=1)[CH3:3].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:1][C@H:2]([C:4]2[N:8]([C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:7]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:6]=3[N:5]=2)[CH3:3])[N:27]=[CH:26][N:25]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
A mixture of 2-{(S)-3-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]piperidin-1-yl}ethanol (35.6 mg, 0.12 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (18 mg, 0.12 mmol), and DIPEA (40 μL, 0.23 mmol) in IPA (1 mL) was stirred at 90° C. for 3 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording 285 as a colourless solid (17 mg, 35%). LCMS (Method K): RT 2.24 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.06 (1H, s), 7.58 (1H, dd, J=8.9, 5.0 Hz), 7.49 (1H, dd, J=9.6, 2.4 Hz), 7.01 (1H, dt, J=9.2, 2.4 Hz), 5.84 (1H, q, J=6.9 Hz), 4.70-4.61 (1H, m), 3.63 (2H, t, J=6.0 Hz), 3.17-3.12 (1H, m), 3.01-2.96 (1H, m), 2.83 (1H, t, J=11.0 Hz), 2.66-2.54 (2H, m), 2.39-2.24 (2H, m), 1.99-1.88 (2H, m), 1.86-1.77 (1H, m), 1.70 (3H, d, J=6.9 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1
Reactant: [H][H]
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A suspension of 3-[2,4-bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (300 m g) and palladium catalyst (50 mg, 10% palladium on carbon) in ethanol was stirred at ambient temperature under 1 atmosphere of hydrogen. After 16 hr, the mixture was filtered through celite and the filtrate was evaporated in vacuo. The product was dissolved in dichloromethane (15 ml). Celite and pyridinium chlorochromate (430 mg) were added and the mixture was stirred at room temperature. After 3 hr, the mixture was filtered through a pad of silica and eluted with petroleum ether/ethyl acetate (10:3, v/v), then purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 4:1 v/v) to furnish the title compound as an oil (200 mg, 70%). δH (CDCl3) 1.7-1.9 (2H, overlapping m), 2.05 (1H, m), 2.15 (1H, m), 2.35-2.60 (4H, overlapping m), 3.37 (1H, m), 3.490 (3H, s), 3.492 (3H, s), 5.15 (2H, s), 5.20 (2H, s), 6.70 (1H, dd), 6.82 (1H, d), 7.09 (1H, d).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[S:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[N:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[S:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nc(CCl)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 4-(chloromethyl)-2-(trifluoromethyl)thiazole (172 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (141 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([NH2:40])[CH2:38][CH3:39].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29]([NH:40][CH2:37][CH2:38][CH3:39])=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCCN
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 94 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (150 mg) was dissolved in chloroform (13 ml) and triethylamine (1.5 ml), and a solution of triphosgene (151 mg) in chloroform was then added to the solution. The mixture was heated under reflux for 5 min. Next, n-propylamine (33 mg) was added to the reaction solution, and the mixture was heated under reflux for additional 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was supported on diatomaceous earth, followed by extraction with chloroform. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (4/1) to give 178 mg (yield 95%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7](OC)=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O-].[Na+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C.C(O)C>[CH3:12][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:16]([C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])=[CH:4][C:3]=2[CH:6]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: C[O-]
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of the product of step (a) (130 g) in dry DMF (400 ml) was added dropwise to a solution of sodium methoxide (56.2 g) in ethanol (400 ml) mechanically stirred under nitrogen. After a further 20 mins, a solution of 2(bromomethyl)benzonitrile (182.2 g) in dry DMF (400 ml) was added dropwise. The mixture was then heated to 75° C. for 30 mins. The solution was allowed to cool for 1 h. A slurry of sodium methoxide (56.2 g) in dry DMF (100 ml) was added and the mixture heated at reflux for 1.5 h. The mixture was concentrated in vacuo and then poured into iced water. The solid was collected, and then triturated with methanol to give the title compound (Intermediate 8) as a beige solid (149.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:13]([O-])([OH:15])=[O:14]>>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Product: O=C(O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Here, 3,4-dichlorophenylacetic acid (66.7 g, 0.325 mol) is added in batches, with stirring at 5° C., to a mixture of fuming nitric acid (600 ml) and concentrated nitric acid (300 ml). The mixture is stirred for one hour while cooling is continued and the solution is allowed to rise to 20° C. over a period of a further 1.5 hours. The reaction mixture is poured onto ice, the precipitate is suction filtered, washed with ice water until neutral and then dried. Yield: 54.2 g. Mp: 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:6].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH:5]([OH:6])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1
Reactant: COc1ccc(OC)c(C(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(OC)c(C(O)c2cccc(N)c2)c1
Yield: 63.1 %

Procedure:
100 g of 2,5-Dimethoxy-3'-nitrobenzophenone was dissolved in 1.3 liters of ethanol. With the addition of a 10% palladium on carbon catalyst, the solution was charged in an autoclave, and hydrogenated for 8 hours at 130° C with an initial hydrogen pressure of 100 kg/cm2. The filtrate obtained on removal of the catalyst was concentrated to obtain white crystals. Filtration and air drying provided 57 g of the subject compound, which had a melting point of 132° to 134° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)c1
Yield: 75.7 %

Procedure:
A solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.80 g, 5.07 mmol), 1-bromoundecane (1.58 ml, 7.60 mmol) and potassium carbonate (1.05 g, 7.06 mmol) in DMF (15 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.90 g (yield: 75.7%)
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH3:9])[CH2:3][O:4][CH2:5][CH:6]1[CH2:8][O:7]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:9])[O:10][CH:6]([CH2:8][OH:7])[CH2:5][O:4][CH2:3]1
Reactant: CC(C)(O)COCC1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COCC(CO)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
2-methyl-1-(oxiran-2-ylmethoxy)propan-2-ol (620 mg, 4.24 mmol) and 10-CSA (300 mg, 1.29 mmol) were dissolved in DCM (30 mL) and stirred at ambient temperature for 24 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous phase was extracted four times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:2) to give the desired product as a colorless oil (400 mg, 64%>). Some starting material was recovered. 1H NMR (400 MHz, CDCl3) δ ppm 3.90-3.96 (1H, m), 3.76 (1H, dd, J= 11.2, 2.8 Hz), 3.56 (1H, dd, J= 11.6, 4.0 Hz), 3.46-3.50 (2H, m), 3.29 (1H, t, J= 11.2 Hz), 3.24 (1H, dd, J= 11.6, 1.2 Hz), 2.69 (1H, br s), 1.35 (3H, s), 1.13 (3H, s).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN1CCCC1=O.ClCC(Cl)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])=[O:18])=[CH:26][CH:27]=2)[C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:41])([F:28])[F:42])=[CH:32][CH:33]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)CC1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)CCl
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)C(=O)Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above resin bound (R)-3-{4-[(4-tert-butylcyclohexylamino)methyl]benzoylamino}-2-hydroxypropionic acid was added 1,2-dichloropropane (500 μL) and BSA (100 μL) and the mixture was vortexed at 25° C. for 1 hour followed by filtration. To the resin was added a solution of 4-(trifluoromethoxy)phenylacetic acid (400 μmol) in a mixture of N-methyl-2-pyrrolidinone, 1,2-dichloropropane and diisopropylethylamine (4.5:4.5:1, 1 mL) was added followed by a solution of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (400 μmol) in 1,2-dichloropropane (500 μL). The mixture was allowed to react for 3 hours at 50° C. and the resin was allowed to cool to 25° C. while washed with N-methyl-2-pyrrolidinone (4×1 mL), and DCM (10×1 mL) afforded the resin bound title compound.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 414).