Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][C:13](=[O:15])[CH3:14])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([NH:12][C:13](=[O:15])[CH3:14])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(=O)c1cccc(N)c1
Reaction time: 0.25 h

Procedure:
3-Nitro-N-(acetyl)phenylcarboxamide (200 mg) was dissolved in 60 ml of ethanol, treated with 200 mg of 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 30 psi for 15 minutes. The reaction mixture was filtered through Celite and concentrated to give the title compound in quantitative yield as a white solid.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C@@H:10]([C:16]2[C:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)=[CH:29][C:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[NH:22][C:18]=3[CH:17]=2)[CH2:9]1)(=O)C>CO>[OH:7][C@@H:8]1[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C@@H:10]([C:16]2[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:36][CH:37]=3)=[CH:29][C:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[NH:22][C:18]=3[CH:17]=2)[CH2:9]1
Reactant: CC(=O)O[C@H]1C[C@H](c2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(S(C)(=O)=O)cc2)N(C(C)=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1C[C@@H](O)C[C@@H]1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.015 ml of 25% sodium methoxide was added to a methanol (2 ml) solution of 40 mg of trans-1-(4-acetoxy-2-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 325, and the reaction liquid was stirred at room temperature for 10 minutes. The solvent was evaporated away under reduced pressure, and the residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([OH:22])[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([O:22][C:30](=[O:32])[CH3:31])[CH:20]=[CH2:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(OC(C)=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 3 °C
Reaction time: 2 h

Procedure:
To a solution of 19.1 g of 1-(1-benzenesulfonyl-1H-indol-2-yl)-allyl alcohol (74 mmol) in 244 ml dichloromethane were added 34 ml triethylamine and 0.7 g 4-dimethyl-aminopyridine. The solution was cooled to 3° C. To the magnetically stirred solution 23.5 ml of acetic anhydride qas added with a dropping funnel at a temperature below 5° C. The reaction mixture was stirred 2 h at 22° C. After cooling in an ice bath 250 ml of water was added at a temperature of 20 to 24° C. The mixture was vigorously stirred for 10 min. The phases were separated, and the water solution extracted with 250 ml of dichloromethane. The combined organic phases were extracted with 250 ml of water three times, and once with 250 ml of brine. The dichloromethane solution was dried on sodium sulfat and finally rotary evaporated (35° C., 50 mbar), yield 22.8 g. In the next step (the cyclocarbonylation) the resulting oil was used without purification (crude quality).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][NH:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].O>C1COCC1>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][N:5]1[CH2:6][C:2]([CH3:21])([CH3:1])[CH:3]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:18])([F:20])[F:19])[CH:10]=2)[C:4]1=[O:7])[CH3:33]
Reactant: CC1(C)CNC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
To a −78° C. stirring solution of 4-(4,4-Dimethyl-2-oxo-pyrrolidin-3-yloxy)-2-trifluoromethyl-benzonitrile (Compound (1), product of Example 3, Step E, 5.00 g, 16.8 mmoles) in 100 mL THF under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide (1 M in THF, 18.4 mL, 18.4 mmoles) and bromoacetic acid ethyl ester (2) (2.0 mL, 18.4 mmoles). The cooling bath was allowed to warm up to ambient temperature overnight. Water (25 mL) was added and the reaction mixture was concentrated in vacuo. Methylene chloride (100 mL) and water (50 mL) was added, the mixture is agitated and the layers are separated. The organic layer was concentrated in vacuo. The product (3) is used as is for the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccncc2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.1 mg, 34%) having the following characteristics.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7]
Reactant: CC(=O)OCC(=O)c1ncn2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CO)c1ncn2ccsc12
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
7-Acetoxyacetylimidazo[5,1-b]thiazole (24.6 mg) was dissolved in 2 ml of methanol and 0.5 ml of water. Potassium carbonate (17.3 mg) was added under ice cooling to the solution. The mixture was stirred for 45 min. Methanol was removed by distillation under the reduced pressure. Water (10 ml) was added to the residue, followed by extraction five times with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure to give 18.8 mg of 7-hydroxyacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O.CN(C=O)C>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][NH:21][C:18]([C:16]2[N:17]=[C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[S:14][CH:15]=2)=[O:20])[CH2:25][CH2:26]1
Reactant: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(NCCN1CCOCC1)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reaction time: 18 h

Procedure:
To a solution consisting of 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 172 mg, 0.61 mmol) in thionyl chloride (10 mL) was added one drop of dry DMF. The solution was heated at reflux for four hours and was subsequently allowed to reach room temperature and stirred for 18 hours. The thionyl chloride was evaporated away under reduced pressure and to the residue was added toluene (2×30 mL), which was evaporated and the residue subjected to high vacuum to remove residual thionyl chloride. The residue was dissolved in dichloromethane (10 mL) and 4-(2-aminoethyl)morpholine (51 mg, 0.051 mL, 0.40 mmol) was added followed by diisopropylethylamine (0.10 mL). The solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between water and diethyl ether. The organics were dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (100% dichloromethane to 9:1 v/v dichloromethane-methanol gradient) through a 40-g Silicycle® flash silica cartridge. The title compound was obtained as an off-white solid (63 mg, 61% yield); Rf 0.70 with 9:1 v/v dichloromethane-methanol; 1H-NMR (300 MHz; CDCl3) δ 9.30 (s, 2H), 8.51 (m, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H), 3.77 (t, 4H); 3.61 (dt, 2H), 2.64 (t, 2H), 2.54 (t, 4H); MS (ESI+) m/z 396 (M+1); H-PGDS FPBA IC50: 2.5 μM.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]([CH3:33])([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].[CH2:36](I)[CH3:37].[NH4+].[Cl-]>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]([CH3:33])([CH3:32])[CH2:23][N:24]([CH2:36][CH3:37])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN(CC(C)(C)COc1cccc2ccc(-c3nnc4ccccn34)nc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of tert-butyl 3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamate (50 mg, 0.11 mmol) in anhydrous DMF (2 mL) was added NaH (7 mg, 60%, 0.17 mmol). After stirring at ambient temperature for 20 min, ethyl iodide (27 μL, 0.34 mmol) was added and the mixture stirred for a further 5 hrs. The mixture was treated with saturated NH4Cl (20 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with water and brine and concentrated to afford a yellow gum. The residue was purified by flash column chromatography using gradient elution (CH2Cl2 to 1% MeOH/CH2Cl2 to 2% MeOH/CH2Cl2) to afford desired product (45 mg, 85%) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][CH2:21][CH2:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[O:24])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Product: O=C(NCC1CN(CCCC(=O)c2ccc(Cl)cc2)CCO1)Nc1ccc(Cl)cc1
Yield: 25.8 %

Procedure:
Example 41 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 4-chloro-1-(4-chlorophenyl)butan-1-one (0.0089 g) to give the title compound (0.0043 g). LC-MS (System A): Rt 2.83 mins, Mass Spectrum m/z 450 [MH+].
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[OH:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([OH:40])[CH:39]=1)[C:34]([OH:36])=O>>[OH:40][C:38]1[CH:37]=[C:33]([CH:32]=[C:31]([OH:30])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:36]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: Cl
Product: CN(C(=O)c1cc(O)cc(O)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dihydroxybenzoic acid followed according to example 12 by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dihydroxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 502 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[O:7]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (7.85 g, 22 mmol) in THF (10 mL) was added potassium tert-butoxide (1.0M solution in THF, 22 mL). After 30 minutes, 4-phenoxybenzaldehyde (3.96 g, 20 mmol) was added to the above mixture. The reaction was diluted with equal volume of hexane after 20 minutes and filtered through silica gel (80 g). The residue was rinsed and washed with 20% ether in hexane. Concentration of the filtrate in vacuo gave the crude product as an off white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C-:37]#[N:38].[Na+].C1OCCOCCOCCOCCOCCOC1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([C:37]#[N:38])[CH:3]=2)[CH:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])=[CH:35][CH:34]=1
Reactant: [C-]#N
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(Cl)cc1)c1cc(F)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(Cl)cc1)c1cc(F)cc(C#N)c1
Temperature: 100 °C

Procedure:
A mixture of N-[2-(3-bromo-5-fluorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Example 330, 92 mg, 0.16 mmol), sodium cyanide (12 mg, 0.24 mmol), 18-crown-6 (63 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol) in 2 mL dioxane was heated under nitrogen at 100° C. for 14 h. After cooling to room temperature, the resulting mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel eluting with 30% EtOAc in hexane to afford the title compound as a racemic mixture. 1H NMR (500 MHz, CD3OD): δ 8.26 (br s, 1H), 7.96 (d, 1H), 7.93 (dd, 1H), 7.30 (br d, 1H), 7.22 (s, 1H), 7.15 (br d, 1H), 7.06 (d, 2H), 7.05 (m, 1H), 6.74 (d, 2H), 4.24 (m, 1H), 3.05 (dd, 1H), 2.91 (m, 1H), 2.63 (dd, 1H), 1.74 (s, 3H), 1.72 (s, 3H), 0.83 (d, 3H). LC-MS: m/e 534 (M+H)+ (4.2 min).
Reaction SMILES: [CH2:1]([N:8]([C@H:13]([CH2:17][CH3:18])[C@H:14]([OH:16])[CH3:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@H:13]([CH2:17][CH3:18])[C@@H:14]([CH3:15])[O:16][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H]([C@@H](C)O)N(Cc1ccccc1)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]1[C@@H](C)OCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide (210 mg, 0.7 mmol) in THF (5 mL) was added to a suspension of NaH (89 mg, 3.7 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then quenched with saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded (5R,6R)-4-benzyl-5-ethyl-6-methylmorpholin-3-one. MS APCl calc'd for C14H19NO2 [M+H]+ 234. found 234.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:18]12[CH2:25][CH:24]1[CH2:23][O:22][CH2:21][C:20](=S)[NH:19]2.[NH3:27].C(OO)(C)(C)C>CO>[NH2:27][C:20]1[CH2:21][O:22][CH2:23][CH:24]2[C:18]([C:3]3[CH:4]=[C:5]([NH:8][C:9]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=4)=[O:10])[CH:6]=[CH:7][C:2]=3[F:1])([CH2:25]2)[N:19]=1
Reactant: O=C(Nc1ccc(F)c(C23CC2COCC(=S)N3)c1)c1ccc(Cl)cn1
Reactant: N
Agent: CC(C)(C)OO
Solvent: CO
Product: NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2COC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 132 %

Procedure:
To mixture of 5-chloro-pyridine-2-carboxylic acid [4-fluoro-3-((1SR,7RS)-3-thioxo-5-oxa-2-aza-bicyclo[5.1.0]oct-1-yl)-phenyl]-amide (intermediate B14A) (142 mg, 0.36 mmol) and 7 N ammonia in methanol (3.1 ml) in methanol (15 ml) at 23° C. was added tert-butylhydroperoxide (70% in water, 0.50 ml, 3.62 mmol) and the mixture was stirred at 23° C. for 20 h. The reaction mixture was extracted with water and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a light yellow oil (180 mg, 132%), which was purified by silica gel column chromatography with dichloromethane to dichloromethane/methanol/ammonium hydroxide 65:10:1 to give the title compound as a white solid (10 mg, 7.4%). MS (ISP): m/z=375.3 [(M+H)+] and 377.3 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
4-amino-3-nitrophenol (25 g, 162 mmol), 4-fluorobenzaldehyde (19.1 g, 154 mmol) and cesium carbonate (58 g, 178 mmol) were stirred in dimethylformamide at 85 degrees centigrade for 20 minutes and then 45 degrees Centigrade for approximately 18 hours. The reaction was allowed to cool to room temperature then filtered through celite and eluted with ethyl acetate. Water, brine and ethyl acetate were added to the filtrate which was then filtered through a glass wool packed Alltech 75 mL Extract-Clean™ filter column. The filtrate was separated into two portions and each was extracted with ethyl acetate then washed with brine four times. The organic layers were combined, dried over magnesium sulfate, concentrated onto basic alumina and purified by silica gel column chromatography (0 to 100% ethyl acetate in hexanes to give 23 g of 4-[(4-amino-3-nitrophenyl)oxy]benzaldehyde. (M+1) 259.0, 2.39 min (LC/MS method A)
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[O:14]COC)[CH2:4][O:3]1>C1COCC1>[O:12]=[C:10]1[O:11][C@H:7]([C@H:5]([CH2:4][OH:3])[OH:6])[C:8]([OH:14])=[C:9]1[OH:13]
Reactant: COCOC1=C(O)C(=O)OC1C1COC(C)(C)O1
Solvent: C1CCOC1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 0.17 h

Procedure:
251 mg of DIAD (1.25 mmol) is added to a solution of triphenylphosphine (326 mg, 1.25 mmol) in anhydrous THF (2 mL) cooled to −15° C. After 15 minutes, a white precipitate of Mitsunobu betaine is formed. Stirring is continued for 10 minutes, then a solution of 5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-3-hydroxy-4-methoxymethoxy-5H-furan-2-one (246 mg, 1.19 mmol) in THF (2 mL) is added followed by 400 mg of 1,1′,2-trisnorsqualenol (1.04 mmol) in 2 mL of THF. The mixture is stirred at −15° C. for 30 min, then the reaction mixture is left to return to room temperature, continuing stirring for an additional time of 2 h. The reaction mixture is then concentrated, the residue is taken up in 20 ml of ethyl acetate and the organic phase is washed successively with a saturated solution of sodium bicarbonate (3 ml) and then with saturated NaCl solution (3 ml). The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude mixture is purified by silica-gel flash chromatography, eluting with cyclohexane/EtOAc mixture (1:1) to give fully protected squalenyl ascorbic acid in the form of a colorless oil (438 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:25]([OH:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[N:10]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[N:68]=[CH:67][CH:66]=[CH:65][N:64]=3)=[CH:59][N:58]=2)[CH2:53][CH:52]1[CH3:69])=[O:50]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:25]([OH:27])[CH3:26])[CH2:24][CH2:23][N:22]([CH2:48][C:49]([N:51]5[CH2:56][CH2:55][N:54]([C:57]6[CH:62]=[CH:61][C:60]([C:63]7[N:64]=[CH:65][CH:66]=[CH:67][N:68]=7)=[CH:59][N:58]=6)[CH2:53][CH:52]5[CH3:69])=[O:50])[CH2:21]4)=[O:19])[CH:15]=3)[N:10]([C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC1CN(c2ccc(-c3ncccn3)cn2)CCN1C(=O)CCl
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC1
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(-c3ncccn3)cn2)CCN1C(=O)CN1CCC(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)(C(C)O)C1
Yield: 84.5 %

Procedure:
Added N—N-Diisopropylethylamine (0.3 ml, 1.72 mmol) to a mixture of 3-(1-Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (6N) (600 mg, 0.98 mmol) and 2-Chloro-1-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-ethanone (360 mg, 1.15 mmol) in DMF (10 ml) at room temperature. The solvent was evaporated and the residue extracted with MeCl2 (100 ml) and H2O (50 ml). The organic layer was separated, washed with saturated NaCl solution (20 ml), dried over MgSO4, filtered and solvent evaporated yielding 9N as a solid (750 mg, 84%) ESMS (MH, 906).