Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[N:6]([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:18])[CH:4]1[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:2].[O:30]1CCCC1>[Ag]=O.O>[C:1]([CH:3]1[N:6]([CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:18])[CH:4]1[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([OH:30])=[O:2]
Reactant: C1CCOC1
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1C=O
Agent: O=[Ag]
Solvent: O
Product: COC(=O)C(c1ccccc1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of methyl 2-(4-formyl-2-oxo-3-phthalimido-1-azetidinyl)-2-phenylacetate (0.38 g.), silver oxide(0.92 g), tetra-hydrofuran (9 ml.) and water (1 ml.) was stirred at ambient temperature for 40 hours. The insoluble materials were filtered off from the reaction mixture and the tetrahydrofuran was removed by distillation from the filtrate under reduced pressure. Water was added to the resultant residue and adjusted to pH 2 with 10% hydrochloric acid, whereafter the mixture was extracted with ethyl acetate. The extract was washed with 1% Aqueous sodium bicarbonate, and the washings were adjusted to pH 2 with 10% hydrochloric acid. The aqueous solution was extracted with ethyl acetate, whereafter this extract and the above-obtained extract were combined, washed with water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2-(4-carboxy-2-oxo-3-phthalimido-1-azetidinyl)-2-phenylacetate [a mixture of two cis isomers (a) and (b) at the third and fourth positions of the azetidine ring, (200 mg.)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([CH3:17])=[N:10]2)=[CH:5][CH:4]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CS(C)=O>[CH:18]1([NH:24][C:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(-n2nc(C)cc2C(=O)O)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(-n2nc(C)cc2C(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2-(4-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (752 mg, 3.24 mmol) was suspended in methylene chloride (25 mL) and DMSO (3 drops) was added. After the reaction was stirred at room temperature for 1 hour, it was concentrated in vacuo. The residue was diluted twice with methylene chloride (60 mL) and concentrated to dryness. The residue was diluted again with methylene chloride (45 mL), cyclohexylamine (650 μL, 5.68 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted further with methylene chloride, washed with NaOH (10%) and 1 N HCl, then dried over Na2SO4. Concentration gave 630 mg of the title compound, which was used in the next reaction without further purification. LC-MS (C18H23N3O2 calculated 313) m/z 314 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:37]2[S:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][CH2:36][N:30]([C:37]4[S:38][C:39]5[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=5[N:41]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@H:17]([C@H:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1)[CH3:18].Cl[C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)[N:31]=1>CN(C=O)C>[CH3:41][O:40][C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:26]([O:16][C@@H:17]([C@H:19]3[CH2:23][NH:22][C:21](=[O:24])[CH2:20]3)[CH3:18])[C:27]3[N:28]([N:42]=[CH:43][CH:44]=3)[CH:29]=2)[CH:37]=[CH:36][C:35]=1[O:38][CH3:39]
Reactant: C[C@H](O)[C@H]1CNC(=O)C1
Reactant: COc1ccc(-c2cn3nccc3c(Cl)n2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A solution of 1M sodium bis(trimethylsilyl) amide in THF (0.18 mL, 0.18 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)pyrrolidin-2-one 1.18 (22.9 mg, 0.18 mmol) in DMF (1 mL) at room temperature, forming a white precipitate. After 8 minutes, a solution of 4-chloro-6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazine 5.03 (34 mg, 0.12 mmol) in DMF (1.1 mL) was added under argon. Dark brown solution stirred at room temperature overnight. Mixture was quenched by addition of water, brine and ethyl acetate and layers were separated. Aqueous was extracted with ethyl acetate and combined organic layers were washed with 50% brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.04.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH2:11]([S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.0 g. (0.051 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 38 ml. of pyridine was added 6.4 g. (0.051 mole) of benzyl chloride portionwise with stirring at room temperature. The reaction was slightly exothermic, the temperature rising from 23° to 30°C. The reaction mixture was stirred at room temperature for 30 minutes, and then heated on the steam bath for one hour at 90°-95°C. The reaction mixture was then cooled to room temperature and poured into a mixture of ice and 80 ml. of concentrated hydrochloric acid. The gummy precipitate, thus formed, was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 7.7 g. (61%) of brown oil, which was crystallized from toluene, containing a little methylcyclohexane, to give 5.0 g. of yellow-brown crystals, m.p. 117°-126°C. Recrystallization of this substance from toluene gave the pure 3-benzylthio-4hydroxy-6-methyl-2-pyrone as cream colored crystals, m.p. 127.5°-128.5°C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:14])([F:13])[C@@H:10]([OH:12])[CH3:11].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]([F:14])([F:13])[C@@H:10]([O:12][C:16](=[O:17])[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[CH3:11]
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Triethylamine (2.3 mL) is added to a solution of 4-dimethylaminopyridine (13 mg), (S)-1,1,1-trifluoro-propan-2-ol (75% in tert-butyl methyl ether; 2.00 g), and 4-nitrophenyl chloroformate (2.90 g) in dichloromethane (80 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 30 min and then at room temperature overnight. The solution is washed with 10% aqueous K2CO3 solution and water and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane) to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([O-:22])=[O:21])O)=[CH:11][CH:10]=1.[Li+]>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C([O-])CC1(O)CCc2ccc(F)cc21
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a stirred, chilled (ice-methanol bath) suspension of lithium 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (0.5 g, 2.3 mmol) in dichloromethane (13.5 mL). After 15 min, the mixture was concentrated in vacuo and the resulting white solid was recrystallized from aqueous acetone to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as white crystals (0.32 g, 73%) identical to compound of Example 1i by mixed m.p., (203°-205° C.) and NMR.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2,2-dimethyl-propan-1-one was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with pivaloyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.98-2.03 (m, 4H), 3.06-3.14 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.40-4.46 (m, 2H), 5.09-5.15 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.39 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=458.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Si:1]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:13]2([CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][CH2:18]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC2(CCC(=O)CC2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CCC2(CCC(O)CC2)CC1
Yield: 31.1 %

Procedure:
To a solution of 9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-one (1.5 g) obtained in Step 3 in methanol (24 mL) was added sodium borohydride (0.17 g) under ice-cooling, followed by stirring the reaction mixture under ice-cooling for 0.5 hour. After addition of saturated aqueous citric acid solution, the reaction mixture was concentrated in vacuo, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:19 to 1:4) to give 9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-ol (0.47 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]([NH2:13])=[O:12])=[C:9]([N+:14]([O-])=O)[C:8]([CH2:17][CH3:18])=[N:7]1)[CH3:2].[H][H]>[Pt].C(OC(C)C)(=O)C>[NH2:14][C:9]1[C:8]([CH2:17][CH3:18])=[N:7][N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: CCOCCn1nc(CC)c([N+](=O)[O-])c1C(N)=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)OC(C)C
Product: CCOCCn1nc(CC)c(N)c1C(N)=O

Procedure:
1-(2-ethoxyethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide from step 1 (15.0 g, 58 mmol), 5% Platinum-on-carbon (0.75 g), and isopropyl acetate (150 mL) were combined and the mixture was stirred under 80 psi of hydrogen for about 50 hours. The mixture was then filtered through celite, the celite was rinsed with acetonitrile, and the filtrate was concentrated. The material eventually crystallized to give 13.7 g as a hydrate of the title compound.
Reaction SMILES: C([CH:3]1[C:8]2[S:9][C:10]([C:12]([OH:14])=O)=[N:11][C:7]=2[CH2:6][CH2:5][N:4]1/[C:15](/[S:23][CH3:24])=[N:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.CCN=C=NCCCN(C)C.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:12]([C:10]1[S:9][C:8]2[CH2:3][N:4]([C:15]([S:23][CH3:24])=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:5][CH2:6][C:7]=2[N:11]=1)=[O:14]
Reactant: CCC1c2sc(C(=O)O)nc2CCN1/C(=N/c1ccccc1)SC
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSC(=Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of ethyl 5-[(Z)-(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid obtained in step III (1 eq), mono Boc-protected o-phenylene diamine (1.2 eq), EDCI (1.2 eq), HOBt (1.2 eq) and triethylamine in DMF were stirred at room temperature for 15 h. Solvent was evaporated and the residue was treated with etheral HCl at room temperature for 5-15 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford methyl 2-[(2-aminophenyl)carbamoyl]-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)carbimidothioate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
0.27 g (0.001 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol and 0.359 ml (0.0025 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.16 ml (0.00125 mol) of 4-chlorobenzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.333 g (81.5%) of 1-(4-bromo-benzyl)-piperidin-4-yl 4-chloro-benzoate was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:13][CH:14]=1)=[O:17]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Combine 6-chloronicotinamide (4.53 g, 28.9 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.9 mmol), potassium carbonate (6 g, 43.4 mmol), and dimethylformamide (200 mL). Heat the reaction mixture to 130° C. under nitrogen, and stir for 18 h. Dilute the reaction mixture with 200 mL of water, extract with diethyl ether (4× 100 mL) and dichloroethane (2× 100 mL). Combine the organics, and dry over magnesium sulfate. Filter, and concentrate in vacuo. Adsorb the residue on silica, and purify by Biotage Flash 40L (elute with 50:50 hexanes/ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid (3.2 g, 46%): 1H NMR (DMSO-d6): 10.0 (s, 1H), 8.59 (d, 1H), 8.26-8.22 (dd, 1H), 7.98-7.95 (m, 2H), 7.10-7.07 (d, 1H), 6.15-5.65 (br m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([O:40][CH2:41][CH3:42])[CH:39]=1)[N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:18]=2)[C:10]1=[O:33])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:41]([O:40][C:38]1[CH:39]=[C:34]([C@@H:8]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[N:18]=3)[C:10]2=[O:33])[CH2:7][C:6]([OH:43])=[O:5])[CH:35]=[N:36][CH:37]=1)[CH3:42]
Reactant: CCOc1cncc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCc3cccc(NCc4ccc(OC)cc4)n3)C2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cncc([C@H](CC(=O)O)N2CCN(CCCc3cccc(NCc4ccc(OC)cc4)n3)C2=O)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 20-12 (0.028 g, 0.047 mmol) in dichloromethane (10 mL) was added TFA (1 mL). After 1 hour, the solvent was removed in vacuo and azeotroped twice with toluene (15 mL). The residue was chromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 20-13 as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(F)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC(C)(C)F)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
(Procedure B) A stirred mixture of the product from Example 7, Step II, (0.37 g, 0.00128 mol), the product from Step III above (0.298 g, 0.0141 mol), sodium bicarbonate (0.21 g, 0.0026 mol) and acetonitrile (11 ml) was refluxed for 5 hours and kept at ambient temperature for 18 hours. It was filtered and the solid was washed with acetonitrile. The filtrate was concentrated and the residue was chromatographed on silica gel with 10% MeOH--CH2Cl2 to give 0.332 g of the titled product, a compound of Formula I'. The mass spectrum had m/z 416 (M+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1>[Si:8]([O:7][CH2:6][CH2:5][C:4]1[C:3]([CH3:18])=[C:2]([CH:17]=[CH:16][CH:15]=1)[CH:26]=[O:27])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)cccc1CCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A colourless solution of (3-bromo-2-methylphenethoxy)(tert-butyl)dimethylsilane [Aromatic Intermediate 22, step c] (2.06 g) in THF (40 mL) was cooled to −78° C. under an atmosphere of nitrogen and treated with butyllithium (2.1M in hexanes, 3.3 mL), added dropwise over 3 minutes. The resulting pale yellow solution was stirred at −78° C. for 30 minutes, treated with N,N-dimethylformamide (0.73 mL) added dropwise over 2 minutes to give a colourless solution, stirred at −78° C. for a further 30 minutes, then removed from the cooling bath and allowed to warm to room temperature over 45 minutes. The solution was quenched by the addition of 10% aqueous ammonium chloride (100 mL), and the resulting mixture was extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the titled compound as a pale yellow oil. Yield 1.74 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.O[CH2:44][C@@H:45]([NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]([O:48][CH3:49])=[O:47]>C1COCC1>[F:32][C:33]([F:41])([F:42])[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:44][C@@H:45]([NH:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]([O:48][CH3:49])=[O:47])=[CH:38][CH:39]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](COc1ccc(C(F)(F)F)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (3 eq) in dry THF under Argon was added diethylazodicarboxylate (3 eq) dropwise. The reaction mixture was stirred at room temperature for 15 minutes before adding a solution of 4-(trifluoromethyl)phenol (3 eq in dry THF) dropwise. The reaction mixture was stirred at room temperature for 1 hour before adding (R)-methyl 3-hydroxy-2-(tritylamino)propanoate (LXXXIX) in dry THF in one portion. The reaction mixture was stirred at room temperature ovenight. The mixture was concentrated to dryness, treated with hexane and filtered. The residue was concentrated to dryness and purified by silica flash chromatography (EtOAc/hexane=1:5). Pure (R)-methyl 3-(4-(trifluoromethyl)phenoxy)-2-(tritylamino)propanoate (XC) was obtained as an off-white solid (50% yield).
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(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:50][NH:51][O:52][CH3:53]>C(Cl)Cl>[CH3:53][O:52][N:51]([CH3:50])[C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3×120 mL), H2O (3×120 mL), saturated NaHCO3 aqueous solution (3×120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 27 as a white solid (20 g, 80%), which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[N:36]=[C:37]=[O:38]>>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[NH:36][C:37]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=2)=[CH:20][CH:21]=1)=[O:38]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)c(OC)c1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 2,4-dimethoxyphenyl isocyanate (131 mg, 0.73 mmoles), the title compound was isolated as a white solid. Yield; 76 mg (36%); (M+H)=522.4