Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20].O>CO>[OH:9][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC(O)CO
Solvent: O
Solvent: CO
Product: OCC(O)CNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C
Yield: 22.1 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.20 mol) and 1-amino-2,3-propanediol (5.46 g, 0.060 mol) was heated at 125° C. for 18 hours in an oil bath. After cooling, the reaction mixture was dissolved in 20 mL of methanol and the solution poured into 150 mL of water. The product separated from the solution as a viscous cream-colored oil that slowly solidified. The solid was collected by filtration and vacuum dried at 40° C. for 18 hours to give 3.81 g (66% yield) of material. The product was recrystallized from methanol-isopropyl ether to give 1.75 g; mp 161°-163° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](OC2C=CC=CC=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)C2C(=CC=CC=2)[NH:8]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN1C(=O)CCC1>[OH:1][C:2]1[C:3]([C:19]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)[C:3]2[C:2](=[CH:18][CH:6]=[CH:5][CH:4]=2)[NH:8]1
Reactant: O=C(Oc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Reactant: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 166.2 %

Procedure:
The phenyl 2-hydroxy-11H-benzo(a)carbazole-3-carboxylate obtained from Example I (5 grams, 14 millimoles), aniline (2.75 grams, 28 millimoles) and 15 milliliters of N-methyl pyrrolidinone were charged in a 100 milliliter 3-neck flask equipped with a magnetic stirrer and a nitrogen inlet. The resulting mixture was stirred and was heated to reflux at an oil bath temperature of ~250° C. under a nitrogen atmosphere. After 3 hours, TLC analysis revealed that all the starting phenyl ester was consumed. The mixture was cooled to room temperature and was poured into a 1 liter beaker containing 400 milliliters of ice cold 5 percent of HCl. The yellow precipitate obtained was isolated by filtration. After washing with water (~200 milliliters) and ~20 milliliters of methanol and vacuum drying, 4.7 grams of crude product resulted. This product was then recrystallized from a mixture of (dimethylformamide) DMF/MeOH/H2O (~30 milliliter each) yielding 4.1 grams (83 percent) of 2-hydroxy-11H-benzo(a)carbazole-3-carboxanilide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH3:15].CC[O-].[Na+]>CCO>[CH2:14]([O:16][C:17](=[O:23])[C:18](=[O:19])[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(CCC(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-methoxyphenyl)-2-butanone (14.9908 g, 84.2 mmol) and diethyloxalate (12.3434 g, 84.2 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 28.1 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred. After 10 min, the reaction completely solidified. An additional 100 mL EtOH was added, the reaction was placed on mechanical shaker overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 22. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 22. 1H (CDCl3, 400 MHz): δ 14.39 (11H, broad s), 7.10 (2H, d, J=7.1 Hz), 6.82 (2H, d, J=6.3 Hz), 6.34 (1H, s), 4.33 (2H, q, J=7.1 Hz), 3.77 (3H, s), 2.91 (2H, t, J=7.3 Hz), 2.78 (2H, t, J=7.3 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 202.53, 166.46, 162.29, 158.36, 132.36, 129.44, 114.20, 102.11, 62.75, 55.47, 43.02, 29.94, 14.27 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 55.47, 14.27; CH2 carbons: 62.75, 43.02, 29.94; CH carbons: 129.44, 114.20, 102.11 ppm. HPLC: 10.12 min. (Starting material: HPLC: 9.10 min.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][OH:13])=[CH:5]2.N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cc2cc(Br)ccc2[nH]1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To solution of 2-(5-bromo-1H-indol-2-yl)ethanol (11.37 g, 47.36 mmol) in DCM (150 mL) was added imidazole (4.0 g, 58.75 mmol). Reaction mixture was cooled to 0° C. before solution of TBSCl (8.60 g, 57.06 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was then diluted with DCM (150 mL), washed with H2O (100 mL) and NaCl (aqueous saturated, 100 mL) and the organic phase was dried over Na2SO4. The solvent was concentrated to afford 5-bromo-2-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-indole which was used directly in the next step. LC-MS 354.2/356.2 [M+H]+, RT 1.85 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: OCCCCc1ccncc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCc2ccncc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.086 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.261 g), stirred for 15 minutes and treated with the mesylate prepared from 0.906 g of 4-pyridinebutanol. The mixture was heated under argon at 60° C. for 4 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (hexane-acetone; 2: 1) to provide 0.58 g of alpha-oxo-4-[4-(4-pyridinyl)butoxy]benzeneacetic acid methyl ester as a colorless oil whose NMR was compatible with the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[OH-].[NH4+:14]>>[NH2:14][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)cc(N)n1
Reaction time: 8 h

Procedure:
2-chloro-6-methyl-4-(trifluoromethyl)pyridine (5.0 g) and conc ammonium hydroxide (150 mL) were heated at 180° C. in a steel reaction vessel with mechanical stirring overnight. The contents were allowed to cool and partitioned between CH2Cl2 and water. The CH2Cl2 layer was dried (MgSO4) and concentrated in vacuo leaving 2-amino-6-methyl-4-(trifluoromethyl)pyridine as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[S:14])=[CH:8][CH:7]=1)=O.C(I)C.CC(C)=O>O>[CH2:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[S:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1ccc(NC(=S)NCc2ccncc2)cc1)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCI
Solvent: O
Product: CCNc1ccc(NC(=S)NCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To 3.54 gms. (0.01 mole) of 1-(p-trifluoroacetamidophenyl)-3-(4-pyridylmethyl)-2-thiourea [prepared by reacting 1-(p-aminophenyl)-3-(4-pyridylmethyl)-2-thiourea (Example 19, supra.) with trifluoroacetic anhydride (method of Hickinbottom, Reactions of Organic Compounds, Longmans, London, 1963)] there is added 6.24 gms. (0.04 mole) of ethyl iodide in 50 ml. of dry acetone. Acetone is stripped and the residue added to 50 ml. of water. The aqueous mixture is warmed to reflux for about 30 minutes and then allowed to stand overnight. The mixture is then stripped of water to give 1-(p-ethylaminophenyl)-3-(4-pyridylmethyl)-2-thiourea.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.N1C=CC=CC=1>C(O)C.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: c1ccncc1
Product: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
10% Degussa Pd on carbon (15 mg, 0.4 mmol) was flushed with nitrogen then diluted in ethanol (2 mL). A solution of 4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine (100 mg, 0.35 mmol) in ethanol (2 mL) and pyridine (14 mg, 0.18 mmol) was subsequently added, and the mixture was flushed again with nitrogen prior to placing a hydrogen balloon on the flask. The mixture was stirred at rt overnight then filtered through Celite® and concentrated. The residue was dissolved in ethyl acetate and filtered through a silica gel plug, eluting with 50-100% ethyl acetate in hexanes, to give 4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine as a clear colorless oil (76 mg, 85%). 1H NMR (CHCl3-d) δ 8.57 (d, J=5.0 Hz, 1H), 7.47 (s, 1H), 7.26 (m, 1H), 6.93 (m, 2H), 6.65 (m, 2H), 3.92 (s, 2H), 3.57 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([CH3:16])([CH2:14][OH:15])[CH2:12]O.C(C=P(CCCC)(CCCC)CCCC)#N.O.O.[Sn](Cl)Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]1([CH3:16])[CH2:14][O:15][CH2:12]1)[NH2:8]
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: Cl[Sn]Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2ccc(N)cc2Br)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (0.145 g, 0.500 mmol) was dissolved in 2.5 mL of anhydrous benzene. Cyanomethylenetributylphosphorane (CMBP) (0.181 g, 0.750 mmol) was then added and the solution was allowed to stir at room temperature for 72 hours. The mixture was evaporated to dryness and then re-dissolved in 4 mL of EtOH. Tin(II) chloride dihydrate (0.564 g, 2.50 mmol) was then added and the resulting solution was heated at 70° C. for 1 hour. The mixture was cooled to room temperature and then quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were evaporated to dryness and purified by preparative LC/MS to yield 3-bromo-4-(3-methyloxetan-3-yl)aniline as a pale yellow oil (0.032 g, 32%) 1H NMR (400 MHz, CD3CN) δ 7.13 (dd, J=0.7, 1.8 Hz, 1H), 6.94-6.88 (m, 2H), 6.75 (br s, 2H), 4.98 (d, J=5.6 Hz, 2H), 4.51 (d, J=6.1 Hz, 2H), 1.74 (s, 3H). ESI-MS m/z calc. 241.0. found; 242.1 (M+1)+ Retention time 0.53 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](O)=[O:27])[CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH:14][C:26]([C:19]2[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=23)=[O:27])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c(N)cnn1C
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (0.100 g, 0.421 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (77.2 mg, 0.473 mmol, 1.12 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (269 mg, 0.519 mmol, 1.23 eq), N,N-diisopropylethylamine (0.15 mL, 0.86 mmol, 2.0 eq), and 4-dimethylaminopyridine (20.1 mg, 0.164 mmol, 0.39 eq) in 5.0 mL N,N-dimethylformamide was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 82.2 mg (51%) of N-(5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 9.31 (d, 1H), 8.67 (d, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.58 (d, 1H), 7.54 (s, 1H), 7.31 (d, 1H), 7.28 (d of d, 1H), 3.85 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C@H:15]2[CH2:18][C@@H:17]([NH:19]C(=O)OC(C)(C)C)[C:16]2([CH3:28])[CH3:27])[C:11]([C:29]#[N:30])=[CH:10][N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:19][C@H:17]1[CH2:18][C@@H:15]([NH:14][C:12]2[C:11]([C:29]#[N:30])=[CH:10][N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]3[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)[C:16]1([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@@H](N)C[C@H]1Nc1nc(NCCc2cccc(Cl)c2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of tert-butyl ((1R,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (82 mg, 0.17 mmol) in dry DCM (2 mL) was added trifluoroacetic acid (1.5 mL) dropwise under cooling in an ice-water bath. The resulting mixture was stirred at room temperature for 30 min. After removal of the organic solvent, the residue was neutralized with ammonia and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by standard methods to afford the title compound (34.3 mg, 0.092 mmol, 55% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.04 (s, 1H), 7.27-7.14 (m, 4H), 4.16-3.97 (m, 1H), 3.74-3.49 (m, 2H), 2.90-2.85 (m, 3H), 2.60-2.49 (m, 1H), 1.92-1.86 (m, 1H), 1.22 (s, 3H), 0.92 (s 3H). MS (ESI) m/z 371.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:39](N=C=NCCCN(C)C)[CH3:40].OC1C2N=NNC=2C=CC=1.C(O)C>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:30]([CH3:32])[CH3:31])[CH:33]([CH3:35])[CH3:34])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][CH2:39][CH3:40])=[O:22])=[CH:36][CH:37]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropanoic acid (2.0 g, 4.0 mmol) in 50 mL of dichloromethane is treated with 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (770 mg, 4.0 mmol), hydroxybenztriazole (540 mg, 4.0 mmol), and ethanol (220 mg, 4.8 mmol) and stirred at room temperature over 3 days. The reaction is concentrated in vacuo and purified by chromatography on silica gel (60 g) with 40-50% ethyl acetate/hexane as the eluent to afford ethyl 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2- methylpropanoate as a colorless foam.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.CS(Cl)(=O)=O.C(OCCCCCCCCOC1C=CC(C(O[C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=2[O:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64](=[O:67])[CH:65]=[CH2:66])=[CH:50][CH:49]=2)=[O:47])[C:39]([OH:41])=[O:40])=O)=CC=1)(=O)C=C.[F:68][C:69]1[CH:76]=[C:75]([OH:77])[CH:74]=[CH:73][C:70]=1[C:71]#[N:72]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:64]([O:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([C:46]([O:45][C:44]2[CH:43]=[CH:42][C:38]([C:39]([O:41][C:76]3[C:69]([F:68])=[C:70]([CH:73]=[CH:74][C:75]=3[O:77][C:39]([C:38]3[CH:42]=[CH:43][C:44]([O:45][C:46]([C:48]4[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64](=[O:67])[CH:6]=[CH2:7])=[CH:50][CH:49]=4)=[O:47])=[CH:36][CH:37]=3)=[O:40])[C:71]#[N:72])=[O:40])=[CH:37][CH:36]=2)=[O:47])=[CH:53][CH:52]=1)(=[O:67])[CH:65]=[CH2:66]
Reactant: CCN(CC)CC
Reactant: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2OC(=O)c2ccc(OCCCCCCCCOC(=O)C=C)cc2)cc1
Reactant: N#Cc1ccc(O)cc1F
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3ccc(C#N)c(F)c3OC(=O)c3ccc(OC(=O)c4ccc(OCCCCCCCCOC(=O)C=C)cc4)cc3)cc2)cc1
Temperature: -25 °C
Reaction time: 1 h
Yield: 456.2 %

Procedure:
0.9 g of triethylamine and then 0.5 g of methanesulphonyl chloride were added dropwise at -25° C. while stirring to a solution of 0.4 g of 3,4-bis(4-[8-acryloyloxyoctyloxy]phenylcarbonyloxy)benzoic acid in 40 ml of tetrahydrofuran. The reaction mixture was stirred at -25° C. for 1 hour, then treated with 0.06 g of 2-fluoro-4-hydroxybenzonitrile and 0.05 g of 4-(dimethylamino)pyridine in 40 ml of tetrahydrofuran, stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of diethyl ether each time. The organic phases were combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 1.2 g of 3,4-bis[4-(4-[8-acryloyloxyoctyloxy]phenylcarbonyloxy)phenylcarbonyloxy]-2-fluorobenzonitrile; m.p. (C-I) 85° C., cl.p. (N-I) 3° C.
Reaction SMILES: [NH:1]1[C:62](=[O:63])[C@@H:61]2[CH2:64][CH2:65][CH2:66][N:60]2[C:58](=[O:59])[C@H:47]([CH2:48][C:49]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][CH:50]=2)[NH:46][C:44](=[O:45])[C@H:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])[NH:35][C:33](=[O:34])[C@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:27][C:25](=[O:26])[C@@H:14]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[NH:13][C:11](=[O:12])[C@@H:2]1[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:67]1[CH:68]=[CH:69][C:70]2[NH:75][CH:74]=C(C[C@@H](N)C(O)=O)[C:71]=2[CH:72]=1.N1CCC[C@H]1C(O)=O>>[NH:1]1[C:62](=[O:63])[C@H:61]([CH2:64][C:65]2[C:71]3[C:70](=[CH:69][CH:68]=[CH:67][CH:72]=3)[NH:75][CH:74]=2)[N:60]([CH3:66])[C:58](=[O:59])[C@H:47]([CH2:48][C:49]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][CH:50]=2)[NH:46][C:44](=[O:45])[C@H:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])[NH:35][C:33](=[O:34])[C@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:27][C:25](=[O:26])[C@@H:14]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[NH:13][C:11](=[O:12])[C@@H:2]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CCCNC(=N)N)NC1=O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](Cc2c[nH]c3ccccc23)N(C)C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CCCNC(=N)N)NC1=O

Procedure:
Particularly preferred is cyclo[Tyr-D-Trp-Leu-Arg-Trp-Pro] where D-Trp is D-tryptophan and Pro is proline.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19](Cl)=[O:20])=[CH:16][C:15]=2[CH:22]=1.O>C1COCC1.C(OCC)(=O)C>[CH3:3][C:4]1[N:5]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([Br:10])=[CH:22][C:15]=3[CH:16]=2)=[O:20])[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cc2cc(Br)ccc2o1
Reactant: Cc1ccc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1C(=O)c1cc2cc(Br)ccc2o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
0.3 g of sodium hydride (60% suspension in paraffin oil) is introduced into 10 ml of THF and 0.5 mL [sic] of 2,5-dimethylpyrrole in 10 ml of THF is added dropwise (5 minutes). After stirring at 50° C. for 1 hour, a reddish suspension is present. 1.3 g of 5-bromobenzofuran-2-carbonyl chloride in 10 ml of THF is [sic] added dropwise at 25° C. (5 minutes) and the mixture is subsequently stirred for 2 hours. The addition of 100 ml of completely deionized water and 100 ml of ethyl acetate follows. The separated organic phase was additionally washed 2× with 100 ml of water and concentrated in vacuo. After chromatography on silica gel (eluent heptane/ethyl acetate 4:1), the residual oil gives 700 mg of yellow crystals (yield 44%), m.p. 115-116°.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:21]([O:23][NH2:24])[CH3:22]>C(N(CC)CC)C>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCCC(=O)C1=C(O)CC2(CCC(C)CC2)OC1=O
Reactant: CCON
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCC(=NOCC)C1=C(O)CC2(CCC(C)CC2)OC1=O
Yield: 86.2 %

Procedure:
The acylated compound (8.20) (1.00 g, 3.75 mmol) was oximated with ethoxyamine hydrochloride (0.39 g, 4.0 mmol) in the presence of triethylamine as described in Part (c) of the general procedure above, to afford the title compound (4.9) (1.00 g, 86%) as a mobile pale yellow oil. (Found: M, 309.196. C17H27NO4 requires 309.194.) 1H n.m.r. δ (CDCl3) 14.80, very broad s, 1H; 4.08, q, J 7 Hz, OCH2CH3 ; 3.00, t, J 7.5 Hz, CH2CH2CH3 ; 2.68, s, 2H5; 2.2-1.2 complex, 11H; 1.30, t, J 7.5 Hz, OCH2CH3 ; 1.15-0.7, m, CH2CH2CH3 & CH3.