Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:29]1([CH2:28][N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@H:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:3]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (190 mg, 0.536 mmol) in dry DMF (2 mL) under nitrogen was added (bromomethyl)cyclopropane (108 mg, 0.800 mmol) and powdered cesium carbonate (264 mg, 0.810 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the combined organic extracts was purified by flash chromatography on silica gel eluting with 6:1 (v/v) hexane:ethyl acetate to afford the title compound (201 mg, 92%) as a white solid. TLC Rf=0.31 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.19 (m, 1H), 0.35-0.62 (m, 3H), 1.15 (m, 1H), 1.37 (s, 9H), 3.50 and 3.55 (dd, 1H, J=7.0 Hz), 4.12 and 4.17 (dd, 1H, J=7.0 Hz), 4.93 (m, 2H), 5.65 (d, 1H, J=7.0 Hz), 7.29 (m, 4H), 7.41 (m, 5H). MS APCI, m/z=309 (M-BOC). LC/MS: 3.08 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].P(I)(I)P(I)I>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: IP(I)P(I)I
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 4 h
Yield: 119.1 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 57 mg of diphosphorus tetraiodide and the mixture was refluxed with stirring in a water bath at 60° C. for 4 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 8.60 g (59.5%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥90%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.BrN1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C1=NCCc2ccccc21
Reaction time: 0.5 h

Procedure:
18.8 ml of 1,2,3,4-tetrahydroisoquinoline(0.15M) was dissolved in 400 ml of dichloromethane; and 29.4 g of N-bromosuccinimide(0.165M) was slowly added thereto at room temperature followed by stirring for 30 minutes. To this, 100 ml of aqueous sodium hydroxide(30%) was added and further stirred for an hour. The organic layer was separated, washed with water and extracted from aqueous hydrochloric acid solution. Ammonia water was added to adjust the pH to 9; and extracted from dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated to give 18.5 g of the title compound in oil form.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>C(OC(=O)C)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ccc1F
Yield: 85.4 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (2.0 g) in ethylacetate (50 mL) was added stannous chloride dihydrate (27.0 g). The mixture was brought to reflux for 1.5 h and allowed to cool. The mixture was partitioned between ethyl acetate and sodium bicarbonate (sat. in water). The aqueous phase was extracted with ethyl acetate four times. The organic phase was washed with 4×H2O, dried over sodium sulfate, filtered and concentrated to leave 4-fluoro-3-cyanoaniline (1.40 g). CI mass spectrum z (rel. intensity) 137 (M+H, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.C(OCC)(=O)C.Cl>[C:24]([O:23][C:21](=[O:22])[CH2:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
To a stirred solution of the methyl 4-(2-(aminomethyl)-4-(2-tert-butoxy-2-oxoethyl)phenoxy)benzoate (690 mg, 1.86 mmol) in dichloromethane (6 ml) was added pyridine (225 μL, 2.78 mmol) followed by methanesulfonyl chloride (287 μL, 3.71 mmol). The reaction was stirred at ambient temperature for 4 hours, after which time additional pyridine (1.5 eq) and methanesulfonyl chloride (2 eq) were added. The reaction was stirred for an additional hour and then diluted with ethyl acetate and 1M HCl. The aqueous layer was extracted with ethyl acetate and the combined organics washed with brine and dried over MgSO4. The crude product was then purified on the Biotage Horizon (40+M, 5% to 75% B:ethyl acetate) to give methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (0.754 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1ccccc1B(O)O
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (550 mg, 2.22 mmol) and 2-(methylthio)phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline. Mass Spectrum (ESI) m/e=336.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>CCOC(C)=O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
A solution of (trifluoro-p-tolyl)-acetic acid (19.85 g, 97.2 mmol) in EtOH (200 mL) was treated with H2SO4, 36N (16.4 mL, 194 mmol). The reaction was heated at reflux. After 48 hours, the reaction was cooled to 23° C., diluted with EtOAc (750 mL), washed with saturated NaHCO3 solution (2×400 mL) and brine (400 mL), dried over MgSO4, and concentrated in vacuo affording 20.98 g of ethyl 2-(4-(trifluoromethyl)phenyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+](C1C=C(S(O[CH2:36][C@@H:37]2[CH2:39][O:38]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][C:5]([O:12][CH2:36][C@@H:37]2[CH2:39][O:38]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (1.78 g, 5.5 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.43 g, 5.5 mmol) and cesiumcarbonate (2.15 g, 6.6 mmol) in NMP (15 mL) was stirred at room temperture overnight. Water was added to the mixture and it was then extracted with with ethyl acetate three times. The combined organinc layers was washed with water, dried over sodium sulphate and solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate/heptane 10-30%), (1.66 g, 79%) of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].Cl.[CH:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[CH:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:38])=[CH:35][CH:34]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(Cl)cc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. meythlene chloride is added 10.4 g. 4-(8-cyclohexyloctylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated an the residue is crystallized from diisopropyl ether.
Reaction SMILES: [CH:1]1([CH2:11][CH2:12]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[N:14]1([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.ClCCC1C2C(=CC=CC=2)C(C)CO1.C1(C[C@H]2COC(=O)N2C(=O)C(C2C=CC=CC=2)C)C=CC=CC=1>>[C@H:1]1([CH2:11][CH2:12][N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: OCCC1OCCc2ccccc21
Reactant: NS(=O)(=O)c1ccc(N2CCCNCC2)cc1
Agent: CC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: CC1COC(CCCl)c2ccccc21
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: NS(=O)(=O)c1ccc(N2CCCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure for EXAMPLE 48 and making non-critical variations (-)-2-(isochroman-1-yl)ethanol (LXXIX) and 4-(homopiperazin-1-yl)benzenesulfonamide (IV; prepared from 4-fluorobenzenesulfonamide (III) and homopiperazine (II, Aldrich) by the method of EXAMPLE 47 Step 1) give the title compound, MS (m/z) 415; [α]D -50° (c 0.9996, methylene chloride); IR (mineral oil) 1153, 1595, 1102, 1511 and 1316 cm-1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].O>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[N:18][OH:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C=NO)cc1OC1CCCC1
Temperature: 25 °C
Yield: 104.9 %

Procedure:
3-cyclopentyloxy-4-methoxybenzaldehyde (13.00 g, 59.02 mM) and hydroxylamine hydrochloride (8.46 g, 118.04 mM) were dissolved in pyridine (120 ml) and the resultant mixture was heated to reflux for 23 hours. The solution obtained was cooled to room temperature, water (100 ml) was added, then the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a green oily residue. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane). The solvent was removed in vacuo and the resultant product was dried to obtain 3-cyclopentyloxy-4-methoxybenzaldehyde oxime 14.57 g as a colorless oil. The 3-cyclopentyloxy-4-methoxybenzaldehyde oxime (14.57 g) thus obtained was dissolved in acetic acid (130 ml) and the resultant mixture was heated to reflux for 22 hours. The solution obtained was ice cooled, then a saturated sodium hydrogencarbonate solution was added to neutralize it. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain a red solid residue. The residue was purified by flash chromatography (SiO2: eluted by 25% ethyl acetate/hexane). The solvent was removed in vacuo and the result dried to obtain 3-cyclopentyloxy-4-methoxybenzonitrile 9.60 g (yield 75.2%) as a yellow-green oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH3:19]I.Cl>CN(C)C=O>[O:11]1[C:10]2[CH:9]=[CH:8][C:7]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4][CH2:3][CH2:12]1
Reactant: CI
Reactant: CCOC(=O)Cc1ccc2c(c1)OCCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2c(c1)OCCO2

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (1.13 g) was added to a solution in N,N-dimethylformamide (65 ml) of ethyl 3,4-ethylenedioxyphenylacetate [M. Sasamoto, Chem. Pharm. Bull., 8, 324 (1969)] (6.00 g) in an ice bath. Thereafter, methyl iodide (1.76 ml) was added dropwise and the resulting mixture was stirred under ice-cooling for 4 hours. To the reaction mixture was added 1 N hydrochloric acid and the resulting mixture was subjected to extraction with diethyl ether, after which the extraction solution was washed with water and then dried. The solvent was removed by distillation under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (5.57 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:16]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[NH2:16])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-2-tertbutoxycarbonylamino butyric acid (1.2 g, 5.8 mmol) in anhydrous THF (20 mL) cooled to −15° C. was added N-methylmorpholine (0.64 mL, 5.8 mmol) and isobutylchloroformate (0.75 mL, 5.8 mmol) under an atmosphere of nitrogen. After 2 minutes, 33% aqueous ammonia (0.5 mL, 8.7 mmol) was added and the resulting mixture stirred at this −15° C. for 2 h. The reaction mixture was left to warm to RT then partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The resulting white solid was used without further purification (1.0 g, 85%). 1H NMR (CDCl3, 300 MHz): δ 6.15 (1H, br s), 5.63 (1H, br s), 5.08 (1H, br s), 4.05 (1H, br s), 1.95-1.80 (1H, m), 1.70-1.53 (1H, m), 1.40 (9H, s), 0.95 (3H, d, J=6.71 Hz). 327997
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.6 %

Procedure:
To 4-hydroxybenzaldehyde (10.0 g, 81.89 mmol) was added 175 mL methylene chloride, 3,4-dihydro-2H-pyran (18.7 mL, 204.97 mmol) and pyridinium p-toluenesulfonate (2.06 g, 8.2 mmol). The reaction mixture was stirred at room temperature for three days. The reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with a second portion of methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, which was then back-extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Silica gel flash chromatography of the residue (10% ether/hexanes to 20% ether/hexanes) afforded 17.32 g of the title compound of Step A. MS 207.4 (M+1)+Step B: [4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine
Reaction SMILES: [CH2:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:8]=1)[CH:2]=[CH2:3].[OH2:25]>Cl.Cl.[Cl-].[Cl-].[Zn+2].[Cl-].[Zn+2].[Cl-]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][N:4]2[C:1]3[C:21](=[CH:22][CH:23]=[CH:3][CH:2]=3)[CH2:20][CH:19]2[CH3:24])=[O:25])=[CH:8][C:9]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: O
Reactant: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 6 h

Procedure:
In a 50 ml round bottom was placed 8 grams of Lucas reagent. The reagent is prepared by dissolving 16 grams of anhydrous zinc chloride in 10 ml of concentrated hydrochloric acid. To this reagent was added 100 mg (0.27 mmols) of 1-allyl-1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine with stirring under nitrogen for a short time to dissolve the solid. The reaction cyclized at 60° C. over 6 hours. The reactant was worked up by pouring the cooled reaction mixture into water and extracting the product into ethyl acetate. The ethyl acetate phase was cross washed several times with water and sodium bicarbonate solution. The ethyl acetate solution is dried with magnesium sulfate, clarified and evaporated to dryness yielding 84 mg of crude 1-(4-chloro-3-sulfamoylbenzamido)-2-methylindoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCCc1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(CCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 5-(3-methoxyphenyl)pentanoate (6.01 g, 25.4 mmol) in a mixed solvent of ethanol (50 mL) and tetrahydrofuran (50 mL) was added 2 M aqueous sodium hydroxide solution (25 mL), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (5.28 g, yield 99%) as a red-brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Na+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[C:10](=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(O)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 100.1 %

Procedure:
To a solution of 4-hydroxy-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (20.0 g, 88.0 mmol) in dichloromethane (170 ml) was added sodium bromide (1.092 g, 10.6 mmol), sodium bicarbonate (2.439 g, 29.0 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl (237.1 mg, 1.49 mmol). The mixture was cooled to −5° C. and sodium hypochlorite solution (9.5% in water, 55.16 ml) was added within 10 min resulting in a red coloration and a temperature rise to 9° C. The mixture was stirred for 35 min at 0-5° C. and, as conversion was incomplete (2.5% starting material remaining), additional sodium hypochlorite solution (9.5% in water, 7.0 ml) was added within 30 min and the mixture stirred for another 30 min at 0° C. GC analysis indicated complete conversion (<0.1% starting material remaining). Sodium thiosulfate solution (10% in water, 100 ml) was added within 10 min resulting in decoloration. The organic phase was separated, washed with water (100 ml), dried over sodium sulfate (50 g), filtered and evaporated (15 mbar, 40° C.) to afford 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as yellowish powder (19.84 g), GC purity 99a %. The powder was dissolved in warm tert-butyl methyl ether (20 ml), heptane (60 ml) was added to induce crystallization and the white suspension stirred at 0-5° C. for 1.5 h. Filtration, washing with heptane (20 ml) and drying (10 mbar, 45° C.) afforded 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (17.25 g, 87%) as white crystalline material, GC purity 100a %. 1H-NMR (CDCl3, 300 MHz): 4.08 (s, CH2(5)), 3.66 (m, CH2(7)), 1.88 (m, CH2(8)), 1.48 (s, tert-Bu), 1.40 (m, 2H), 0.81 (m, 2H).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N[C@H](C(O)=O)CCC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCC[C@H](N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCC[C@H](N)C(=O)O
Reaction time: 1 h

Procedure:
The component amino acid (Fmoc-X-OH,1 equivalent) is mixed with Fmoc-Nle-OH (1 equivalent), then dissolved and activated by the addition of PyBOP, HOBt and NMM solutions. After 10 minutes the mixture is added to Nva-PAL-Pepsyn K support (5 mg). After 2 hours the support is washed with DMF repeatedly, treated with 30% piperidine in DMF (to remove incorporated Fmoc- groups), washed with DMF, and methanol, then treated with TFA/water (95:5) for 2 hours. The TFA solution is expelled into a vial, a known proportion of it dried down in vacuo, and the resultant mixed dipeptides X-Nva and Nle-Nva are hydrolysed with 6M HCl at 150 degrees for 1 hour. The relative incorporations of X and Nva are then determined by amino acid analysis. A graph is constructed plotting molar % X (in this initial round X is 50%) against molar percentage incorporated; and the curve which results when using extremities points at 0 and 100% is used to predict what molar percent X would give equal incorporation to that of Nle.