Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[C:14](=[O:17])(O)[O-].[Na+].O.[O:20]1[CH2:25][CH2:24]OCC1>>[C:14]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:17])[C:7]1[C:25](=[CH:24][CH:4]=[CH:5][CH:6]=1)[OH:20]
Reactant: NCCCCCCCC(=O)O
Reactant: C1COCCO1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCCNC(=O)c1ccccc1O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A 10N sodium hydroxide solution of (4.4 mL, 44.0 mmol, 1.18 eq), 8-aminocaprylic acid (5.93 g, 37.2 mmol, 1.00 eq), sodium bicarbonate (0.88 g, 10.4 mmol, 0.28 eq) and water (5 mL) were added to a 250 mL round bottom flask equipped with a magnetic stir bar and an addition funnel. The white cloudy mixture was treated with a solution of oligosalicylate (5.20 g, 42.9 mmol 1.15 eq) and dioxane (20 mL), added over five minutes. The addition funnel was replaced with a condenser, and the reaction mixture was heated to 90 degrees C. for 3 hours (at which time the reaction was determined to have finished, by HPLC). The clear orange reaction mixture was cooled to 40 degrees C., filtered and acidified to pH=1 with 3% (by vol.) aqueous hydrochloric acid. All of the dioxane and some of the water were stripped (60 degrees C., 50 mm). The solid (which precipitated from solution during stripping) was isolated by filtration while still warm. The light pink solid was recrystallized from 50 mL of 65% ethanol-water. The solid was recovered by filtration and was dried over 18 hours in a 50 degrees C. vacuum oven. The N-(salicyloyl)-8-aminocaprylic acid was isolated as a white solid (5.35 g, 51%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][N:41]5[CH:45]=[N:44][N:43]=[CH:42]5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][N:41]5[CH:42]=[N:43][N:44]=[CH:45]5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4cnnc4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4cnnc4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.37 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:20→1:19), and was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 155) (681.4 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: Fc1ccccc1Oc1cncc(Cl)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccccc3F)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method EE with 2-chloro-6-(2-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (234 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.42 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.69 (s, 2H, Harom2′+6′), 7.24-7.41 (m, 4H, Harom), 7.83 (s, 1H, HPz 5), 7.96 (s, 1H, HPz 3), 9.57 (s, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH:31](=O)[CH2:32][CH3:33].[BH4-].[Na+]>ClCCl.COCCOC.O>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:31][CH2:32][CH3:33])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CCC=O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCCNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionaldehyde (5.1 μL, 0.10 mmol) and Ti(OPr)4 (82 μL, 0.30 mmol) were dissolved in dichloromethane (1.0 mL) and mono-glyme (1.0 mL). The mixture was allowed to stir at 25° C. for 16 hours. NaBH4 (5.7 mg, 0.15 mmol) was added and the reaction was stirred for an additional 1 h. The reaction was diluted to 5 mL with dichloromethane before water (5 mL) was added. The reaction was filtered through celite to remove the titanium salts and the layers separated. The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((propylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide (7.8 mg, 14%). ESI-MS m/z calc. 442.6, found 443.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: [NH2:1][C:2]1([C:5]#[N:6])[CH2:4][CH2:3]1.[C:7](Cl)(=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:5]([C:2]1([NH:1][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][CH2:3]1)#[N:6]
Reactant: N#CC1(N)CC1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)NC1(C#N)CC1
Yield: 77.4 %

Procedure:
General procedure F was used to couple 1.68 mmols of 1-amino-1-cyclopropanecarbonitrile to 2.184 mmols of palmitoyl chloride. After standard purification techniques, 1.3 mmols (77%) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 5.95 (s, 1H), 2.16 (t, J=7.6, 2H), 1.65-1.59 (m, 2H), 1.58 (s, 1H), 1.57-1.53 (m, 2H), 1.39-1.15 (m, 28H), 0.88 (dd, J=6.0, 7.0, 3H). 13C NMR (126 MHz, CDCl3) δ 119.97, 36.08, 31.91, 29.64, 25.17, 22.68, 20.32, 16.85, 14.25.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.P(Br)(Br)[Br:19].[OH-].[Na+].Cl>CN(C)C=O>[Br:19][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(O)c1C
Reactant: BrP(Br)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(Br)c1C
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
5 g (21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 40 ml of N,N-dimethylformamide and the resulting suspension was warmed to 65° C. 8.1 g (30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react at 75° C. for 30 minutes. The reaction solution was cooled to room temperature, poured onto 500 g of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again to pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100 ml of water and the dried to obtain 4.1 g of the title compound.
Reaction SMILES: BrCCCCCBr.[Mg].II.Br[C:12](Br)([CH2:15][CH3:16])[CH2:13][CH3:14].[CH:18]1([CH2:25][C:26](=[O:28])[CH3:27])[CH2:24][CH2:23][CH2:22]CCC1.C1C[O:32]CC1>>[OH:32][CH:12]([CH2:15][CH3:16])[CH2:13][CH2:14][CH2:27][C:26]1([OH:28])[CH2:22][CH2:23][CH2:24][CH2:18][CH2:25]1
Reactant: C1CCOC1
Reactant: CCC(Br)(Br)CC
Reactant: CC(=O)CC1CCCCCC1
Agent: BrCCCCCBr
Agent: II
Agent: [Mg]
Product: CCC(O)CCCC1(O)CCCCC1

Procedure:
A solution of 1,5-dibromopentane (5.66 gms, 24.6 mmol) in dry THF (30 ml) was added slowly to a suspension of Magnesium turning (3.2 gms, 131 mmole) in dry THF (70 ml) and catalytic amount of iodine under nitrogen atmosphere. After the addition of about 5 ml of dibromopentane solution in THF, Grignard reaction was initiated. The addition was continued maintaining a gentle reflux. The mixture was refluxed for 18 hours to complete the formation of the Grignard reagent. To the reaction mixture was added a solution of a solution of lactone (20, 3 gms, 23.4 mmol) in dry THF (20 ml). The resulting mixture was refluxed for 10 hours under nitrogen and then quenched by addition of saturated solution of ammonium chloride at 0° C. The product was extracted in ethylacetate. Organic layer was washed with water, brine and dried over anh. Na2SO4. Drying agent was filtered off and the solvent was removed under vacuum to give 2.8 gms of diol (21), which was used without any further purification in the next step.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>COCCOC>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]2[C:7]=1[CH:8]=[N:23][NH:24]2
Reactant: NN
Reactant: O=Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reaction time: 18 h
Yield: 98 %

Procedure:
To a stirred solution of 6-fluoro-2-(2-fluoro-4-iodo-phenylamino)-3-nitro-benzaldehyde (864 mg, 2.14 mmol) in DME (15 ml) was slowly added hydrazine hydrate (10 mL) at room temperature and the reaction mixture stirred for 18 hours. The organic solvent was removed in vacuo and the mixture diluted with water (50 mL). The resulting solid was collected by filtration, washed with water and dried under vacuum to yield the title compound (839 mg, 98%). LCMS (Method B): RT=3.61 min, [M+H]+=399.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13](=[O:21])(=[O:20])[NH:12][N:11]=2)=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Br[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39]>CN(C=O)C>[CH2:28]([N:12]1[N:11]=[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:1]([CH2:37][C:38]([OH:40])=[O:39])[CH:2]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13]1(=[O:21])=[O:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: BrCc1ccccc1
Reactant: O=S1(=O)NN=C(c2c[nH]c3ccccc23)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(C2=NN(Cc3ccccc3)S(=O)(=O)c3ccccc32)c2ccccc21
Temperature: 75 °C
Reaction time: 8 h

Procedure:
The product of step c) (93 mg, 0.3 mmol) was dissolved in 3 mL DMF and treated with K2CO3 (50 mg, 0.36 mmol) and benzyl bromide (57 mg, 0.33 mmol). After stirring at 75° C. overnight, t-butyl bromoacetate (0.36 mmol, 70 mg) and was added along with an additional quantity of K2CO3 (0.39 mmol, 54 mg). The reaction was heated for an additional 2 hours. The crude reaction was partitioned between EtOAc and water. The organic layer was concentrated to dryness and treated with TFA (3 mL). After 1 h, the reaction was concentrated and purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 8.15 (d, 1H, J=3.6 Hz), 8.07-7.94 (m, 3H), 7.92 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.51-7.31 (m, 6H), 7.22 (t, J=7.2 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 5.12 (s, 2H), 5.07 (s, 2H); MS: ESI (negative): 444 (M−H).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:5][C:6]1[C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][S:9][N:10]=1)[CH3:4]>>[I-:2].[CH2:3]([S:5][C:6]1[C:7]([C:11]2[CH:12]=[N+:13]([CH3:1])[CH:14]=[CH:15][CH:16]=2)=[N:8][S:9][N:10]=1)[CH3:4]
Reactant: CCSc1nsnc1-c1cccnc1
Reactant: CI
Product: CCSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of 3-(4-ethylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[F:34])[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 41; 0.03 mg, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-4-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=452.2 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].N1C=CC=CC=1.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=O.O>ClCCl>[CH3:5][CH:4]([C:3]1[N:7]=[C:16]([C:15]([Cl:20])([Cl:19])[Cl:14])[O:1][N:2]=1)[CH3:6]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)C(=N)NO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 76.3 %

Procedure:
A stirred solution of N-hydroxy-2-methylpropanimidamide (16.33 g, 160 mmol) in pyridine (16.81 mL, 208 mmol) and dichloromethane (165 mL) at −15° C. was treated with trichloroacetyl chloride (19.63 mL, 176 mmol) over 40 min. The reaction was allowed to warm to ambient temperature and stirred for 42 h. Water (100 mL) was added and the reaction was stirred for 30 min. The dichloromethane was removed and the residue was diluted with water (50 mL) and extracted with ether (300 mL). The ether layer was washed with water, dried over MgSO4 and concentrated to afford 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (28.0 g, 76% yield) as an orange liquid. 1H NMR (400 MHz, CDCl3): δ 3.13 (septet, 1H, J=7.0 Hz), 1.36 (d, 6H, J=7.0 Hz).
Reaction SMILES: [H-].[Na+].O=[C:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]1=2.[OH2:16].[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C.[C].[Pd]>[C:14]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]([CH2:19][C:18]([O:17][CH2:21][CH3:20])=[O:16])[CH2:13][CH2:12][CH2:11]2)#[N:15]
Reactant: O
Reactant: C1CCOC1
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.75 g of 50% sodium hydride was suspended in 120 ml of tetrahydrofuran and 14.5 g of triethyl phosphonoacetate was added thereto. The mixture was stirred at room temperature for 15 minutes and 10.2 g of 5-oxo-5,6,7,8-tetrahydro-2-naphthonitrile was added thereto. The resulting mixture was heated under reflux for 1 hour. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried and then concentrated in vacuo. The residue was purified by column chromatography on 100 g of silica gel to give an oily product. The product was dissolved in 80 ml of ethanol and 1.5 g of 10% palladium carbon was added thereto. The mixture was catalytically reduced. After absorption of hydrogen gas was completed, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 12.1 g of ethyl 2-(6-cyano-1,2,3,4-tetrahydro-1-naphthyl)acetate as crystals with m.p. 45°-47° C.
Reaction SMILES: N[C:2]1[C:10](Cl)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4](OC)[CH:3]=1.C(N1C=CN=C1)([N:16]1C=CN=C1)=O.CCCCCCCCCCN>CN(C=O)C>[C:6]([NH2:16])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCCCCCCCCCN
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 160.7 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (375 mg, 1.86 mmol) in DMF (1.9 mL) was added carbonyldiimidazole (302 mg, 1.86 mmol). After 1 hour at room temperature a solution of the amine 10 (257 mg, 1.86 mmol) in DMF (1.9 mL) was added and the resulting pale yellow solution was stirred at room temperature for 3 days. Concentration gave a yellow solid which was triturated with ethyl acetate (6 mL), filtered, and rinsed with cold (0° C.) ethyl acetate (1.5 mL). The solid was dried in vacuo at 45° C. to give the free base of the title compound 11 as a pale yellow solid (362 mg, 60%). To a solution of free base (343 mg) in 95% ethanol (10 mL) was added ethanolic HCl[prepared from acetyl chloride (75 mg, 1.07 mmol) and 95% ethanol (0.5 mL)]. The solution was allowed to stand at 0° C. for 24 hours and filtration of the resulting crystalline solid and rinsing with cold (0° C.) 95% ethanol (1.5 mL) gave the desired material which was dried at 63° C. in vacuo for 16 hours to afford the title compound 11 (337 mg, 88%) as an almost colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2ccc(OCCCCCBr)c(C(C)=O)c2c1
Yield: 100.1 %

Procedure:
A mixture of 1.1 g of [[8-acetyl-7-hydroxy-2-naphthalenyl]oxy]acetic acid methyl ester, 9.2 g of 1,5-dibromopentane and 0.83 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and filtrate was concentrated at 60° C./0.15 mm to an oil which was purified by flash column chromatography to yield 1.7 g of [[8-Acetyl-7-(5-bromopentyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH3:33])=[C:25]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([CH:53]([OH:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35]>CS(C)=O>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH3:33])=[C:25]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([C:53](=[O:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Dess-Martin periodinane (195 mg) was added as a solid to a solution of N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2',6'-dichlorobenzyloxy)pentanoic acid, t-butyl ester (96 mg) in DMSO (1.5 ml). The resulting solution was stirred under a nitrogen atmosphere at room temperature for thirty minutes, then partitioned between EtOAc and water. The organic phase was washed with water (2×) and brine, dried (Na2SO4), and concentrated to give a white solid (83 mg). Flash chromotographic purification with EtOAc/hexanes (1:1) afforded the title product as a white solid (54 mg). TLC (EtOAc/hexanes; 1:1, silica gel): Rf =0.52.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.FC1C=C(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)C=CC=1>>[CH3:32][CH:31]([CH3:33])[C@H:27]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)=[O:34])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[C:23]1=[O:26])[C:28]([OH:30])=[O:29]
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4)cc3)cc2C1=O
Yield: 88 %

Procedure:
The compound of example 16 was prepared analogous to compound of example 8 by hydrolysis of compound of example 14.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
N-Acetylethylenediamine (10.2 g, 100 mmol) and triethylamine (15 ml, 10.9 g, 108 mmol) were dissolved in dichloromethane (300 ml) and the solution cooled to 0° C. Methanesulphonyl chloride (8 ml, 11.8 g, 103 mmol) was dissolved in dichloromethane (10 ml) and added dropwise, and stirring was continued at 0° C. for 3 hours. The dichloromethane was removed in vacuo, and the residue was suspended in a mixture of ether and acetone, removing the insoluble material by filtration. The filtrate was concentrated in vacuo to give the title compound as a pale brown gum (14.5 g, 88.3 mmol, 88%); δH [2H6]DMSO 7.93 (1H,br t), 7.05 (1H,t), 3.11 (2H,t), 2.97 (2H,t), 2.89 (3H,s), 2.09 (3H,s).