Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[CH:34]=[CH:35][CH:36]=[C:27]([C:28]=23)[S:26]1(=[O:38])=[O:37].C(=O)([O-])O.[Na+].O>CN1CCN(C)C1=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH:16]4[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][N:25]5[C:29]6[CH:30]=[CH:31][CH:32]=[C:33]7[CH:34]=[CH:35][CH:36]=[C:27]([C:28]=67)[S:26]5(=[O:38])=[O:37])[CH2:20][CH2:21]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c3c(c2c1)CN(CC1CCNCC1)CC3
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(CN2CCc3[nH]c4ccc(F)cc4c3C2)CC1
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A mixture of 4-(8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-2-ylmethyl)piperidine (1 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (0.94 g) and sodium hydrogen carbonate (0.59 g) in 1,3-dimethyl-2-imidazolidinone (25 cc) is brought to 150° C. for 16 hours. After return to a temperature in the vicinity of 25° C., this solution is poured into water (75 cc) and the mixture is extracted with ethyl acetate (3×75 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg: 2.7 kPa). The residue is purified by flash chromatography on a silica column under nitrogen at moderate pressure (0.5-1.5 bar) with a dichloromethane/methanol mixture (90:10 by volume) as eluent. 2-{2-[4-(8-Fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-2-ylmethyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.35 g), m.p. 228° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:13]([CH3:14])[CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)OC(=O)Cc1ccc(F)cc1

Procedure:
A mixture of 4-fluorophenylacetic acid (123.0 g), 2-propanol (96.0 g), p-toluenesulphonic acid (9.6 g) and benzene (1.3 g) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (2×500 ml) and with water (2×500 ml). After drying over magnesium sulphate, the solvent and the excess 2-propanol are evaporated in vacuo. The residue is distilled (51°-53° /3.10 -2 Torr) to yield isopropyl 4-fluorophenylacetate.
Reaction SMILES: CO.C(Cl)(=O)C.[CH3:7][C:8]([O:11][C:12]([C@@H:14]1[CH2:30][S:29][S:28][CH2:27][C@H:26]([NH:31]C(OC(C)(C)C)=O)[C:25](=[O:39])[NH:24][CH2:23][CH2:22][C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16](=[O:40])[NH:15]1)=[O:13])([CH3:10])[CH3:9]>C(OCC)(=O)C>[CH3:10][C:8]([O:11][C:12]([C@@H:14]1[CH2:30][S:29][S:28][CH2:27][C@H:26]([NH2:31])[C:25](=[O:39])[NH:24][CH2:23][CH2:22][C:17]2([CH2:18][CH2:19][CH2:20][CH2:21]2)[C:16](=[O:40])[NH:15]1)=[O:13])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSSC[C@@H](C(=O)OC(C)(C)C)NC(=O)C2(CCCC2)CCNC1=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](N)C(=O)NCCC2(CCCC2)C(=O)N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
To a mixture of methanol (0.15 mL, 3.8 mmol) in 5 mL of ethyl acetate was added at 0° C., under an atmosphere of argon, acetyl chloride (0.27 mL, 3.8 mmol). The solution was stirred at 0° C. for 10 min, and at room temperature for 30 min. To the solution was added (8R,13R)-13-[[(1,1-dimethylethoxy)carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester (130 mg, 0.25 mmol). The mixture was stirred for 7 hours. The precipitate was collected on a glass frit and washed with ethyl ether. After drying under high vacuum, 92 mg of (8R,13R)-13-amino-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester was obtained (96% yield based on recovered starting material after evaporation of the filtrate and washes).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+].I[CH2:32][CH3:33]>O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[Br:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13]([CH2:32][CH3:33])(=[O:15])=[O:14])[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]2([CH3:19])[CH3:18]
Reactant: CCI
Reactant: CC(=O)N1CC(C)(C)c2cc(Br)c(S(=O)(=O)Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: CCS(=O)(=O)c1cc2c(cc1Br)C(C)(C)CN2C(C)=O
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A suspension of 1-acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (300 mg, 0.81 mmol), Na2SO3 (206 mg, 1.6 mmol) and NaHCO3 (134 mg, 1.6 mmol) in water (5 mL) was stirred at 105° C. for 1.5 h. The resulting solution was cooled to 70° C., then TBABr (1.5 mg, 0.005 mmol) and iodoethane (323 μL, 4 mmol) were added and the stirring maintained at the same temperature for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water (15 mL) and extracted with DCM (3×). The organic phase was dried (MgSO4), filtered and concentrated and the crude material was purified using SiO2 chromatography (50% EtOAc/Petrol) to give the title compound (0.21 g) as a pale yellow oil. 1H NMR (CDCl3): 8.92 (1H, s), 7.45 (1H, s), 3.87 (2H, s), 3.43 (2H, q), 2.23 (3H, s), 1.39 (6H, s), 1.33-1.26 (3H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[K+].C(O)COCCO.Cl>O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCCCC(=O)CCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCCO
Reaction time: 2 h
Yield: 85 %

Procedure:
1.00 g (3.68 millimole) of 15-hydroxy-12-ketopentadecanoic acid, 0.73 g (11.0 millimole) of 85 wt.% potassium hydroxide, 0.50 g (8.5 millimole) of 85 % hydrated hydrazine and 5 ml of diethylene glycol were charged into a frask and heated under reflux over 1.5 hours. Subsequently, while evaporating the produced light boiling components such as water to the outside of the system, the internal temperature was elevated to 195 to 205° C., and the heating under reflux was continued at the same temperature range over 2 hours. After completion of the reaction, the solution was cooled, diluted by addition of 5 ml of water and added with 3 ml of 6N-HCl, followed by collection of the precipitated pail brown solid by filtration. The solid was recrystallized from benzene to obtain 0.81 g (3.14 millimole, Yield: 85 %) of a white crystl.
Reaction SMILES: [CH2:1]([N:8]1C2C(=CC=CC=2)C(C2OC(C(O)=O)=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[F:26][C:27]1[CH:42]=[CH:41][CH:40]=[CH:39][C:28]=1[C:29]([C:31]1[O:35][C:34]([C:36]([OH:38])=O)=[CH:33][CH:32]=1)=[O:30].C(NN)C1C=CC=CC=1>CO.C(O)(=O)C>[CH2:1]([NH:8][N:9]=[C:36]([C:34]1[O:35][C:31]([C:29](=[O:30])[C:28]2[CH:39]=[CH:40][CH:41]=[CH:42][C:27]=2[F:26])=[CH:32][CH:33]=1)[OH:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2F)o1
Agent: NNCc1ccccc1
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(c1ccc(C(O)=NNCc2ccccc2)o1)c1ccccc1F

Procedure:
1-Benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt: 70.26 g (0.3 mol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid were initially charged in 350 ml of methanol, 109.95 g (0.9 mol) of benzylhydrazine were added and the mixture was, after addition of 8 ml of glacial acetic acid, heated under reflux for 6 h. For work-up, the mixture was concentrated using a rotary evaporator, the residue was taken up in 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The residue that remained after drying and concentration using a rotary evaporator was recrystallized from ethyl acetate/n-hexane. The 68.3 g (0.20 mol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid benzylhydrazone (m.p.: 147° C. (decomp.)) obtained in this manner were dissolved in 400 ml of DMF, 45.38 g (0.40 mol) of potassium tert-butoxide were introduced and the mixture was heated under reflux for 30 minutes. The precipitate was filtered off with suction, washed with dichloromethane and recrystallized from ethanol/water (95:5). This gave 57.7 g (54%) of the title compound. The corresponding cyclization of the precursor which was still contained in the mother liquor gave 25.9 g of product. m.p.: >300 ° C. 1H-NMR (D6 -DMSO): δ=5.73 (s, 2H, CH2), 6.68 (d, 1H, H-3'), 6.92 (d, 1H, H-4'), 7.18-7.38 (m, 6H, phenyl-H, H-5), 7.45 (t, 1H, H-6), 7.75 (d, 1H, H-7), 8.18 (d, 1 H, H-4)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CC(C)([O-])C.[Na+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([NH:18][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCCCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CCCCCCNc1ccc(C(C)(C)C)cc1
Yield: 92.4 %

Procedure:
According to the general procedure B, 4-tert-butylbromobenzene (108 mg, 0.51 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 1 mol % of Pd(OAc)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in THF at 80° C. for 2 h to give the title compound (110 mg, 94%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.26 (d, 2H, J=8.4 Hz), 6.62 (d, 2H, J=8.4 Hz), 3.51 (bs, 1H), 3.14 (t, 2H, J=7.2 Hz), 1.66 (m, 2H), 1.34-1.43 (m, 6H), 1.34 (s, 9H, t-Bu), 0.96 (t, 3H, J=6.3 and 6.9 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.14, 139.75, 125.92, 112.35, 44.11, 33.76, 31.63, 31.53, 29.58, 26.86, 22.62, 14.05. GC/MS(EI): m/z 233 (M+). Anal. Calcd for C16H27N: C, 82.34; H, 11.82; N, 6.00. Found: C,82.55; H, 11.82; N, 6.06.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]#[C:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(CC#C)C=CC=CC=1.C=O.CNC.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[CH3:13][N:2]([CH3:1])[CH:3]=[CH:4][C:5](=[O:33])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CC#CCc1ccccc1
Agent: C#CCc1ccccc1
Agent: C=O
Agent: CNC
Solvent: ClCCl
Product: CN(C)C=CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice cold solution of 1-dimethylamino-4-phenyl-2-butyne (0.5 g; prepared by the Mannich reaction of 3-phenyl-1-propyne with formaldehyde and dimethylamine as per Mornet, et.al. Bull.Soc.Chim.Fr. 1974, 206) in dichloromethane (12 ml) was added in small portions 3-chloroperoxybenzoic acid (0.52 g). After the reaction was stirred at 0° C. for 20 minutes, the mixture was passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 10% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The residue was treated successively three times with small portions of methanol (ca. 10 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 25 mL by addition of methanol. The methanolic solution of the N-oxide was heated to reflux for approximately 4 hours and cooled. The solvent was evaporated to dryness in vacuo and the residue was chromatographed over silica gel (95:5 ethyl acetate-hexanes was used as the eluant) to give upon evaporation of the solvent in vacuo the desired product as an oil. MS(+ES) m/z: 190 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:15]2[O:16][CH2:17][CH2:18][C:14]=2[C:13]2[C@H:12]([CH2:19][CH2:20][NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:11][CH2:10][C:9]=2[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:15]2[O:16][CH2:17][CH2:18][C:14]=2[C:13]2[C@H:12]([CH2:19][CH2:20][NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(OC)c3c(c21)CCO3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=O)NCC[C@@H]1CCc2cc(O)c3c(c21)CCO3
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Boron tribromide (6.92 mmol) was added dropwise into a solution of (S)—N-(2-[4-methoxy-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl)propionamide (1.00 g. 3.46 mmol) in methylene chloride (15 mL) at about −50° C. The mixture was stirred for 2 hours at temperatures ranging from −50 to 0° C. Crushed ice was added and the mixture was stirred for further 2 hours at room temperature, followed by extracting with methanol-chloroform. The extracted solution was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 320 mg, 34%) as a white powder. This compound is also referred to as metabolite 1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.5 g of 4-hydroxy-8-trifluoromethyl-3 -quinoline-carboxylic acid in 5 ml of thionyl chloride was stirred at room temperature for 24 hours and the precipitate formed was recovered by vacuum filtration to obtain 0.4 g of 4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylic acid chloride melting at 222° C.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:33][CH2:34][CH3:35])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:26]([N:17]([C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]([CH2:33][CH2:34][CH3:35])=[N:10][C:11]=2[CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCCC3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCCC3)ccc2n1CC(=O)O

Procedure:
[5-(Benzyl-cyclohexanecarbonyl-amino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.50 (d, 1H), 7.21 (m, 6H), 6.95 (m, 1H), 5.09 (s, 2H), 4.86 (s, 2H), 2.72 (t, 2H), 2.18 (m, 1H), 1.60 (m, 9H), 1.10 (m, 1H), 0.99 (t, 3H), 0.85 (m, 2H). MS calculated for C26H31N3O3+H: 434, observed: 434.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:16])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CI
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (2.16 g, 10 mmol) in dry DMF (50 mL) was added NaH (440 mg, 60% in mineral oil, 11 mmol) at 0° C. under N2. After the reaction mixture was allowed to warm to room temperature and stirred for 20 minutes, CH3I (0.75 mL, 1.7 g, 12 mmol) was added via syringe. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL), washed with saturated NH4Cl solution (2×100 mL), water (50 mL) and brine (40 mL), and concentrated to result in a residue that was subjected to chromatography with gradient mixed solvents from hexanes/EtOAc (1:1) to (1:9) to afford the title compound. 1H NMR (DMSO-d6) 3.45 (s, 3H), 7.71 (s, 1H), 8.63 (s, 1H); ESI-MS m/z 230.0 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])[C:2]#[CH:3].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[C:2]#[CH:3]
Reactant: C#CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl 2-propargyloxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoate (467 mg, 1.2 mmol) from Step 1 above was dissolved in methanol (10 mL) and to the stirred solution was added 1N NaOH (2.4 mL). The reaction was stirred for 4 h at 50° C. The cooled reaction was acidified with 5% aqueous citric acid (25 mL). The methanol was removed under reduced pressure and the remaining aqueous was extracted with methylene chloride (4×50 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give 2-propargyloxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]([OH:17])[C:14]([OH:16])=[O:15])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:17][CH:13]([C:9]1([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]1)[C:14]([OH:16])=[O:15])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)C1(NC(=O)OC(C)(C)C)CCC1

Procedure:
(1-Tert-butoxycarbonylaminocyclobutyl)-hydroxyacetic acid (201.5 mg, 0.822 mmol) was stirred with acetic anhydride (95 mL) in pyridine (1.5 mL) for 24 h. The mixture was first concentrated under vacuum, and then diluted with 5 mL EtOAc. The organic solution was washed with 1N HCl (2 mL) followed by saturated aqueous NaCl (2 mL), dried (Na2SO4), and evaporated under vacuum which gave the title compound. LC-UV/MS API-ES− m/z 286 [M−H]−1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (s, 1H), 5.00 (s, 1H, CHOAc), 2.28 (m, 2H), 2.07 (s, 3H, Me), 2.04 (m, 2H), 1.81 (m, 1H), 1.67 (m, 1H), 1.35 (s, 9H, Boc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[N:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:4][N:3]=2)[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc2c(-c3ccc(C)s3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: COc1ccc2c(-c3ccc(C)s3)nnc(NC3CCN(Cc4ccccc4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(5-methylthiophen-2-yl)phthalazine with 4-amino-1-benzylpiperidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:59])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:25]([O:53][CH3:54])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:51][CH3:52])[C@@H:35]([CH3:50])[C:36]([NH:38][C@H:39]([C:47](O)=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:59])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:25]([O:53][CH3:54])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:51][CH3:52])[C@@H:35]([CH3:50])[C:36]([NH:38][C@@H:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:47]([NH:67][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:48])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C

Procedure:
36 mg (43 μmol) of N-(tert.-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 39) and 4.6 mg (43 μmol) of benzyl amine were absorbed in 5 ml of DMF, mixed with 7.5 μl (88 μmol) of N,N-diisopropylethylamine, 10 mg (65 μmol) of HOBt as well as 10 mg (52 μmol) of EDC, and then stirred over night at RT. Then, the reaction composition was evaporated and the residue purified by means of preparative HPLC. This way, 29 mg (73% o. th.) of Fmoc protected intermediate of N-(tert.-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-1-oxo-3-phenylpropane-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][O:16][C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[Br:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(O)c1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(OCC[C@H]2CN(Cc3ccccc3)CCN2)c1
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.0 g, 4.5 mmol), 2-bromo-5-methoxyphenol (1.0 g, 5.0 mmol), di-tert-butyl azodicarboxylate (1.57 g, 6.81 mmol), polymer-supported triphenylphosphine resin (4.354 g, 9.08 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound.